|
1
|
Chen M, Pang H, Pham TTH, He Y, Gao Q, Liao Y, Zhu C, Chen L, Yan G, Mo S, Han C. 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione from Averrhoa carambola L. roots: Suppressing hepatocellular carcinoma progression through ROS accumulation and p53 pathway-mediated apoptosis. Toxicol Appl Pharmacol 2025; 498:117296. [PMID: 40086489 DOI: 10.1016/j.taap.2025.117296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/21/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
This study explores the anti-tumor effects of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD), a compound derived from Averrhoa carambola L roots, on hepatocellular carcinoma (HCC) cells and a xenograft mouse model, focusing on its underlying mechanisms. Cell viability following DMDD treatment was assessed using the CCK-8 assay. Flow cytometry determined changes in cell cycle distribution and apoptosis rates, while migration and invasion capabilities were assessed using wound healing and transwell assays, respectively. Transcriptome sequencing (RNA-seq) was conducted to analyze differential gene expression and pathway enrichment. Z-VAD-FMK, a pan-caspase inhibitor, was used to confirm the apoptotic mechanism induced by DMDD. The expression levels of p53, Bax, Bcl-2, and cleaved caspase 3 were quantified via Western blot analysis. A xenograft mouse model was developed to assess the in vivo effects of DMDD on HCC. DMDD suppressed proliferation, migration, and invasion, and induced apoptosis in Huh7 and Hep3b cells. RNA-seq revealed significant enrichment of p53 and apoptosis signaling pathways among differentially expressed genes. DMDD downregulated Bcl-2 expression and upregulated p53, Bax and cleaved caspase 3. In addition, Z-VAD-FMK partially inhibited DMDD-induced apoptosis. DMDD also inhibited tumor growth in mice. DMDD effectively inhibited tumor growth in HCC cell lines and xenograft models, potentially through ROS elevation and p53-mediated activation of the intrinsic apoptotic pathway.
Collapse
Affiliation(s)
- Meifeng Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China; Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China
| | - Hongbing Pang
- Research department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Thi Thai Hoa Pham
- Research and Development Centre of Zhuang and Yao Medicines, Guangxi International Zhuang Medical Hospital, Nanning, China
| | - Yongfei He
- Department of Hepatobiliary and Pancreatic Surgery, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Qiang Gao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuan Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chunyi Zhu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Linqian Chen
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Guohong Yan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China; Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China
| | - Shutian Mo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
| | - Chuangye Han
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China.
| |
Collapse
|
|
2
|
Huang W, Pan Y, Wang H, Jiang L, Liu Y, Wang S, Dai H, Ye R, Yan C, Li Y. Delta-radiomics Analysis Based on Multi-phase Contrast-enhanced MRI to Predict Early Recurrence in Hepatocellular Carcinoma After Percutaneous Thermal Ablation. Acad Radiol 2024; 31:4934-4945. [PMID: 38902111 DOI: 10.1016/j.acra.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/27/2024] [Accepted: 06/01/2024] [Indexed: 06/22/2024]
Abstract
RATIONALE AND OBJECTIVES It is critical to predict early recurrence (ER) after percutaneous thermal ablation (PTA) for hepatocellular carcinoma (HCC). We aimed to develop and validate a delta-radiomics nomogram based on multi-phase contrast-enhanced magnetic resonance imaging (MRI) to preoperatively predict ER of HCC after PTA. MATERIALS AND METHODS We retrospectively enrolled 164 patients with HCC and divided them into training, temporal validation, and other-scanner validation cohorts (n = 110, 29, and 25, respectively). The volumes of interest of the intratumoral and/or peritumoral regions were delineated on preoperative multi-phase MR images. Original radiomics features were extracted from each phase, and delta-radiomics features were calculated. Logistic regression was used to train the corresponding radiomics models. The clinical and radiological characteristics were evaluated and combined to establish a clinical-radiological model. A fusion model comprising the best radiomics scores and clinical-radiological risk factors was constructed and presented as a nomogram. The performance of each model was evaluated and recurrence-free survival (RFS) was assessed. RESULTS Child-Pugh grade B, high-risk tumor location, and an incomplete/absent tumor capsule were independent predictors of ER. The optimal radiomics model comprised 12 delta-radiomics features with areas under the curve (AUCs) of 0.834, 0.795, and 0.769 in the training, temporal validation, and other-scanner validation cohorts, respectively. The nomogram showed the best predictive performance with AUCs as 0.893, 0.854, and 0.827 in the three datasets. There was a statistically significant difference in RFS between the risk groups calculated using the delta-radiomics model and nomogram. CONCLUSIONS The nomogram combined with the delta-radiomic score and clinical-radiological risk factors could non-invasively predict ER of HCC after PTA.
Collapse
Affiliation(s)
- Wanrong Huang
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Yifan Pan
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Huifang Wang
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Lu Jiang
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Yamei Liu
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Shunli Wang
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Hanting Dai
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China
| | - Rongping Ye
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China; Department of Radiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Chuan Yan
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China; Department of Radiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Yueming Li
- Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China; Department of Radiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Key Laboratory of Radiation Biology of Fujian higher education institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China.
| |
Collapse
|
|
3
|
Wang Q, Yu J, Sun X, Li J, Cao S, Han Y, Wang H, Yang Z, Li J, Hu C, Zhang Y, Jin L. Sequencing of systemic therapy in unresectable hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2024; 204:104522. [PMID: 39332750 DOI: 10.1016/j.critrevonc.2024.104522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/18/2024] [Accepted: 09/21/2024] [Indexed: 09/29/2024] Open
Abstract
PURPOSE For patients with advanced or unresectable hepatocellular carcinoma (HCC), safe and effective therapies are urgently needed to improve their long-term prognosis. Although the guidelines recommend first-line treatments such as sorafenib, lenvatinib, and atezolizumab in combination with bevacizumab (T+A) and second-line treatments such as regorafenib, the efficacy comparison between drugs is lacking, that is, a treatment is not recommended as the optimal or alternative choice for a specific patient population. Therefore, we will conduct a high-quality network meta-analysis based on Phase III randomized controlled trials (RCTs) to systematically evaluate and compare overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and serious adverse events (SAE) of different treatment protocols in the context of first-line and second-line therapies, which are critical for clinical decision making and prognostic improvement in advanced HCC patients. METHODS The studies of interest were Phase III RCTs evaluating the efficacy or safety of first- or second-line therapies in patients with unresectable or advanced HCC. Literature published in English from the four databases of PubMed, Embase, Cochrane Library, and Web of Science was comprehensively searched from the inception to May 23, 2022. Outcomes of interest included OS, PFS, ORR, and SAE. A league table was developed to show the results of the comparison between different treatments. A histogram of cumulative probability was drawn to discuss the ranking probability of treatments based on different outcomes. The effectiveness and safety of various treatments were comprehensively considered and the two-dimensional diagram was plotted to guide clinical practice. The Gemtc package in R Studio was used for network meta-analysis in a Bayesian framework. RESULTS The results showed that HAIC-FO was superior to T+A regimen, regardless of OS, PFS or ORR. TACE combined with lenvatinib performed better than T+A in PFS, and ORR. In addition to the T+A regimen, Sintilimab combined with IBI305 and camrelizumab combined with apatinib were also associated with longer OS, PFS, and ORR, and their SAE incidence was not higher than that of T+A, especially for camrelizumab combined with apatinib, its safety was better than that of T+A regimen. There were no new treatments or combinations that were more effective than regorafenib. It was important to note that for PFS, the efficacy of apatinib and cabozantinib was not statistically different from that of regorafenib, so these two treatments could be used as alternative treatment options in cases where regorafenib was not tolerated or treatment failed. CONCLUSIONS We conducted a network meta-analysis to evaluate the efficacy and safety of multiple treatment modalities by integrating the results of direct and indirect comparisons. This study included high-quality multicenter Phase III RCTs, collated and summarized all treatments involved in advanced or unresectable HCC in first-line and second-line settings, and compared with T+A and regorafenib, respectively, and ranked based on efficacy and safety to support clinical decision making.
Collapse
Affiliation(s)
- Qi Wang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jianan Yu
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xuedong Sun
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jian Li
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shasha Cao
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yanjing Han
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Haochen Wang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Zeran Yang
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Jianjun Li
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Caixia Hu
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Yonghong Zhang
- Interventional therapy center for oncology, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China.
| | - Long Jin
- Department of interventional radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| |
Collapse
|
|
4
|
Sun J, Liu C, He D, Jiang D, Cheng S, Shi J. A new chemotherapy strategy for advanced hepatocellular carcinoma with exrahepatic metastasis: predictors of long-term survival. J Chemother 2024; 36:580-586. [PMID: 38189681 DOI: 10.1080/1120009x.2023.2298156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/03/2023] [Accepted: 12/15/2023] [Indexed: 01/09/2024]
Abstract
The prognosis of hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM) is extremely poor. This study aimed to identify prognostic factors for systemic chemotherapy of HCC with EHM. Eighty-five patients who received systemic chemotherapy for HCC with EHM between May 2014 and October 2021 were retrospectively evaluated. Patient demographic data and characteristics of hepatic tumors and EHM were assessed to identify factors that were significantly associated with prognosis. Of the 85 patients, 68 (80.0%) had pulmonary metastasis, 11 (12.9%) had abdominal lymph node metastasis, 7 (8.2%) had abdominal metastasis, and 4 (4.7%) had bone metastasis. The median overall survival (OS) was 17.0 months, and the median progression-free survival (PFS) was 5.1 months. Univariate analysis of OS showed that synchronous EHM-HCC, serum albumin level<35 g/l and number of hepatic tumors>1 were significantly associated with poorer OS. The results of the multivariate analysis indicated that the serum albumin level and number of hepatic tumors were independent prognostic factors. Subgroup analysis of patients with 0, 1, or 2 of these independent prognostic factors showed that the median OS was 24.0 months, 16.2 months and 7.7 months and that the ORR was 38.3%, 22.6% and 0, respectively. Systemic chemotherapy is beneficial for well-selected HCC patients with EHM. The number of hepatic tumors and serum albumin level were independent risk factors for prognosis, and the number of risk factors significantly influenced OS. Therefore, these factors need to be considered before administering systemic chemotherapy for HCC patients with EHM.
Collapse
Affiliation(s)
- Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chang Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dandan He
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dafeng Jiang
- Department of Oncology, Zhejiang Sian International Hospital, Jiaxing, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jie Shi
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| |
Collapse
|
|
5
|
Radwan AM, Abosharaf HA, Sharaky M, Abdelmonem R, Effat H. Functional combination of resveratrol and tamoxifen to overcome tamoxifen-resistance in breast cancer cells. Arch Pharm (Weinheim) 2024; 357:e2400261. [PMID: 38943449 DOI: 10.1002/ardp.202400261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/10/2024] [Accepted: 06/12/2024] [Indexed: 07/01/2024]
Abstract
Researchers are encountering challenges in addressing the issue of cancer cells becoming unresponsive to various chemotherapy treatments due to drug resistance. This study was designed to study the influence of antioxidant resveratrol (RSV) to sensitize resistant breast cancer (BC) cells toward tamoxifen (TAM). The cytotoxic effects of RSV and TAM against TAM-resistant LCC2 cells and their parental michigan cancer foundation-7 BC cells were determined by sulphorhodamine B assay. Further, the expression levels of multidrug resistance (MDR) genes including ABCB1, ABCC2, ABCG2, and MRP1 using quantitative polymerase chain reaction, apoptosis induction, and reactive oxygen species (ROS) content using flow cytometry were evaluated in either LCC2 cells treated with RSV, TAM, or their combination. The obtained results showed that resistant cells have a magnificent level of MDR genes. This elevated expression dramatically lowered upon receiving the combined therapy of RSV and TAM. Additionally, our work assessed the possible role of RSV in modulating the expression of MDR genes by controlling the expression of certain microRNAs (miRNAs) that target ATP-binding cassette (ABC) transporters. According to the obtained data, the TAM and RSV combination increased the expression of tumor inhibitor miRNAs such miR-10b-3p, miR-195-3p, and miR-223-3p, which made LCC2 cells more sensitive to TAM. Furthermore, this combination showed an elevation in apoptotic levels and total ROS content. The combination between RSV and TAM could be a functional therapy in the fight against TAM-resistant BC cells via modulating miRNA and ABC transporters.
