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Li C, Pan J, Shi Z, Zeng X, Xia X, He X, Wang W, Qiu B, Ding W, Huang D. Engineered Endometrial Clear Cell Cancer-on-a-Chip Reveals Early Invasion-Metastasis Cascade of Cancer Cells. Biomater Res 2025; 29:0177. [PMID: 40231208 PMCID: PMC11994883 DOI: 10.34133/bmr.0177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/04/2025] [Accepted: 03/11/2025] [Indexed: 04/16/2025] Open
Abstract
Endometrial clear cell cancer (ECCC) is an extremely rare and highly malignant subtype of endometrial cancer. For most ECCC patients, cancer metastasis is the major cause of death. To date, due to the complexity of cancer evolution and the small number of cases, the metastasis of ECCC at the early stage remains largely unknown. Herein, we modeled the early invasion-metastasis cascade of ECCC by coculturing the ECCC patient-derived tumor cells (PDTCs) and primary human vascular endothelial cells on a microfluidic chip. With the chip, we for the first time replicated the dynamic migration of PDTCs into the surrounding stroma, including the intravasation and extravasation of PDTCs through the capillaries/microvessels, and presented the changes in the morphology and permeability of capillaries, with the decreased diameter and the increased permeability after cancer metastasis. We found that PDTCs were more invasive than the common endometrial adenocarcinoma cells. In addition, we preliminarily explored the inhibition of drugs on the early PDTC infiltration. This study provides new ideas for better understanding of ECCC evolution.
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Affiliation(s)
- Chengpan Li
- Department of Electronic Engineering and Information Science, School of Information Science and Technology,
University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jing Pan
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Zhengdi Shi
- Department of Electronic Engineering and Information Science, School of Information Science and Technology,
University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Xinyan Zeng
- Department of Integrated Traditional Chinese and Western Medicine,
Anhui Medical University, Hefei, Anhui 230032, China
| | - Xiaoping Xia
- Department of Obstetrics and Gynecology, Anhui Provincial Children’s Hospital, Children’s Hospital of Fudan University Anhui Hospital, Children’s Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Xiaogang He
- Department of Urology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Wei Wang
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Bensheng Qiu
- Department of Electronic Engineering and Information Science, School of Information Science and Technology,
University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Weiping Ding
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Dabing Huang
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine,
University of Science and Technology of China, Hefei, Anhui 230001, China
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Wu Y, Xie BB, Zhang BL, Zhuang QX, Liu SW, Pan HM. Apatinib regulates the glycolysis of vascular endothelial cells through PI3K/AKT/PFKFB3 pathway in hepatocellular carcinoma. World J Gastroenterol 2025; 31:102848. [PMID: 40124275 PMCID: PMC11924011 DOI: 10.3748/wjg.v31.i11.102848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/17/2025] [Accepted: 02/11/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy in the Chinese population; the severe vascularization by the tumor makes it difficult to cure. The high incidence and poor survival rates of this disease indicate the search for new therapeutic alternatives. Apatinib became a drug of choice because it inhibits tyrosine kinase activity, mainly through an effect on vascular endothelial growth factor receptor-2, thereby preventing tumor angiogenesis. This mechanism of action makes apatinib effective in the treatment of HCC. AIM To investigate the effect of apatinib on the glycolysis of vascular endothelial cells (VECs). METHODS This present study has investigated the effects of HCC cells on VECs, paying particular attention to changes in the glycolytic activity of VECs. The co-culture system established in the present study examined key cellular functions such as extracellular acidification rate and oxygen consumption rate. It also discusses participation of apatinib in the above processes. Core to the findings is the phosphatidylinositol 3-kinase (PI3K)/AKT/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathway, emphasizing the function of phosphorylated AKT and its interaction with PFKFB3, an essential regulator of glycolysis. In the investigation, molecular mechanisms by which such a pathway could influence the above VECs functions of proliferation, migration, and tube formation were underlined through coimmunoprecipitation analysis. Besides, supplementary in vivo experiments on nude mice provided additional biological relevance to the obtained results. RESULTS The glycolytic metabolism in VECs co-cultured with HCC cells is highly active, and the increased glycolysis in these endothelial cells accelerates the malignant transformation of HCC cells. Apatinib has been shown to inhibit this glycolytic activity in the VECs. It also hinders the development, multiplication, and movement of these cells while encouraging their programmed cell death. Moreover, biological analysis revealed that apatinib mainly influences VECs by regulating the PI3K/AKT signaling pathway. Subsequent research indicated that apatinib blocks the PI3K/AKT/PFKEB3 pathway, which in turn reduces glycolysis in these cells. CONCLUSION Apatinib influences the glycolytic pathway in the VECs of HCC a through the PI3K/AKT/PFKFB3 signaling pathway.