Collapse
Affiliation(s)
- Aliaa M Radwan
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Hamed A Abosharaf
- Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt
| | - Marwa Sharaky
- Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Rehab Abdelmonem
- Department of Industrial Pharmacy, Faculty of Pharmacy, Misr University for Science & Technology, 6th October City, Egypt
| | - Heba Effat
- Medical Biochemistry and Molecular Biology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo, Egypt
| |
Collapse
|
|
6
|
Cai K, Fang Y, Zhang Y, Liu J, Ye Q, Ding L, Cai X. Cetylpyridinium chloride inhibits hepatocellular carcinoma growth and metastasis through regulating epithelial-mesenchymal transition and apoptosis. PLoS One 2024; 19:e0310391. [PMID: 39302935 DOI: 10.1371/journal.pone.0310391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/30/2024] [Indexed: 09/22/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is characterized by a lack of obvious clinical features in the early stages and is likely to progress to advanced HCC. Advanced HCC is a highly malignant tumor. However, there are few treatment options for advanced HCC. Therefore, screening for new drugs that target HCC will provide a new approach to the treatment of HCC. The CCK8 assay was performed to screen compounds inhibiting HCC cell proliferation and to evaluate the IC50 (half-maximal inhibitory concentration) of compounds on cell lines. Colony formation assay was used to determine HCC cell proliferation. The effect of compounds on HCC cell migration and invasion were analyzed using wound healing and transwell assays, respectively. Tumor growth and metastasis were assessed in vivo in a xenograft mouse model. Flow cytometry was carried out to measure apoptotic cells. Reverse transcription and quantitative real-time polymerase chain reaction (RT‒qPCR) and Western blot were performed to examine the expression of epithelial-mesenchymal transition (EMT)- and apoptosis-related genes. Through large-scale screening, we have discovered the anti-tumor activity of cetylpyridinium chloride (CPC) against HCC cells. CPC inhibited the proliferation, invasion and metastasis of HCC cells. Cancer cells are more sensitive to CPC than normal cells. CPC suppressed HCC tumor growth and metastasis in vivo. Mechanistically, CPC promoted apoptosis of HCC cells by affecting the expression of apoptosis-related genes, and inhibited HCC invasion and metastasis by suppressing EMT and expression of EMT markers. Our investigation showed that CPC significantly inhibited HCC cell proliferation, invasion and metastasis in vivo and in vitro, by inducing the expression of apoptosis-related genes and inhibiting expression of EMT markers, suggesting that CPC is a potential agent for HCC treatment.
Collapse
Affiliation(s)
- Kundi Cai
- Jiangxi Normal University, Jiangxi, China
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Yihui Fang
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Yanan Zhang
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Jie Liu
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Qinong Ye
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | - Lihua Ding
- Laboratory of advanced biotechnology, Department of Cell Engineering, Beijing Institute of Biotechnology, Beijing, China
| | | |
Collapse
|
|
7
|
Kaushik N, Jaiswal A, Bhartiya P, Choi EH, Kaushik NK. TFCP2 as a therapeutic nexus: unveiling molecular signatures in cancer. Cancer Metastasis Rev 2024; 43:959-975. [PMID: 38451384 DOI: 10.1007/s10555-024-10175-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/18/2024] [Indexed: 03/08/2024]
Abstract
Tumor suppressor genes and proto-oncogenes comprise most of the complex genomic landscape associated with cancer, with a minimal number of genes exhibiting dual-context-dependent functions. The transcription factor cellular promoter 2 (TFCP2), a pivotal transcription factor encoded by the alpha globin transcription factor CP2 gene, is a constituent of the TFCP2/grainyhead family of transcription factors. While grainyhead members have been extensively studied for their crucial roles in developmental processes, embryogenesis, and multiple cancers, the TFCP2 subfamily has been relatively less explored. The molecular mechanisms underlying TFCP2's involvement in carcinogenesis are still unclear even though it is a desirable target for cancer treatment and a therapeutic marker. This comprehensive literature review summarizes the molecular functions of TFCP2, emphasizing its involvement in cancer pathophysiology, particularly in the epithelial-mesenchymal transition and metastasis. It highlights TFCP2's critical function as a regulatory target and explores its potential as a prognostic marker for survival and inflammation in carcinomas. Its ambiguous association with carcinomas underlines the urgent need for an in-depth understanding to facilitate the development of more efficacious targeted therapeutic modality and diagnostic tools. This study aims to elucidate the multifaceted effects of TFCP2 regulation, through a comprehensive integration of the existing knowledge in cancer therapeutics. Furthermore, the clinical relevance and the inherent challenges encountered in investigating its intricate role in cancer pathogenesis have been discussed in this review.
Collapse
Affiliation(s)
- Neha Kaushik
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong, 18323, Korea
| | - Apurva Jaiswal
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea
| | - Pradeep Bhartiya
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong, 18323, Korea
| | - Eun Ha Choi
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea.
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center/Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Korea.
| |
Collapse
|
|
8
|
Yu Y, Fan Y, Mei W, Xu X, Chen Y, Zhao Y, Ruan B, Shen Z, Lu Y, Zheng S, Jie W. Dendrobium nobile active ingredient Dendrobin A against hepatocellular carcinoma via inhibiting nuclear factor kappa-B signaling. Biomed Pharmacother 2024; 177:117013. [PMID: 38901205 DOI: 10.1016/j.biopha.2024.117013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/16/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024] Open
Abstract
OBJECTIVE Dendrobin A, a typical active ingredient of the traditional Chinese medicine Dendrobium nobile, has potential clinical application in cancer treatment; however, its effect and mechanism in anti-hepatocellular carcinoma (HCC) remain unsolved. METHOD The effects of Dendrobin A on the viability, migration, invasion, cycle, apoptosis, and epithelial-mesenchymal transition of HepG2 and SK-HEP-1 cells were verified by in vitro experiments. mRNA sequencing was performed to screen the differentially expressed genes (DEGs) of HCC cells before and after Dendrobin A treatment, following GO enrichment and KEGG signaling pathway analyses. Mechanistically, molecular docking was used to evaluate the binding of Dendrobin A with proteins p65 and p50, before further verifying the activation of nuclear factor kappa-B (NF-κB) signaling. Finally, the antiproliferative effect of Dendrobin A on HCC cells was explored through animal experiments. RESULTS Dendrobin A arrested cell cycle, induced apoptosis, and inhibited proliferation, migration, invasion, and blocked epithelial-mesenchymal transition in HepG2 and SK-HEP-1 cells. mRNA sequencing identified 830 DEGs, involving various biological processes. KEGG analysis highlighted NF-κB signaling. Molecular docking revealed strong binding of Dendrobin A with p65 and p50 proteins, and western blotting confirmed reduced levels of p-p65 and p-p50 in HCC cells post Dendrobin A treatment. NF-κB agonist PMA reversed Dendrobin A-inhibited cell proliferation migration and invasion. In vivo experiments showed that Dendrobin A inhibited HCC cell growth. CONCLUSION Our findings suggest that Dendrobin A exhibits anti-HCC properties by inhibiting the activation of the NF-κB pathway. These results provide a scientific basis for utilizing Dendrobium nobile in anti-HCC therapies.
Collapse
Affiliation(s)
- Yaping Yu
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Yonghao Fan
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Wenli Mei
- Key Laboratory of Natural Products Research and Development from Li Folk Medicine of Hainan Province, Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou 571199, PR China
| | - Xiaoqing Xu
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Yan Chen
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Yangyang Zhao
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Banzhan Ruan
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China
| | - Zhihua Shen
- Department of Pathophysiology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang 524023, PR China
| | - Yanda Lu
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China.
| | - Shaojiang Zheng
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China.
| | - Wei Jie
- Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases & the Department of Oncology of the First Affiliated Hospital, Hainan Medical University, Haikou 570102, PR China.
| |
Collapse
|
|
9
|
Yu Q, Ding J, Li S, Li Y. Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions. Cancer Lett 2024; 590:216856. [PMID: 38583651 DOI: 10.1016/j.canlet.2024.216856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.
Collapse
Affiliation(s)
- Qiang Yu
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Jiajun Ding
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Shisen Li
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China
| | - Yunlong Li
- Department of Digestive Surgery, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
| |
Collapse
|
|
10
|
El-Derby AM, Khedr MA, Ghoneim NI, Gabr MM, Khater SM, El-Badri N. Plasma-derived extracellular matrix for xenofree and cost-effective organoid modeling for hepatocellular carcinoma. J Transl Med 2024; 22:487. [PMID: 38773585 PMCID: PMC11110239 DOI: 10.1186/s12967-024-05230-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/23/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) causes significant cancer mortality worldwide. Cancer organoids can serve as useful disease models by high costs, complexity, and contamination risks from animal-derived products and extracellular matrix (ECM) that limit its applications. On the other hand, synthetic ECM alternatives also have limitations in mimicking native biocomplexity. This study explores the development of a physiologically relevant HCC organoid model using plasma-derived extracellular matrix as a scaffold and nutritive biomatrix with different cellularity components to better mimic the heterogenous HCC microenvironment. Plasma-rich platelet is recognized for its elevated levels of growth factors, which can promote cell proliferation. By employing it as a biomatrix for organoid culture there is a potential to enhance the quality and functionality of organoid models for diverse applications in biomedical research and regenerative medicine and to better replicate the heterogeneous microenvironment of HCC. METHOD To generate the liver cancer organoids, HUH-7 hepatoma cells were cultured alone (homogenous model) or with human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (heterogeneous model) in plasma-rich platelet extracellular matrix (ECM). The organoids were grown for 14 days and analyzed for cancer properties including cell viability, invasion, stemness, and drug resistance. RESULTS HCC organoids were developed comprising HUH-7 hepatoma cells with or without human mesenchymal stromal and endothelial cells in plasma ECM scaffolds. Both homogeneous (HUH-7 only) and heterogeneous (mixed cellularity) organoids displayed viability, cancer hallmarks, and chemoresistance. The heterogeneous organoids showed enhanced invasion potential, cancer stem cell populations, and late-stage HCC genetic signatures versus homogeneous counterparts. CONCLUSION The engineered HCC organoids system offers a clinically relevant and cost-effective model to study liver cancer pathogenesis, stromal interactions, and drug resistance. The plasma ECM-based culture technique could enable standardized and reproducible HCC modeling. It could also provide a promising option for organoid culture and scaling up.
Collapse
Affiliation(s)
- Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Mennatallah A Khedr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Nehal I Ghoneim
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt
| | - Mahmoud M Gabr
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Sherry M Khater
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, 6th of October City, Giza, 12582, Egypt.
| |
Collapse
|
|
11
|
Kim SJ, Cummins KC, Tsung A. Immunotherapy as a Complement to Surgical Management of Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1852. [PMID: 38791931 PMCID: PMC11120323 DOI: 10.3390/cancers16101852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 03/29/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor in adults, and the fourth leading cause of cancer-related deaths worldwide. While surgical and ablative therapies remain the standard of care in early localized disease, late presentation with advanced stages of disease, impaired hepatic function, or local recurrence following surgical resection preclude operative management as the sole treatment modality in a subgroup of patients. As such, systemic therapies, namely immunotherapy, have become an integral part of the HCC treatment algorithm over the past decade. While agents, such as atezolizumab/bevacizumab, have well-established roles as first-line systemic therapy in intermediate- and advanced-stage HCC, the role of immunotherapy in disease amenable to surgical management continues to evolve. In this review, we will discuss the current evidence and aggregate impact of immunotherapy in the context of HCC amenable to surgical management, including its application in the neoadjuvant and adjuvant settings.
Collapse
Affiliation(s)
| | | | - Allan Tsung
- Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA
| |
Collapse
|
|
12
|
Wang S, He Y, Wang J, Luo E. Re-exploration of immunotherapy targeting EMT of hepatocellular carcinoma: Starting from the NF-κB pathway. Biomed Pharmacother 2024; 174:116566. [PMID: 38631143 DOI: 10.1016/j.biopha.2024.116566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/15/2024] [Accepted: 04/04/2024] [Indexed: 04/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancies worldwide, and its high morbidity and mortality have brought a heavy burden to the global public health system. Due to the concealment of its onset, the limitation of treatment, the acquisition of multi-drug resistance and radiation resistance, the treatment of HCC cannot achieve satisfactory results. Epithelial mesenchymal transformation (EMT) is a key process that induces progression, distant metastasis, and therapeutic resistance to a variety of malignant tumors, including HCC. Therefore, targeting EMT has become a promising tumor immunotherapy method for HCC. The NF-κB pathway is a key regulatory pathway for EMT. Targeting this pathway has shown potential to inhibit HCC infiltration, invasion, distant metastasis, and therapeutic resistance. At present, there are still some controversies about this pathway and new ideas of combined therapy, which need to be further explored. This article reviews the progress of immunotherapy in improving EMT development in HCC cells by exploring the mechanism of regulating EMT.
Collapse
Affiliation(s)
- Shuang Wang
- Department of Hepatobiliary and Pancreatic Surgery, Chengdu Fifth People's Hospital, Chengdu, Sichuan 611130, PR China
| | - Yan He
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Jun Wang
- Department of Hepatobiliary and Pancreatic Surgery, Chengdu Fifth People's Hospital, Chengdu, Sichuan 611130, PR China
| | - En Luo
- Department of Hepatobiliary and Pancreatic Surgery, Chengdu Fifth People's Hospital, Chengdu, Sichuan 611130, PR China.
| |
Collapse
|
|
13
|
Newhook TE, Tsai S, Meric-Bernstam F. Precision Oncology in Hepatopancreatobiliary Cancer Surgery. Surg Oncol Clin N Am 2024; 33:343-367. [PMID: 38401914 DOI: 10.1016/j.soc.2023.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Abstract
Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.
Collapse
Affiliation(s)
- Timothy E Newhook
- Department of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Susan Tsai
- Division of Surgical Oncology, Department of Surgery, Ohio State University Comprehensive Cancer Center, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, FC8.3044, Houston, TX 77030, USA.
| |
Collapse
|
|
14
|
Sun L, Li Y, Zhao R, Fan Q, Liu F, Zhu Y, Han J, Liu Y, Jin N, Li X, Li Y. Platycodin D2 enhances P21/CyclinA2-mediated senescence of HCC cells by regulating NIX-induced mitophagy. Cancer Cell Int 2024; 24:79. [PMID: 38374035 PMCID: PMC10875888 DOI: 10.1186/s12935-024-03263-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 02/05/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) cells usually show strong resistance to chemotherapy, which not only reduces the efficacy of chemotherapy but also increases the side effects. Regulation of autophagy plays an important role in tumor treatment. Cell senescence is also an important anti-cancer mechanism, which has become an important target for tumor treatment. Therefore, it is of great clinical significance to find anti-HCC drugs that act through this new mechanism. Platycodin D2 (PD2) is a new saponin compound extracted from the traditional Chinese medicine Platycodon grandiflorum. PURPOSE Our study aimed to explore the effects of PD2 on HCC and identify the underlying mechanisms. METHODS First, the CCK8 assay was used to detect the inhibitory effect of PD2 on HCC cells. Then, different pathways of programmed cell death and cell cycle regulators were measured. In addition, we assessed the effects of PD2 on the autophagy and senescence of HCC cells by flow cytometry, immunofluorescence staining, and Western blotting. Finally, we studied the in vivo effect of PD2 on HCC cells by using a mouse tumor-bearing model. RESULTS Studies have shown that PD2 has a good anti-tumor effect, but the specific molecular mechanism has not been clarified. In this study, we found that PD2 has no obvious toxic effect on normal hepatocytes, but it can significantly inhibit the proliferation of HCC cells, induce mitochondrial dysfunction, enhance autophagy and cell senescence, upregulate NIX and P21, and downregulate CyclinA2. Gene silencing and overexpression indicated that PD2 induced mitophagy in HCC cells through NIX, thereby activating the P21/CyclinA2 pathway and promoting cell senescence. CONCLUSIONS These results indicate that PD2 induces HCC cell death through autophagy and aging. Our findings provide a new strategy for treating HCC.
Collapse
Affiliation(s)
- Lili Sun
- Medical College, Yanbian University, Yanji, 133002, People's Republic of China
- Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun, 130000, People's Republic of China
| | - Yaru Li
- Medical College, Yanbian University, Yanji, 133002, People's Republic of China
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China
| | - Renshuang Zhao
- Medical College, Yanbian University, Yanji, 133002, People's Republic of China
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China
| | - Qinlei Fan
- Chinese Center for Animal Hygiene and Epidemiology, Qingdao, 266032, People's Republic of China
| | - Fei Liu
- Chinese Center for Animal Hygiene and Epidemiology, Qingdao, 266032, People's Republic of China
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, People's Republic of China
| | - Jicheng Han
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, People's Republic of China
| | - Yunyun Liu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China
| | - Ningyi Jin
- Medical College, Yanbian University, Yanji, 133002, People's Republic of China.
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China.
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, People's Republic of China.
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, People's Republic of China.
| | - Xiao Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China.
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, People's Republic of China.
| | - Yiquan Li
- Medical College, Yanbian University, Yanji, 133002, People's Republic of China.
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, People's Republic of China.
| |
Collapse
|
|
15
|
Li Y, Liu W, Chen J, Chen Y, Guo J, Pang H, Zhang W, An C, Li C. Efficiency and safety of hepatic arterial infusion chemotherapy (HAIC) combined with anti-PD1 therapy versus HAIC monotherapy for advanced hepatocellular carcinoma: A multicenter propensity score matching analysis. Cancer Med 2024; 13:e6836. [PMID: 38196277 PMCID: PMC10807563 DOI: 10.1002/cam4.6836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/06/2023] [Accepted: 12/08/2023] [Indexed: 01/11/2024] Open
Abstract
PURPOSE To investigate the clinical efficacy and safety of combination therapy of hepatic arterial infusion chemotherapy (HAIC) and anti-programmed cell death protein-1 (PD-1) therapy in the treatment of advanced hepatocellular carcinoma (HCC). METHODS In this retrospective clinical research, from March 2018 to December 2019, 1158 HCC patients categorized as BCLC stage C were reviewed for eligibility. We utilized propensity score matching (PSM) to mitigate initial disparities between the groups. The evaluation of the best tumor response was conducted in accordance with mRECIST 1.1 criteria. The difference in survival outcomes including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) between groups were compared. RESULTS Following the eligibility review, 453 patients underwent a combined treatment of HAIC with PD1 inhibitors (HAIC-PD1 group), while 221 patients received HAIC monotherapy (HAIC group) met the inclusion criteria and were finally enrolled in this study. In the entire cohort, the HAIC-PD1 group exhibited significantly prolonged overall survival (median overall survival: 40.4 months vs. 9.7 months, p < 0.001) and progression-free survival (median progression-free survival: 22.1 months vs. 5.8 months, p < 0.001). By propensity score, patients were matched according to baseline differences, resulting in all 442 patients in group HAIC-PD1 (n = 221) and group HAIC (n = 221). After PSM adjustment, as well, the survival of the HAIC-PD1 group was still distinctly longer than the HAIC group (median overall survival time, 40.4 months vs 9.7 months, p < 0.001; median progression-free survival, 22.1 months vs 5.7 months, p < 0.001). Univariate and multivariable analysis demonstrated that AFP level, metastasis, and therapeutic schedule were independent predictive factors for overall survival. CONCLUSION The combination therapy of HAIC and PD1 inhibitors successfully extended OS to advanced HCC patients and could be a better choice than HAIC monotherapy.
Collapse
Affiliation(s)
- Yangyang Li
- Department of Interventional Radiology and Vascular SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongP. R. China
| | - Wendao Liu
- Department of Interventional TherapyGuangdong Provincial Hospital of Chinese Medicine and Guangdong Provincial Academy of Chinese Medical SciencesGuangzhouGuangdongP. R. China
| | - Junwei Chen
- Department of Interventional RadiologyThe Third Affiliated Hospital of Sun Yat‐Sen UniversityGuangzhouGuangdongP. R. China
| | - Yongxin Chen
- Department of Interventional Radiology and Vascular SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongP. R. China
| | - Jiandong Guo
- Department of Interventional Radiology and Vascular SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongP. R. China
| | - Huajin Pang
- Division of Vascular and Interventional Radiology, Department of General SurgeryNanfang Hospital, Southern Medical UniversityGuangzhouGuangdongP. R. China
| | - Wentao Zhang
- Department of RadiologyThe First Affiliated Hospital, Nanchang UniversityNanchangJiangxiP. R. China
| | - Chao An
- Department of Minimal Invasive InterventionSun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer MedicineGuangzhouP.R. China
| | - Chengzhi Li
- Department of Interventional Radiology and Vascular SurgeryThe First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongP. R. China
| |
Collapse
|
|
16
|
Vogel A, Grant RC, Meyer T, Sapisochin G, O'Kane GM, Saborowski A. Adjuvant and neoadjuvant therapies for hepatocellular carcinoma. Hepatology 2023:01515467-990000000-00690. [PMID: 38108634 DOI: 10.1097/hep.0000000000000726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.
Collapse
Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, ON, Canada
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Robert C Grant
- Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, London, UK
- Royal Free Hospital, London, UK
| | - Gonzalo Sapisochin
- Department of Abdominal Transplant & HPB Surgical Oncology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Grainne M O'Kane
- Trinity St. James's Cancer Institute, St. James's Hospital, Dublin, Ireland
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology, Infectiology and Endocrinology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
17
|
Shibu MA, Chen YJ, Yang HS, He YH, Lo YH, Lin WT. Principle active metabolites of Pinus morrisonicola Hayata synergistically inhibit cell proliferation and autophagy to elevate apoptosis in hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2023; 38:3018-3025. [PMID: 37615216 DOI: 10.1002/tox.23935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/22/2023] [Accepted: 07/29/2023] [Indexed: 08/25/2023]
Abstract
Hepatocellular carcinoma (HCC), a common primary tumor of liver is a leading cause of cancer-associated deaths. Improving cellular apoptosis and enhancing autophagic clearance is been considered to improve treatment outcomes of HCC. Polyphenols from Pinus morrisonicola (Hayata) have shown various physiological and therapeutic benefits and the flavonoid chrysin is been known for their anticancer effects. However, the main bioactive principle and the mechanism underlying the antitumor activity of pine needle extract are not clear yet. In this study, the effects of ethanol extract from pine needle on HCC cells were determined. The results show that when compared with administration of chrysin alone, a fraction containing pinocembrin, chrysin, and tiliroside significantly reduced autophagy and increased apoptosis. The results also correlated with decrease in cell cycle regulators and the autophagic proteins like LC3-II. Collectively, the results imply the fraction containing pinocembrin, chrysin, and tiliroside as an ideal complementary medicine for an effective antitumor activity.
Collapse
Affiliation(s)
| | - Yi-Ju Chen
- Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Animal Science and Biotechnology, Tunghai University, Taichung, Taiwan
| | - Hong-Siang Yang
- Department of Food Science College of Agriculture and Health, Tunghai University, Taichung, Taiwan
| | - Yen-Hua He
- Department of Hospitality Management College of Agriculture and Health, Tunghai University, Taichung, Taiwan
- R&D Division, Utopia Holiday Hotel Corporation, Taichung, Taiwan
| | - Yun-Hsin Lo
- Department of Hospitality Management College of Agriculture and Health, Tunghai University, Taichung, Taiwan
- R&D Division, Utopia Holiday Hotel Corporation, Taichung, Taiwan
| | - Wan-Teng Lin
- Department of Hospitality Management College of Agriculture and Health, Tunghai University, Taichung, Taiwan
| |
Collapse
|
|
18
|
Dou WT, Qiu P, Shi Y, Zhu L, Guo C, Li N, Zang Y, Liu T, Zhao S, Pan Y, Dong L, Sessler JL, Tan Y, Li J, Wang H, Tian H, He XP. Orthogonally Engineered Albumin with Attenuated Macrophage Phagocytosis for the Targeted Visualization and Phototherapy of Liver Cancer. J Am Chem Soc 2023; 145:17377-17388. [PMID: 37497917 DOI: 10.1021/jacs.3c05052] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.
Collapse
Affiliation(s)
- Wei-Tao Dou
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
| | - Peng Qiu
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
| | - Yuanyuan Shi
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| | - Ling Zhu
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
| | - Chen Guo
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
| | - Na Li
- National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 333 Haike Rd, Pudong New District, Shanghai 201210, P. R. China
| | - Yi Zang
- National Centre for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Rd, Shanghai 201203, P. R. China
- Lingang laboratory, Shanghai 201203, P. R. China
| | - Tingting Liu
- iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Rd, Pudong New District, Shanghai 201210, P. R. China
| | - Suwen Zhao
- iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Rd, Pudong New District, Shanghai 201210, P. R. China
| | - Yufei Pan
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| | - Liwei Dong
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| | - Jonathan L Sessler
- Department of Chemistry, The University of Texas at Austin, 105 East 24th Street-A5300, Austin, Texas 78712-1224, United States of America
| | - Yexiong Tan
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| | - Jia Li
- National Centre for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shoujing Rd, Shanghai 201203, P. R. China
| | - Hongyang Wang
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| | - He Tian
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
| | - Xiao-Peng He
- Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, P. R. China
- National Center for Liver Cancer, The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai 200433, P. R. China
| |
Collapse
|
|
19
|
Lu Q, Long Y, Gai Y, Liu Q, Jiang D, Lan X. [ 177Lu]Lu-PSMA-617 theranostic probe for hepatocellular carcinoma imaging and therapy. Eur J Nucl Med Mol Imaging 2023; 50:2342-2352. [PMID: 36877233 DOI: 10.1007/s00259-023-06155-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 02/13/2023] [Indexed: 03/07/2023]
Abstract
PURPOSE This study aimed to explore the feasibility of using [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 and [177Lu]Lu-Evans blue (EB)-PSMA-617 for in vivo radioligand therapy by single-dose administration in a PSMA-positive hepatocellular carcinoma (HCC) xenograft mouse model. METHODS [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 were prepared, and labelling efficiency and radiochemical purity were determined. A HepG2 human HCC subcutaneous xenograft mouse model was established. After intravenous injection of [177Lu]Lu-PSMA-617 or [177Lu]Lu-EB-PSMA-617 (37 MBq) into the mouse model, single-photon emission computed tomography/computed tomography (SPECT/CT) was performed. Biodistribution studies were conducted to verify targeting specificity and pharmacokinetics. In the radioligand therapy study, mice were randomized into 4 groups: 37 MBq [177Lu]Lu-PSMA-617, 18.5 MBq [177Lu]Lu-PSMA-617, 7.4 MBq [177Lu]Lu-EB-PSMA-617, and saline (control). A single-dose administration was applied at the beginning of therapy studies. Tumor volume, body weight, and survival were monitored every 2 days. After the end of therapy, mice were euthanized. Tumors were then weighed, and systemic toxicity was evaluated via blood testing and histological examination of healthy organs. RESULTS [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 were successfully prepared with high purity and stability. SPECT/CT and biodistribution showed that tumor uptake was higher and persisted longer for [177Lu]Lu-EB-PSMA-617 compared with [177Lu]Lu-PSMA-617. [177Lu]Lu-PSMA-617 was rapidly cleared from the blood, while [177Lu]Lu-EB-PSMA-617 persisted for significantly longer. In radioligand therapy studies, tumor growth was significantly suppressed in the 37 MBq [177Lu]Lu-PSMA-617, 18.5 MBq [177Lu]Lu-PSMA-617, and 7.4 MBq [177Lu]Lu-EB-PSMA-617 groups compared to the saline group. Median survival was 40, 44, 43, and 30 days, respectively. No healthy organ toxicity was observed in safety and tolerability evaluation. CONCLUSIONS Radioligand therapy using [177Lu]Lu-PSMA-617 and [177Lu]Lu-EB-PSMA-617 significantly suppressed tumor growth and prolonged survival time in PSMA-positive HCC xenograft mice without obvious toxicity. These radioligands appear promising for clinical use in humans, and future studies are warranted.
Collapse
Affiliation(s)
- Qiaomiao Lu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China
| | - Yu Long
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China
| | - Yongkang Gai
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China
- Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, 430022, China
| | - Qingyao Liu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China
- Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, 430022, China
| | - Dawei Jiang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China
- Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, 430022, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, Hubei, 430022, China.
- Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, 430022, China.
| |
Collapse
|
|
20
|
Fonseca LG, Chen AT, de Oliveira IS, Chagas AL, Kruger JA, Carrilho FJ. Brazilian Landscape of Hepatocellular Carcinoma. JCO Glob Oncol 2023; 9:e2200416. [PMID: 37348031 PMCID: PMC10497258 DOI: 10.1200/go.22.00416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/28/2023] [Accepted: 04/25/2023] [Indexed: 06/24/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is expected to increase in the coming years, and strategies to mitigate the burden of this disease are needed in different regions. Geographic variations in epidemiology and risk factors, such as viral hepatitis and metabolic disease, pose challenges in adopting programs for early detection programs and management of patients with HCC. Brazil, like other countries, has high economic and social inequality, with heterogeneous access to health care. Viral hepatitis is the main risk factor but there is growing awareness of fatty liver disease. Risk factor monitoring and screening programs are unmet priorities because patients are often diagnosed at later stages. Advances in the management of patients with HCC have been made in recent years, including new tools for selecting patients for liver transplantation, sophisticated surgical techniques, and new systemic agents. High-volume academic centers often achieve favorable results through the adoption and application of established treatments, but this is not a reality in most regions of Brazil, because of disparities in wealth and resources. As HCC management requires a coordinated and multidisciplinary team, the role of local referral centers in decentralizing access to treatments and promoting health education in different regions should be encouraged and supported.
Collapse
Affiliation(s)
- Leonardo G. Fonseca
- Medical Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Andre T.C. Chen
- Department of Radiation Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Irai S. de Oliveira
- Department of Radiology, Hospital das Clínicas, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Aline L. Chagas
- Department of Gastroenterology, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
- Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Jaime A.P. Kruger
- Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Flair J. Carrilho
- Department of Gastroenterology, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
- Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| |
Collapse
|
|
21
|
Zhao S, Chen S, Liu W, Wei S, Wu X, Cui D, Jiang L, Chen S, Wang J. Integrated machine learning and bioinformatic analyses used to construct a copper-induced cell death-related classifier for prognosis and immunotherapeutic response of hepatocellular carcinoma patients. Front Pharmacol 2023; 14:1188725. [PMID: 37266152 PMCID: PMC10229845 DOI: 10.3389/fphar.2023.1188725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 04/27/2023] [Indexed: 06/03/2023] Open
Abstract
Background: Copper as phytonutrient has powerful activity against health diseases. A newly discovered mechanism of cell death that affects energy metabolism by copper ("cuproptosis") can induce multiple cuproptosis-related genes. Hepatocellular carcinoma (HCC) is a poorly prognosed widespread cancer having danger of advanced metastasis. Therefore, earlier diagnosis followed by the specific targeted therapy are required for improved prognosis. The work herein constructed scoring system built on ten cuproptosis-related genes (CRGs) to predict progression of tumor and metastasis more accurately and test patient reaction toward immunotherapy. Methods: A comprehensive assessment of cuproptosis patterns in HCC samples from two databases and a real-world cohort was performed on ten CRGs, that were linked to immune cell infiltration signatures of TME (tumor microenvironment). Risk signatures were created for quantifying effect of cuproptosis on HCC, and the effects of related genes on cellular function of HCC were investigated, in addition to the effects of immunotherapy and targeted therapy drugs. Results: Two distinct cuproptosis-associated mutational patterns were identified, with distinct immune cell infiltration characteristics and survival likelihood. Studies have shown that assessment of cuproptosis-induced tumor mutational patterns can help predict tumor stage, phenotype, stromal activity, genetic diversity, and patient prognosis. High risk scores are characterized by lower survival and worse treatment with anti-PD-L1/CTAL4 immunotherapy and first-line targeted drugs. Cytological functional assays show that CDKN2A and GLS promote proliferation, migration and inhibit copper-dependent death of HCC cells. Conclusion: HCC patients with high-risk scores exhibit significant treatment disadvantage and survival rates. Cuproptosis plays a non-negligible role in the development of HCC. Quantifying cuproptosis-related designs of tumors will aid in phenotypic categorization, leading to efficient personalized and targeted therapeutics and precise prediction of prognosis and metastasis.
Collapse
Affiliation(s)
- Shuai Zhao
- Department of Transplantation, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuxian Chen
- Department of Oncology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wangrui Liu
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiyin Wei
- Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Xinrui Wu
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Cui
- Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lifeng Jiang
- Department of Gastroenterology, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Siyu Chen
- Department of Oncology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Wang
- Department of Transplantation, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
22
|
Lin JP, Huang MH, Sun ZT, Chen L, Lei YH, Huang YQ, Qi M, Fan SR, Chen SG, Chung CW, Chan MC, Liu JS, Hu M, Chen MF, Ye WC, Chen YY, Deng LJ. Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway. Life Sci 2023; 324:121715. [PMID: 37100377 DOI: 10.1016/j.lfs.2023.121715] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/28/2023]
Abstract
AIMS We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.
Collapse
Affiliation(s)
- Jia-Peng Lin
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Mao-Hua Huang
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Zhi-Ting Sun
- Research Center of Cancer Diagnosis and Therapy, Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, PR China
| | - Lei Chen
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Yu-He Lei
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, PR China
| | - Yu-Qing Huang
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China
| | - Ming Qi
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Shu-Ran Fan
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Shou-Guo Chen
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China
| | - Chi-Wing Chung
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China
| | - Mei-Ching Chan
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China
| | - Jun-Shan Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, PR China; Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, PR China; Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Southern Medical University, Guangzhou, PR China
| | - Min Hu
- Department of Hepatobiliary Surgery, Jinan University First Affiliated Hospital, Guangzhou, PR China
| | - Min-Feng Chen
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Wen-Cai Ye
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China
| | - Yue-Yue Chen
- Affiliated Jiangmen TCM Hospital of Jinan University, Jiangmen, PR China.
| | - Li-Juan Deng
- Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, Jinan University, Guangzhou, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, PR China.
| |
Collapse
|
|
23
|
Ito R, Miyanishi K, Kubo T, Hamaguchi K, Osuga T, Tanaka S, Ohnuma H, Murase K, Takada K, Nagayama M, Kimura Y, Mizuguchi T, Takemasa I, Kato J. Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma. Hepatol Int 2023; 17:735-744. [PMID: 36738397 DOI: 10.1007/s12072-023-10484-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/06/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.
Collapse
Affiliation(s)
- Ryo Ito
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Tomohiro Kubo
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kota Hamaguchi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Takahiro Osuga
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.,Department of Infection Control and Laboratory Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kazuyuki Murase
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Minoru Nagayama
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Toru Mizuguchi
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan.,Postgraduate School of Health Science and Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| |
Collapse
|
|
24
|
Zhao M, Chen S, Li C, Du Y, Li P. Neoadjuvant Immune Checkpoint Inhibitors for Resectable Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2023; 15:600. [PMID: 36765557 PMCID: PMC9913451 DOI: 10.3390/cancers15030600] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Resectable hepatocellular carcinoma (HCC) has poor prognosis because of its high recurrence rate. Immunotherapy has been tried for neoadjuvant therapy as it has shown excellent performance in the treatment of advanced HCC. This systematic review and meta-analysis aimed to assess the reported efficacy and safety of neoadjuvant immune checkpoint inhibitors (ICIs) for resectable HCC. Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify published and ongoing studies evaluating the efficacy and safety of neoadjuvant ICIs for resectable HCC up to October 2022. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity and subgroup analyses were performed, and data quality was assessed. The study was registered with PROSPERO (registration number: CRD42022371495). A total of 193 patients from 9 studies were included in this meta-analysis. The overall pathological complete response (pCR) rate was 12.9% (95%CI, 6.7-19.1%), and major pathological response (MPR) rate was 27.3% (95%CI, 15.1-39.4%), indicating a favorable association with neoadjuvant ICIs (pCR: OR = 0.17, p < 0.00001; MPR: OR = 0.38, p = 0.001). The pooled OR values for the incidence of grade 3 to 4 treatment-related adverse events and surgical delay rate were 0.26 and 0.05, respectively, which were significantly in favor of neoadjuvant ICIs (p < 0.0001; p < 0.00001, respectively). The subgroup analyses did not demonstrate superiority of one ICI over another ICI or combination therapy. The present study found that neoadjuvant ICIs were well tolerated by patients with resectable HCC and conferred therapeutic benefits in view of histopathological response results.
Collapse
Affiliation(s)
- Mei Zhao
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei 230032, China
| | - Shanwen Chen
- Department of Otorhinolaryngology—Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Conggui Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Yingying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Ping Li
- Department of Chinese Integrative Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Department of Integrated Traditional Chinese and Western Medicine, Anhui Medical University, Hefei 230032, China
| |
Collapse
|
|
25
|
Arif A, Alameri AA, Tariq UB, Ansari SA, Sakr HI, Qasim MT, Aljoborae FFM, Ramírez-Coronel AA, Jabbar HS, Gabr GA, Mirzaei R, Karampoor S. The functions and molecular mechanisms of Tribbles homolog 3 (TRIB3) implicated in the pathophysiology of cancer. Int Immunopharmacol 2023; 114:109581. [PMID: 36527874 DOI: 10.1016/j.intimp.2022.109581] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022]
Abstract
Currently, cancer ranks as the second leading cause of death worldwide, and at the same time, the burden of cancer continues to increase. The underlying molecular pathways involved in the initiation and development of cancer are the subject of considerable research worldwide. Further understanding of these pathways may lead to new cancer treatments. Growing data suggest that Tribble's homolog 3 (TRIB3) is essential in oncogenesis in many types of cancer. The mammalian tribbles family's proteins regulate various cellular and physiological functions, such as the cell cycle, stress response, signal transduction, propagation, development, differentiation, immunity, inflammatory processes, and metabolism. To exert their activities, Tribbles proteins must alter key signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. Recent evidence supports that TRIB3 dysregulation has been linked to various diseases, including tumor development and chemoresistance. It has been speculated that TRIB3 may either promote or inhibit the onset and development of cancer. However, it is still unclear how TRIB3 performs this dual function in cancer. In this review, we present and discuss the most recent data on the role of TRIB3 in cancer pathophysiology and chemoresistance. Furthermore, we describe in detail the molecular mechanism TRIB3 regulates in cancer.
Collapse
Affiliation(s)
- Anam Arif
- Department of Government DHQ hospital Narowal, Gujranwala medical college, Gujranwala, Pakistan
| | - Ameer A Alameri
- Department of Chemistry, College of Science, University of Babylon, Babylon, Iraq
| | | | - Shakeel Ahmed Ansari
- Department of Biochemistry, Batterjee Medical College for Science and Technology, Jeddah, Saudi Arabia
| | - Hader Ibrahim Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Egypt; Department of Medical Physiology, Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Fadhil F M Aljoborae
- Department of Anesthesia Techniques, Al-Mustaqbal University College, Babylon, Iraq
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador
| | - Hijran Sanaan Jabbar
- Department of Chemistry, College of Science, Salahaddin University, Erbil, Iraq; Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Erbil, Iraq
| | - Gamal A Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
26
|
Ishtiaq SM, Arshad MI, Khan JA. PPARγ signaling in hepatocarcinogenesis: Mechanistic insights for cellular reprogramming and therapeutic implications. Pharmacol Ther 2022; 240:108298. [PMID: 36243148 DOI: 10.1016/j.pharmthera.2022.108298] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 11/30/2022]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) is leading cause of cancer-related mortalities globally. The therapeutic approaches for chronic liver diseases-associated liver cancers aimed at modulating immune check-points and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway during multistep process of hepatocarcinogenesis that played a dispensable role in immunopathogenesis and outcomes of disease. Herein, the review highlights PPARγ-induced effects in balancing inflammatory (tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1) and anti-inflammatory cytokines (IL-10, transforming growth factor beta (TGF-β), and interplay of PPARγ, hepatic stellate cells and fibrogenic niche in cell-intrinsic and -extrinsic crosstalk of hepatocarcinogenesis. PPARγ-mediated effects in pre-malignant microenvironment promote growth arrest, cell senescence and cell clearance in liver cancer pathophysiology. Furthermore, PPARγ-immune cell axis of liver microenvironment exhibits an immunomodulation strategy of resident immune cells of the liver (macrophages, natural killer cells, and dendritic cells) in concomitance with current clinical guidelines of the European Association for Study of Liver Diseases (EASL) for several liver diseases. Thus, mechanistic insights of PPARγ-associated high value targets and canonical signaling suggest PPARγ as a possible therapeutic target in reprogramming of hepatocarcinogenesis to decrease burden of liver cancers, worldwide.
Collapse
Affiliation(s)
- Syeda Momna Ishtiaq
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad 38040, Pakistan
| | | | - Junaid Ali Khan
- Department of Pharmacology and Physiology, MNS University of Agriculture, Multan 60000, Pakistan.
| |
Collapse
|
|
27
|
Peng W, Jiang X, Zhang W, Hu J, Zhang Y, Zhang L. A radiomics-based model can predict recurrence-free survival of hepatocellular carcinoma after curative ablation. Asian J Surg 2022:S1015-9584(22)01409-9. [DOI: 10.1016/j.asjsur.2022.09.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/16/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
|
|
28
|
Jonas E, Bernon M, Robertson B, Kassianides C, Keli E, Asare KO, Alatise IO, Okello M, Blondel NO, Mulehane KO, Abubeker ZA, Nogoud AA, Nashidengo PR, Chihaka O, Tzeuton C, Dusheiko G, Sonderup M, Spearman CW. Treatment of hepatocellular carcinoma in sub-Saharan Africa: challenges and solutions. Lancet Gastroenterol Hepatol 2022; 7:1049-1060. [PMID: 35810767 DOI: 10.1016/s2468-1253(22)00042-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/30/2022] [Accepted: 02/02/2022] [Indexed: 06/15/2023]
Abstract
Most patients who develop hepatocellular carcinoma reside in resource-poor countries, a category that includes most countries in sub-Saharan Africa. Age-standardised incidence rates of hepatocellular carcinoma in western, central, eastern, and southern Africa is 6·53 per 100 000 inhabitants to 11·1 per 100 000 inhabitants. In high-income countries, around 40% of patients are diagnosed at an early stage, in which interventions with curative intent or palliative interventions are possible. By contrast, 95% of patients with hepatocellular carcinoma in sub-Saharan Africa present with advanced or terminal disease. In high-income countries, targets of 30-40% that have been set for intervention with curative intent are regularly met, with expected 5-year overall survival rates in the region of 70%. These outcomes are in sharp contrast with the very small proportion of patients in sub-Saharan Africa who are treated with curative intent. Primary prevention through the eradication and reduction of risk factors is still suboptimal because of logistical challenges. The challenges facing primary prevention, in combination with difficult-to-manage historic and emerging risk factors, such as ethanol overconsumption and metabolic dysfunction-associated liver disease, mandates secondary prevention for populations at risk through screening and surveillance. Although the increased treatment needs yielded by screening and surveillance in high-income countries are manageable by the incremental expansion of existing interventional resources, the lack of resources in sub-Saharan Africa will undermine the possible benefits of secondary prevention. An estimate of the projected effect of the introduction and expansion of screening and surveillance, resulting in stage migration and possibilities for active interventions for hepatocellular carcinoma, would facilitate optimal planning and development of resources.
Collapse
Affiliation(s)
- Eduard Jonas
- Department of Surgery, University of Cape Town, Cape Town, South Africa.
| | - Marc Bernon
- Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - Barbara Robertson
- Division of Radiation Oncology, Department of Radiation Medicine, University of Cape Town, Cape Town, South Africa
| | - Chris Kassianides
- Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Elie Keli
- Department of General and Digestive Surgery, Hôpital Militaire d'Abidjan, Abidjan, Côte d'Ivoire
| | - Kwaku Offei Asare
- Department of Surgery, Korle Bu Teaching Hospital and the University of Ghana Medical School, Accra, Ghana
| | - Isaac Olusegun Alatise
- Department of Surgery, Obafemi Awolowo University, Obafemi Awolowo University Teaching Hospital Complex, Ile Ife, Nigeria
| | - Michael Okello
- Department of Surgery, Uganda Martyrs Hospital Lubaga, Kampala, Uganda
| | - Nana Oumarou Blondel
- Centre Hospitalier d'Essos and Department of Surgery, University of Yaoundé, Yaoundé, Cameroon
| | | | - Zeki Abdurahman Abubeker
- Department of Surgery, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | | | - Pueya Rashid Nashidengo
- Department of Surgery, Windhoek Central Hospital, University of Namibia School of Medicine, Windhoek, Namibia
| | - Onesai Chihaka
- Department of Surgery, University of Zimbabwe, Harare, Zimbabwe
| | - Christian Tzeuton
- Faculty of Medicine and Pharmaceutical Sciences of Douala, University of Douala, Douala, Cameroon
| | - Geoffrey Dusheiko
- Institute of Liver Studies, King's College Hospital, London, UK; University College London Medical School, London, UK
| | - Mark Sonderup
- Division of Hepatology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| |
Collapse
|
|
29
|
Hassan A, Al-Salmi FA, Abuamara TMM, Matar ER, Amer ME, Fayed EMM, Hablas MGA, Mohammed TS, Ali HE, Abd EL-fattah FM, Abd Elhay WM, Zoair MA, Mohamed AF, Sharaf EM, Dessoky ES, Alharthi F, Althagafi HAE, Abd El Maksoud AI. Ultrastructural analysis of zinc oxide nanospheres enhances anti-tumor efficacy against Hepatoma. Front Oncol 2022; 12:933750. [PMID: 36457501 PMCID: PMC9706544 DOI: 10.3389/fonc.2022.933750] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 09/12/2022] [Indexed: 09/01/2023] Open
Abstract
Zinc oxide nanomaterial is a potential material in the field of cancer therapy. In this study, zinc oxide nanospheres (ZnO-NS) were synthesized by Sol-gel method using yeast extract as a non-toxic bio-template and investigated their physicochemical properties through various techniques such as FTIR, XR, DLS, and TEM. Furthermore, free zinc ions released from the zinc oxide nanosphere suspended medium were evaluated by using the ICP-AS technique. Therefore, the cytotoxicity of ZnO nanospheres and released Zn ions on both HuH7 and Vero cells was studied using the MTT assay. The data demonstrated that the effectiveness of ZnO nanospheres on HuH7 was better than free Zn ions. Similarly, ZnO-Ns were significantly more toxic to HuH7 cell lines than Vero cells in a concentration-dependent manner. The cell cycle of ZnO-Ns against Huh7 and Vero cell lines was arrested at G2/M. Also, the apoptosis assay using Annexin-V/PI showed that apoptosis of HuH7 and Vero cell lines by ZnO nanospheres was concentration and time-dependent. Caspase 3 assay results showed that the apoptosis mechanism may be intrinsic and extrinsic pathways. The mechanism of apoptosis was determined by applying the RT-PCR technique. The results revealed significantly up-regulated Bax, P53, and Cytochrome C, while the Bcl2 results displayed significant down-regulation and the western blot data confirmed the RT-PCR data. There is oxidative stress of the ZnO nanospheres and free Zn+2 ions. Results indicated that the ZnO nanospheres and free Zn+2 ions induced oxidative stress through increasing reactive oxygen species (ROS) and lipid peroxidation. The morphology of the HuH7 cell line after exposure to ZnO nanospheres at different time intervals revealed the presence of the chromatin condensation of the nuclear periphery fragmentation. Interestingly, the appearance of canonical ultrastructure features of apoptotic morphology of Huh7, Furthermore, many vacuoles existed in the cytoplasm, the majority of which were lipid droplets, which were like foamy cells. Also, there are vesicles intact with membranes that are recognized as swollen mitochondria.
Collapse
Affiliation(s)
- Amr Hassan
- Department of Bioinformatics, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat, Egypt
| | - Fawziah A. Al-Salmi
- Biology Department, College of Sciences, Taif University, Taif, Saudi Arabia
| | | | - Emadeldin R. Matar
- Departments of Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohamed E. Amer
- Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Ebrahim M. M. Fayed
- Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | | | - Tahseen S. Mohammed
- Department of Public Health and Community Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Haytham E. Ali
- Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Fayez M. Abd EL-fattah
- Department of Anatomy and Embryology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Wagih M. Abd Elhay
- Department of Histology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohammad A. Zoair
- Department of Physiology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Aly F. Mohamed
- Research and development department, Egyptian Organization for Biological Products and Vaccines [Holding Company for Vaccine and Sera Production (VACSERA)], Giza, Egypt
| | - Eman M. Sharaf
- Department of Bacteriology, Immunology, and Mycology, Animal Health Research Institute (AHRI), Shebin El Kom, Egypt
| | | | - Fahad Alharthi
- Biology Department, College of Sciences, Taif University, Taif, Saudi Arabia
| | | | - Ahmed I. Abd El Maksoud
- Department of Industrial Biotechnology, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat, Egypt
| |
Collapse
|
|
30
|
Sun J, Liu C, Shi J, Wang N, Jiang D, Mao F, Gu J, Zhou L, Shen L, Lau WY, Cheng S. A novel chemotherapy strategy for advanced hepatocellular carcinoma: a multicenter retrospective study. Chin Med J (Engl) 2022; 135:2338-2343. [PMID: 36103975 PMCID: PMC9771239 DOI: 10.1097/cm9.0000000000001952] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Chemotherapy is a common treatment for advanced hepatocellular carcinoma, but the effect is not satisfactory. The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid (ATRA) to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) for advanced hepatocellular carcinoma (HCC). METHODS We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, and Zhejiang Sian International Hospital and retrospectively compared for overall survival. The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age, sex, and disease stage. RESULTS From July 2013 to July 2018, 111 patients with HCC were included in this study. The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group ( P < 0.001). The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group (3.6 months vs. 1.8 months, P < 0.001). Hazard ratios for overall survival and disease progression were 0.465 (95% confidence interval: 0.298-0.726; P = 0.001) and 0.474 (0.314-0.717; P < 0.001) after adjusting for potential confounders, respectively. CONCLUSION ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.
Collapse
Affiliation(s)
- Juxian Sun
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Chang Liu
- Department of Integrative Oncology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Jie Shi
- Department of Outpatient Department, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Nanya Wang
- Department of Oncology, First Hospital of Jilin University, Changchun, Jilin 130000, China
| | - Dafeng Jiang
- Department of Oncology Zhejiang Sian International Hospital, Jiaxing, Zhejiang 314000, China
| | - Feifei Mao
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200040, China
| | - Jingwen Gu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Liping Zhou
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Li Shen
- Department of Outpatient Department, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Wan Yee Lau
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
- Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR 999077, China
| | - Shuqun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China
| |
Collapse
|
|
31
|
Pei Y, Li W, Wang Z, Liu J. Successful conversion therapy for unresectable hepatocellular carcinoma is getting closer: A systematic review and meta-analysis. Front Oncol 2022; 12:978823. [PMID: 36176393 PMCID: PMC9513549 DOI: 10.3389/fonc.2022.978823] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/09/2022] [Indexed: 11/24/2022] Open
Abstract
Background Conversion therapy provides selected patients with unresectable hepatocellular carcinoma the opportunity to undergo a curative hepatectomy and achieve long-term survival. Although various regimens have been used for conversion therapy, their conversion rate and safety remain uncertain. Therefore, we conducted some meta-analyses to evaluate the efficacy and safety of several conversion regimens in order to elucidate the optimal regimen. Method We performed systematic literature research on PubMed, Embase, and the Web of Science until July 30, 2022. Chemotherapy, transcatheter arterial chemoembolization (TACE), molecular therapy (targeted therapy, immunotherapy, or a combination of both), and combined locoregional-systemic therapy were the conversion regimens we targeted. Results Twenty-four studies were included. The pooled conversion rates for chemotherapy, TACE, molecular therapy, and combined locoregional-systemic therapy were 13% (95% confidence interval [CI], 7%-20%; I² = 82%), 12% (95% CI, 9%-15%; I² = 60%), 10% (95% CI, 3%-20%; I² = 90%), and 25% (95% CI, 13%-38%; I² = 89%), respectively. The pooled objective response rates (ORR) for chemotherapy, TACE, molecular therapy, and combined locoregional-systemic therapy were 19% (95% CI, 12%-28%; I² = 77%), 32% (95% CI, 15%-51%; I² = 88%), 30% (95% CI, 15%-46%; I² = 93%), and 60% (95% CI, 41%-77%; I² = 91%), respectively. The pooled grade ≥3 AEs for chemotherapy, TACE, molecular therapy, and combined locoregional-systemic therapy were 67% (95% CI, 55%-78%; I² = 79%), 34% (95% CI, 8%-66%; I²= 92%), 30% (95% CI, 18%-43%; I² = 84%), and 40% (95% CI, 23%-58%; I² = 89%), respectively. Subgroup analyses showed the conversion rate, ORR and grade ≥3 AE rate for tyrosine kinase inhibitor (TKI) combined with immune checkpoint inhibitor (ICI) and locoregional therapy (LRT) were 33% (95% CI, 17%-52%; I² = 89%), 73% (95% CI, 51%-91%; I² = 90%), 31% (95% CI, 10%-57%; I² = 89%), respectively. Conclusion Combined locoregional-systemic therapy, especially TKI combined with ICI and LRT, may be the most effective conversion therapy regimen, associated with a significant ORR, conversion potential, and an acceptable safety profile.
Collapse
Affiliation(s)
| | | | | | - Jinlong Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Chengde Medical University, Chengde, China
| |
Collapse
|
|
32
|
A Review of Current and Emerging Therapies for Advanced Hepatocellular Carcinoma. Curr Oncol 2022; 29:6445-6462. [PMID: 36135076 PMCID: PMC9498097 DOI: 10.3390/curroncol29090507] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma remains a leading cause of cancer-related deaths worldwide. Liver disease including cirrhosis and viral hepatitis remains among the leading causes of hepatocellular carcinoma and despite increased screening, many patients are diagnosed in the advanced stages precluding them from locoregional therapy. Therapeutic agents for advanced hepatocellular carcinoma were limited to Sorafenib for several years; however, with the emergence of molecular targeted therapies including tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors, in addition to immunotherapies, the way hepatocellular carcinoma is treated has changed significantly. In this review, we summarize the key clinical trials that lead to the approval of these agents for systemic treatment of hepatocellular carcinoma and discuss the preferred sequence of treatment options as well as prospective studies for management of hepatocellular carcinoma.
Collapse
|
|
33
|
Kahraman DC, Bilget Guven E, Aytac PS, Aykut G, Tozkoparan B, Cetin Atalay R. A new triazolothiadiazine derivative inhibits stemness and induces cell death in HCC by oxidative stress dependent JNK pathway activation. Sci Rep 2022; 12:15139. [PMID: 36071119 PMCID: PMC9452548 DOI: 10.1038/s41598-022-17444-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 07/26/2022] [Indexed: 11/09/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, and resistant to both conventional and targeted chemotherapy. Recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the incidence and mortality of different types of cancers. Here, we investigated the cellular bioactivities of a series of triazolothiadiazine derivatives on HCC, which have been previously reported as potent analgesic/anti-inflammatory compounds. From the initially tested 32 triazolothiadiazine NSAID derivatives, 3 compounds were selected based on their IC50 values for further molecular assays on 9 different HCC cell lines. 7b, which was the most potent compound, induced G2/M phase cell cycle arrest and apoptosis in HCC cells. Cell death was due to oxidative stress-induced JNK protein activation, which involved the dynamic involvement of ASK1, MKK7, and c-Jun proteins. Moreover, 7b treated nude mice had a significantly decreased tumor volume and prolonged disease-free survival. 7b also inhibited the migration of HCC cells and enrichment of liver cancer stem cells (LCSCs) alone or in combination with sorafenib. With its ability to act on proliferation, stemness and the migration of HCC cells, 7b can be considered for the therapeutics of HCC, which has an increased incidence rate of ~ 3% annually.
Collapse
Affiliation(s)
- Deniz Cansen Kahraman
- Cancer Systems Biology Laboratory, Graduate School of Informatics, METU, 06800, Ankara, Turkey.
| | - Ebru Bilget Guven
- Department of Molecular Biology and Genetics, Bilkent University, 06800, Ankara, Turkey.,Department of Molecular Biology and Genetics, Kadir Has University, 34083, Istanbul, Turkey
| | - Peri S Aytac
- Department of Pharmaceutical Chemistry, Hacettepe University, 06800, Ankara, Turkey
| | - Gamze Aykut
- Department of Molecular Biology and Genetics, Bilkent University, 06800, Ankara, Turkey
| | - Birsen Tozkoparan
- Department of Pharmaceutical Chemistry, Hacettepe University, 06800, Ankara, Turkey
| | - Rengul Cetin Atalay
- Section of Pulmonary and Critical Care Medicine, the University of Chicago, Chicago, IL, 60637, USA
| |
Collapse
|
|
34
|
TKIs beyond immunotherapy predict improved survival in advanced HCC. J Cancer Res Clin Oncol 2022; 149:2559-2574. [PMID: 35773429 DOI: 10.1007/s00432-022-04115-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/06/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response. METHODS We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan-Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis. RESULTS For all patients, median overall survival (mOS) was 13 months (95% CI 8-19), and median progression-free survival (mPFS) was 6 months (95% CI 4-10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s), p < 0.0001) and mOS (not met vs. 11 vs. 3 months, p < 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months p = 0.133) and mOS (17 vs. 9 months; p = 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months, p = 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (p = 0.0043). CONCLUSION We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.
Collapse
|
|
35
|
Lei F, Xiong Y, Wang Y, Zhang H, Liang Z, Li J, Feng Y, Hao X, Wang Z. Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents. J Med Chem 2022; 65:7975-7992. [PMID: 35639640 DOI: 10.1021/acs.jmedchem.2c00520] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 μM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 μM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Fang Lei
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yongxia Xiong
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuqing Wang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Honghua Zhang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Ziyi Liang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Junfang Li
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Yiyue Feng
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China
| | - Xiangyong Hao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Zhen Wang
- School of Pharmacy, Lanzhou University, Lanzhou 730000, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.,State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| |
Collapse
|
|
36
|
Hou JY, Xiao YT, Huang JB, Jiang XH, Jiang K, Li X, Xu L, Chen MS. Real-Life Experience of Regorafenib in Patients With Advanced Hepatocellular Carcinoma. Front Pharmacol 2022; 13:917384. [PMID: 35734398 PMCID: PMC9207200 DOI: 10.3389/fphar.2022.917384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The RESORCE trial reported that regorafenib was effective as the second-line treatment for patients with hepatocellular carcinoma (HCC) after progression on sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Objective: We aimed to evaluate the efficacy and safety of regorafenib after disease progression with sorafenib in Chinese patients with advanced HCC. Patients and Methods: A total of 41 patients with advanced HCC who did not respond to sorafenib and followed a regorafenib regimen were enrolled in this retrospective study. Overall survival (OS), progression-free survival (PFS), radiological responses, and adverse events (AEs) were evaluated. Survival curves were compared by using the log-rank test and constructed with the Kaplan–Meier method. Results: The median PFS with regorafenib was 6.6 months (range: 5.0–8.2 months), and the median OS with regorafenib was not reached. The 1-year OS rate of regorafenib was 66.4%. The median OS of sequential sorafenib to regorafenib treatment was 35.3 months [95% confidence interval (CI), 24.3–46.3], and the 2-year OS rate of sequential sorafenib to regorafenib treatment was 74.4%. The most common AEs of regorafenib treatment were elevated aspartate aminotransferase [17/41 patients (41.5%)], elevated alanine aminotransferase [16/41 patients (39%)] and hand-foot syndrome [14/41 patients (34.1%)]. Conclusion: Regorafenib appears to be safe and clinically effective in patients with advanced HCC who progressed on first-line sorafenib.
Collapse
Affiliation(s)
- Jing-Yu Hou
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
| | - Ya-ting Xiao
- School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China
| | - Jing-Bo Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, China
| | - Xin-Hua Jiang
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Kai Jiang
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xun Li
- School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Li Xu
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
| | - Min-Shan Chen
- Department of Liver Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangzhou, China
- *Correspondence: Li Xu, ; Min-Shan Chen,
| |
Collapse
|
|
37
|
Lv YF, Deng ZQ, Bi QC, Tang JJ, Chen H, Xie CS, Liang QR, Xu YH, Luo RG, Tang Q. Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin. Drug Deliv 2022; 29:1743-1753. [PMID: 35635315 PMCID: PMC9176673 DOI: 10.1080/10717544.2022.2081384] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
It is a decade-long controversy that transarterial chemoembolization (TACE) has definite priority over transarterial embolization (TAE) in treating patients with hepatocellular carcinoma (HCC), since HCC cells are regularly resistant to chemotherapy by enhanced expression of proteins that confer drug resistance, and ABC transporters pump the intracellular drug out of the cell. We addressed this issue by modulating the chemo-environment. In an animal model, sevelamer, a polymeric phosphate binder, was introduced as an embolic agent to induce intratumoral inorganic phosphate (Pi) starvation, and trans-arterially co-delivered with doxorubicin (DOX). The new type of TACE was named as DOX-TASE. This Pi-starved environment enhanced DOX tumoral accumulation and retention, and DOX-TASE thereby induced more severe tumor necrosis than that induced by conventional TACE (C-TACE) and drug-eluting bead TACE (D-TACE) at the same dose. In vitro tests showed that Pi starvation increased the cellular accumulation of DOX in an irreversible manner and enhanced cytotoxicity and cell apoptosis by suppressing the expression of ABC transporters (P-glycoprotein (P-gp), BCRP, and MRP1) and the production of intracellular ATP. Our results are indicative of an alternative interventional therapy combining chemotherapy with embolization more effectively.
Collapse
Affiliation(s)
- Yang-Feng Lv
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Zhi-Qiang Deng
- Department of Oncology, The First People's Hospital of Fuzhou, Fuzhou, China
| | - Qiu-Chen Bi
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Jian-Jun Tang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hong Chen
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Chuan-Sheng Xie
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Qing-Rong Liang
- Institute for Advanced Study, Nanchang University, Nanchang, China
| | - Yu-Hua Xu
- Department of Interventional Radiology, Jiangxi Province Chest Hospital, Nanchang, China
| | - Rong-Guang Luo
- Department of Medical Imaging and Interventional Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qun Tang
- School of Public Health, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Institute for Advanced Study, Nanchang University, Nanchang, China.,Department of Oncology, The First People's Hospital of Fuzhou, Fuzhou, China
| |
Collapse
|
|
38
|
Chiu CC, Chen YC, Bow YD, Chen JYF, Liu W, Huang JL, Shu ED, Teng YN, Wu CY, Chang WT. diTFPP, a Phenoxyphenol, Sensitizes Hepatocellular Carcinoma Cells to C2-Ceramide-Induced Autophagic Stress by Increasing Oxidative Stress and ER Stress Accompanied by LAMP2 Hypoglycosylation. Cancers (Basel) 2022; 14:cancers14102528. [PMID: 35626132 PMCID: PMC9139631 DOI: 10.3390/cancers14102528] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/14/2022] [Accepted: 05/16/2022] [Indexed: 12/29/2022] Open
Abstract
Simple Summary Chemotherapy is the major treatment modality for advanced or unresectable hepatocellular carcinoma (HCC). Unfortunately, chemoresistance carries a poor prognosis in HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects; however, recent reports showed ceramide resistance, which limits the development of the ceramide-based cancer treatment diTFPP, a novel phenoxyphenol compound that has been shown to sensitize HCC cells to ceramide treatment. Here, we further clarified the mechanism underlying diTFPP-mediated sensitization of HCC to C2-ceramide-induced stresses, including oxidative stress, ER stress, and autophagic stress, especially the modulation of LAMP2 glycosylation, the lysosomal membrane protein that is crucial for autophagic fusion. This study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics. Abstract Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects. However, recent reports suggest that sphingolipid metabolism in ceramide-resistant cancer cells favors the conversion of exogenous ceramides to prosurvival sphingolipids, conferring ceramide resistance to cancer cells. However, the mechanism underlying ceramide resistance remains unclear. We previously demonstrated that diTFPP, a novel phenoxyphenol compound, enhances the anti-HCC effect of C2-ceramide. Here, we further clarified that treatment with C2-ceramide alone increases the protein level of CERS2, which modulates sphingolipid metabolism to favor the conversion of C2-ceramide to prosurvival sphingolipids in HCC cells, thus activating the unfolded protein response (UPR), which further initiates autophagy and the reversible senescence-like phenotype (SLP), ultimately contributing to C2-ceramide resistance in these cells. However, cotreatment with diTFPP and ceramide downregulated the protein level of CERS2 and increased oxidative and endoplasmic reticulum (ER) stress. Furthermore, insufficient LAMP2 glycosylation induced by diTFPP/ceramide cotreatment may cause the failure of autophagosome–lysosome fusion, eventually lowering the threshold for triggering cell death in response to C2-ceramide. Our study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics.
Collapse
Affiliation(s)
- Chien-Chih Chiu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- The Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yen-Chun Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
| | - Yung-Ding Bow
- Ph.D. Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Jeff Yi-Fu Chen
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
| | - Wangta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
| | - Jau-Ling Huang
- Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan 711, Taiwan;
| | - En-De Shu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
| | - Yen-Ni Teng
- Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan;
| | - Chang-Yi Wu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (C.-C.C.); (Y.-C.C.); (J.Y.-F.C.); (W.L.); (E.-D.S.); (C.-Y.W.)
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
| | - Wen-Tsan Chang
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-312-1101 (ext. 7651); Fax: +886-7-312-6992
| |
Collapse
|
|
39
|
Tan L, Xu Z, Mao Q, Zhou S, Zhu J, Zhang X, Li H. Purified PTEN-Long Induces Liver Cancer Cells to Undergo Autophagy and Apoptosis. Front Surg 2022; 9:767611. [PMID: 35647006 PMCID: PMC9130590 DOI: 10.3389/fsurg.2022.767611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background PTEN-Long is a translational variant of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). This tumor suppressor is frequently lost or mutated and even it has been shown as the determinant in several human tumors. Therefore, we will determine the significant roles of PTEN-Long in the development of liver cancer. Methods In the present study, we characterized the antitumor effects of PTEN-Long and PTEN in proliferation, migration of HepG2 cells, apoptosis and autophagy in liver cancer cells. To extends, we have also measured the effects of purified PTEN and PTEN-Long in the above index of HepG2 cells. Results PTEN and PTEN-Long were ectopic-expressed in HepG2 cells, and their phenotypic effects were recorded. As expected, there was less expression of PTEN-Long and PTEN in liver cancer samples than in paired normal tissues. Ectopic expression of PTEN-Long or PTEN significantly decreased the proliferation and migration of HepG2 cells and increased apoptosis. PTEN ectopic-expression increased the number of GFP-/RFP+-LC3 puncta and levels of beclin-1 and LC3BII/LC3BI, suggesting autophagy induction. Purified PTEN-Long freely entered cells, decreased proliferation, and increased autophagy and apoptosis, while purified PTEN did not. Conclusions Our results identify an antitumor function of purified PTEN-Long and suggest its potential utility for liver cancer treatment.
Collapse
Affiliation(s)
- Lin Tan
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Ningbo University, Ningbo First Hospital, Ningbo, China
| | - Zeping Xu
- Department of Pharmacy, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| | - Qiqi Mao
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| | - Shaocheng Zhou
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| | - Jie Zhu
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| | - Xie Zhang
- Department of Pharmacy, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| | - Hong Li
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Ningbo University, LiHuiLi Hospital, Ningbo, China
| |
Collapse
|
|
40
|
Fan Y, Xue H, Zheng H. Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook. J Hepatocell Carcinoma 2022; 9:233-263. [PMID: 35388357 PMCID: PMC8977221 DOI: 10.2147/jhc.s358082] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/15/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged the culprit of cancer-related mortality worldwide with its dismal prognosis climbing. In recent years, ground-breaking progress has been made in systemic therapy for HCC. Targeted therapy based on specific signaling molecules, including sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab, has been widely used for advanced HCC (aHCC). Immunotherapies such as pembrolizumab and nivolumab greatly improve the survival of aHCC patients. More recently, synergistic combination therapy has boosted first-line (atezolizumab in combination with bevacizumab) and second-line (ipilimumab in combination with nivolumab) therapeutic modalities for aHCC. This review aims to summarize recent updates of systemic therapy relying on the biological mechanisms of HCC, particularly highlighting the approved agents for aHCC. Adjuvant and neoadjuvant therapy, as well as a combination with locoregional therapies (LRTs), are also discussed. Additionally, we describe the promising effect of traditional Chinese medicine (TCM) as systemic therapy on HCC. In this setting, the challenges and future directions of systemic therapy for HCC are also explored.
Collapse
Affiliation(s)
- Yinjie Fan
- College of Integrated Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, 110847, People’s Republic of China
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Hang Xue
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
| | - Huachuan Zheng
- Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China
- Correspondence: Huachuan Zheng, Department of Oncology and Experimental Center, the Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Tel +86-0314-2279458, Fax +86-0314-2279458, Email
| |
Collapse
|
|
41
|
Liu S, Bu X, Kan A, Luo L, Xu Y, Chen H, Lin X, Lai Z, Wen D, Huang L, Shi M. SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback. Cancer Lett 2022; 528:16-30. [PMID: 34958891 DOI: 10.1016/j.canlet.2021.12.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022]
Abstract
Oxaliplatin-based chemotherapy is widely used to treat advanced hepatocellular carcinoma (HCC), but many patients develop drug resistance that leads to tumor recurrence. Cancer stem cells (CSCs) are known to contribute to chemoresistance, the underlying mechanism, however, remains largely unknown. In this study, we discovered a specificity protein 1 (SP1)-induced long noncoding RNA--DPPA2 upstream binding RNA (DUBR) and its high expression in HCC tissues and liver CSCs. DUBR was associated with HCC progression and poor chemotherapy response. Moreover, DUBR facilitated the stemness and oxaliplatin resistance of HCC in vitro and in vivo. Mechanistically, DUBR upregulated cancerous inhibitor of protein phosphatase 2A (CIP2A) expression through E2F1-mediated transcription regulation. DUBR also exerted function by binding microRNA (miR)-520d-5p as a competing endogenous RNA to upregulate CIP2A at mRNA level. CIP2A, in turn, stabilized E2F1 protein and activated the Notch1 signaling pathway, thereby increasing the stemness feature of HCC and leading to chemoresistance. In conclusion, we identified SP1/DUBR/E2F1-CIP2A as a critical axis to activate the Notch1 signaling pathway and promote stemness and chemoresistance of HCC. Therefore, DUBR could be a potential target in HCC treatment.
Collapse
Affiliation(s)
- S Liu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xy Bu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Anna Kan
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - L Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yj Xu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hl Chen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xj Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zc Lai
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ds Wen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lc Huang
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - M Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| |
Collapse
|
|
42
|
Hou Z, Liu J, Jin Z, Qiu G, Xie Q, Mi S, Huang J. Use of chemotherapy to treat hepatocellular carcinoma. Biosci Trends 2022; 16:31-45. [PMID: 35173139 DOI: 10.5582/bst.2022.01044] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatic malignancies remain a global challenge. Hepatocellular carcinoma (HCC) accounts for around 90% of patients with liver cancer and is the sixth most common neoplasm worldwide and the fourth leading cause of cancer-related death. However, the long-term prognosis for HCC remains far from satisfactory, with a late diagnosis and limited treatment. DOX has served as conventional chemotherapy with the longest history of use. Although conventional chemotherapy is being challenged by molecular therapy and immune therapy, there is renewed optimism and interest in both systematic and locoregional therapy. Combined chemotherapy is widely used in clinical practice. In specific terms, FOLFOX can serve as a first-line (category 2B) option as recommended by the 2021 NCCN guidelines, while the efficacy of LTLD plus RFA has been confirmed in the phase III HEAT study. These approaches have challenged the dominant status of molecular therapy in terms of health economics and they have potential benefits in Asia, where HBV-related hepatocellular carcinoma is prevalent. Moreover, locoregional chemotherapy can be achieved with TACE and HAIC (possibly involving FOLFOX, DOX, mitomycin C, cisplatin, epirubicin, etc.). TACE was officially recommended by the 2021 NCCN guidelines for patients with Child-Pugh class B liver disease. In addition, HAIC has demonstrated a potential advantage in preliminary clinical practice, although it hasn't been included in any guidelines. Hence, this review summarizes large-scale trials and studies examining the development and innovative use of chemotherapeutic agents. Mounting clinical evidence warrants an exploration of the efficacy of chemotherapy.
Collapse
Affiliation(s)
- Ziqi Hou
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Liu
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhaoxing Jin
- Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guoteng Qiu
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qingyun Xie
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shizheng Mi
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiwei Huang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
43
|
Sheikh A, Alhakamy NA, Md S, Kesharwani P. Recent Progress of RGD Modified Liposomes as Multistage Rocket Against Cancer. Front Pharmacol 2022; 12:803304. [PMID: 35145405 PMCID: PMC8822168 DOI: 10.3389/fphar.2021.803304] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/22/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is a life-threatening disease, contributing approximately 9.4 million deaths worldwide. To address this challenge, scientific researchers have investigated molecules that could act as speed-breakers for cancer. As an abiotic drug delivery system, liposomes can hold both hydrophilic and lipophilic drugs, which promote a controlled release, accumulate in the tumor microenvironment, and achieve elongated half-life with an enhanced safety profile. To further improve the safety and impair the off-target effect, the surface of liposomes could be modified in a way that is easily identified by cancer cells, promotes uptake, and facilitates angiogenesis. Integrins are overexpressed on cancer cells, which upon activation promote downstream cell signaling and eventually activate specific pathways, promoting cell growth, proliferation, and migration. RGD peptides are easily recognized by integrin over expressed cells. Just like a multistage rocket, ligand anchored liposomes can be selectively recognized by target cells, accumulate at the specific site, and finally, release the drug in a specific and desired way. This review highlights the role of integrin in cancer development, so gain more insights into the phenomenon of tumor initiation and survival. Since RGD is recognized by the integrin family, the fate of RGD has been demonstrated after its binding with the acceptor’s family. The role of RGD based liposomes in targeting various cancer cells is also highlighted in the paper.
Collapse
Affiliation(s)
- Afsana Sheikh
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Nabil A. Alhakamy
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shadab Md
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
- *Correspondence: Prashant Kesharwani,
| |
Collapse
|
|
44
|
Chen CT, Liu TH, Shao YY, Liu KL, Liang PC, Lin ZZ. Revisiting Hepatic Artery Infusion Chemotherapy in the Treatment of Advanced Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:12880. [PMID: 34884684 PMCID: PMC8657421 DOI: 10.3390/ijms222312880] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/25/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatic artery infusion chemotherapy (HAIC) is a well-established and common treatment for advanced hepatocellular carcinoma (HCC), particularly in East Asia. However, HAIC is not recognized internationally. Although several trials have demonstrated the safety and efficacy of HAIC, evidence corroborating its overall survival (OS) benefits compared with standard treatments is insufficient. Nevertheless, HAIC may provide prominent benefits in selected patients such as patients with portal vein thrombosis or high intrahepatic tumor burden. Moreover, HAIC has been combined with several therapeutic agents and modalities, including interferon-alpha, multikinase inhibitors, radiation therapy, and immunotherapy, to augment its treatment efficacy. Most of these combinations appeared to increase overall response rates compared with HAIC alone, but results regarding OS are inconclusive. Two prospective randomized controlled trials comparing HAIC plus sorafenib with sorafenib alone have reported conflicting results, necessitating further research. As immunotherapy-based combinations became the mainstream treatments for advanced HCC, HAIC plus immunotherapy-based treatments also showed encouraging preliminary results. The trials of HAIC were heterogeneous in terms of patient selection, chemotherapy regimens and doses, HAIC combination agent selections, and HAIC technical protocols. These heterogeneities may contribute to differences in treatment efficacy, thus increasing the difficulty of interpreting trial results. We propose that future trials of HAIC standardize these key factors to reveal the clinical value of HAIC-based treatments for HCC.
Collapse
Affiliation(s)
- Ching-Tso Chen
- Department of Oncology, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan;
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
| | - Tsung-Hao Liu
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Yu-Yun Shao
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Kao-Lang Liu
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Cancer Center, Taipei 106328, Taiwan
| | - Po-Chin Liang
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Department of Medical Imaging, National Taiwan University Hospital Hsinchu Branch, Hsinchu 300195, Taiwan
| | - Zhong-Zhe Lin
- Department of Oncology, National Taiwan University Hospital, Taipei 100225, Taiwan; (T.-H.L.); (Y.-Y.S.)
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
- Department of Medical Oncology, National Taiwan University Cancer Center, Taipei 106328, Taiwan
| |
Collapse
|
|
45
|
Natu A, Singh A, Gupta S. Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities. World J Hepatol 2021; 13:1568-1583. [PMID: 34904030 PMCID: PMC8637668 DOI: 10.4254/wjh.v13.i11.1568] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/12/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per year. The diagnosis of hepatocellular carcinoma (HCC) has relied on scanning techniques and serum-based markers such as α-fetoprotein. These measures have limitations due to their detection limits and asymptomatic conditions during the early stages, resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is offered. However, the aid of conventional therapy for patients in the advanced stage of HCC has limited outcomes. Thus, it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the disease. Researchers have used the omics profile of HCC patients for sub-classification of tissues into different groups, which has helped us with prognosis. Despite these efforts, a promising target for treatment has not been identified. The hurdle in this situation is genetic and epigenetic variations in the tumor, leading to disparities in response to treatment. Understanding reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized therapy. Many clinical trials of inhibitors of epigenetic modifiers (also known as epi-drugs) are in progress. Epi-drugs like azacytidine or belinostat are already approved for other cancer treatments. Furthermore, epigenetic changes have also been observed in drug-resistant HCC tumors. In such cases, combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.
Collapse
Affiliation(s)
- Abhiram Natu
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Anjali Singh
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| | - Sanjay Gupta
- Epigenetics and Chromatin Biology Group, Gupta Laboratory, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
- Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, Maharashtra, India
| |
Collapse
|
|
46
|
Li J, Zhou W, Mao Q, Gao D, Xiong L, Hu X, Zheng Y, Xu X. HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway. Front Oncol 2021; 11:739145. [PMID: 34778055 PMCID: PMC8578906 DOI: 10.3389/fonc.2021.739145] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/12/2021] [Indexed: 12/26/2022] Open
Abstract
Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.
Collapse
Affiliation(s)
- Junhua Li
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Wei Zhou
- Basic and Clinical Medical Research Center, Department of Gastroenterology, The First People's Hospital of Jingmen, Jingmen, China
| | - Qiang Mao
- Department of Statistics, The First People's Hospital of Jingmen, Jingmen, China
| | - Dandan Gao
- Department of Infectious Diseases, The First People's Hospital of Jingmen, Jingmen, China
| | - Lin Xiong
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongfa Zheng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
47
|
Chen J, Wang J, Xie F. Comparative efficacy and safety for second-line treatment with ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis. Medicine (Baltimore) 2021; 100:e27013. [PMID: 34559096 PMCID: PMC8462645 DOI: 10.1097/md.0000000000027013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 12/22/2020] [Accepted: 08/05/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment. METHODS A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0. RESULTS A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50-0.90). CONCLUSIONS The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.
Collapse
Affiliation(s)
- Jianxin Chen
- Department of Medical Oncology, Quzhou People′s Hospital, Quzhou, Zhejiang, China
| | - Junhui Wang
- Department of Radiation Oncology, Quzhou People′s Hospital, Quzhou, Zhejiang, China
| | - Fangwei Xie
- Department of Oncology, the 900th Hospital of Joint Logistics Support Forces of Chinese PLA, Fuzhou, China
| |
Collapse
|
|
48
|
Sharifian M, Baharvand P, Moayyedkazemi A. Liver Cancer: New Insights into Surgical and Nonsurgical Treatments. CURRENT CANCER THERAPY REVIEWS 2021. [DOI: 10.2174/1573394717666210219104201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Introduction:
Hepatocellular carcinoma (HCC) is the most common type of liver cancer
that has increased in recent years worldwide. Primary liver cancer or HCC is considered the 5th and
7th most common cancer among men and women, respectively. It is also the second leading cause
of cancer death worldwide. Unfortunately, HCC is frequently diagnosed at an advanced stage when
the majority of the patients do not have access to remedial therapies. Furthermore, current systemic
chemotherapy shows low efficacy and minimum survival benefits. Liver cancer therapy is a multidisciplinary,
multiple-choice treatment based on the complex interaction of the tumour stage, the
degree of liver disease, and the patient's general state of health.
Methods:
In this paper, we reviewed new insights into nonsurgical and surgical treatment of liver
cancer in five English databases, including Scopus, PubMed, Web of Science, EMBASE, and Google
Scholar up to December 2019.
Results:
The results demonstrated, in addition to current therapies such as chemotherapy and surgical
resection, new approaches, including immunotherapy, viral therapy, gene therapy, new ablation
therapies, and adjuvant therapy, are widely used for the treatment of HCC. In recent years, biomaterials
such as nanoparticles, liposomes, microspheres, and nanofibers are also regarded as reliable
and innovative patents for the treatment and study of liver cancers.
Conclusion:
Multidisciplinary and multi-choice treatments and therapies are available for this liver
cancer, while there are differences in liver cancer management recommendations among specialties
and geographic areas. Current results have shown that treatment strategies have been combined
with the advancement of novel treatment modalities. In addition, the use of new approaches with
greater efficacy, such as combination therapy, biomaterials, ablation therapy, etc. can be considered
the preferred treatment for patients.
Collapse
Affiliation(s)
- Masoud Sharifian
- Department of Surgery, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Parastoo Baharvand
- Department of Social Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Alireza Moayyedkazemi
- Department of Internal Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| |
Collapse
|
|
49
|
Lee J, Hwang JH, Chun H, Woo W, Oh S, Choi J, Kim LK. PLEKHA8P1 Promotes Tumor Progression and Indicates Poor Prognosis of Liver Cancer. Int J Mol Sci 2021; 22:7614. [PMID: 34299245 PMCID: PMC8304620 DOI: 10.3390/ijms22147614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) records the second-lowest 5-year survival rate despite the avalanche of research into diagnosis and therapy. One of the major obstacles in treatment is chemoresistance to drugs such as 5-fluorouracil (5-FU), making identification and elucidation of chemoresistance regulators highly valuable. As the regulatory landscape grows to encompass non-coding genes such as long non-coding RNAs (lncRNAs), a relatively new class of lncRNA has emerged in the form of pseudogene-derived lncRNAs. Through bioinformatics analyses of the TCGA LIHC dataset, we have systematically identified pseudogenes of prognostic value. Initial experimental validation of selected pseudogene-derived lncRNA (PLEKHA8P1) and its parental gene (PLEKHA8), a well-studied transport protein in Golgi complex recently implicated as an oncogene in both colorectal and liver cancer, indicates that the pseudogene/parental gene pair promotes tumor progression and that their dysregulated expression levels affect 5-FU-induced chemoresistance in human HCC cell line FT3-7. Our study has thus confirmed cancer-related functions of PLEKHA8, and laid the groundwork for identification and validation of oncogenic pseudogene-derived lncRNA that shows potential as a novel therapeutic target in circumventing chemoresistance induced by 5-FU.
Collapse
MESH Headings
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- Computational Biology/methods
- Databases, Genetic
- Disease Progression
- Drug Resistance, Neoplasm/genetics
- Fluorouracil/pharmacology
- Gene Expression Profiling/methods
- Gene Expression Regulation, Neoplastic/genetics
- Humans
- Kaplan-Meier Estimate
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- MicroRNAs/genetics
- Prognosis
- Pseudogenes
- RNA, Long Noncoding/genetics
Collapse
Affiliation(s)
- Jiyeon Lee
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (J.L.); (W.W.)
| | - Ji-Hyun Hwang
- Interdisciplinary Program of Integrated OMICS for Biomedical Science, The Graduate School, Yonsei University, Seoul 03722, Korea;
| | - Harim Chun
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea;
| | - Wonjin Woo
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (J.L.); (W.W.)
| | - Sekyung Oh
- Department of Medical Science, Catholic Kwandong University College of Medicine, Incheon 22711, Korea;
| | - Jungmin Choi
- Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea;
| | - Lark Kyun Kim
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea; (J.L.); (W.W.)
| |
Collapse
|
|
50
|
Wu TC, Shen YC, Cheng AL. Evolution of systemic treatment for advanced hepatocellular carcinoma. Kaohsiung J Med Sci 2021; 37:643-653. [PMID: 34213069 DOI: 10.1002/kjm2.12401] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/30/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) was considered an inherently refractory tumor in the chemotherapy era (1950-2000). However, systemic therapy has evolved to molecular targeted therapy and immunotherapy, and nine treatment regimens have been approved worldwide during the past 20 years. The approved regimens target tumor angiogenesis or tumor immunity, the two cancer hallmarks. Recently, the combination of atezolizumab (antiprogrammed cell death ligand 1) and bevacizumab (anti-vascular endothelial growth factor) has improved the efficacy of systemic therapy in treating advanced HCC without excessive toxicities or deterioration of quality of life. This review summarizes the major advances in systemic therapy and provides future perspectives on the next-generation systemic therapy for advanced HCC.
Collapse
Affiliation(s)
- Tsung-Che Wu
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ying-Chun Shen
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.,Department of Medical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.,Graduate Institute of Oncology, School of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|