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Affiliation(s)
- Yi Wu
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bin-Bin Xie
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bing-Liang Zhang
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Qing-Xin Zhuang
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Shi-Wei Liu
- Section of Oncology, Ningxia Hui Autonomous Region General Hospital, Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Hong-Ming Pan
- Division of Cancer Medicine, Sir Run Run Shaw Medical Center, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [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: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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Xue Y, Ruan Y, Wang Y, Xiao P, Xu J. Signaling pathways in liver cancer: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:20. [PMID: 38816668 PMCID: PMC11139849 DOI: 10.1186/s43556-024-00184-0] [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: 01/04/2024] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.
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Affiliation(s)
- Yangtao Xue
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yeling Ruan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yali Wang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Peng Xiao
- Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China.
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
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Tan J, Yu X. A pyroptosis-related lncRNA-based prognostic index for hepatocellular carcinoma by relative expression orderings. Transl Cancer Res 2024; 13:1406-1424. [PMID: 38617506 PMCID: PMC11009817 DOI: 10.21037/tcr-23-1804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 01/29/2024] [Indexed: 04/16/2024]
Abstract
Background Hepatocellular carcinoma (HCC) is an invasive malignant tumor, and pyroptosis makes an important contribution to the pathology and progression of liver cancer. Many prognostic models have been proposed for HCC based on the quantitative expression level of candidate genes, which are unsuitable for clinical application due to their vulnerability against experimental batch effects. The aim of this study was to develop a novel pyroptosis-related long non-coding RNA (lncRNA)-based prognostic index (PLPI) for HCC based on relative expression orderings (REOs). Methods Firstly, the pyroptosis-related lncRNAs were identified through the Wilcoxon rank-sum test and gene co-expression analyses. Then, the novel prognostic model PLPI was constructed by pyroptosis-related lncRNA pairs, which were identified by multiple machine learning algorithms. Gene set enrichment, somatic mutation, and drug sensitivity analyses were conducted to measure the differences between high- and low-risk patients. Multiple immune analyses were used to explore the association between PLPI and the immunological microenvironment. Results In this study, a novel prognostic model PLPI based on 10 pyroptosis-related lncRNA pairs was constructed, which was proven to be an independent prognostic risk factor. The receiver operating characteristic (ROC) curves showed that the model had a good prognostic ability in the training, testing, and external set, respectively [5-year area under the curve (AUC) =0.73, 5-year AUC =0.81, 4-year AUC =0.79]. The results of survival, somatic mutation, and immune analyses showed that the patients in the low-risk group had a better prognosis, lower rates of somatic mutation, and better immune cell infiltration. Personalized chemotherapeutic drugs were also identified for the patients with HCC. Conclusions The novel PLPI not only greatly predicted the prognosis of patients with HCC but could also offer novel ideas and approaches for the therapeutic management of HCC.
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Affiliation(s)
- Jinhua Tan
- School of Sciences, Shanghai Institute of Technology, Shanghai, China
| | - Xiaoqing Yu
- School of Sciences, Shanghai Institute of Technology, Shanghai, China
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Duan XP, Qin BD, Jiao XD, Liu K, Wang Z, Zang YS. New clinical trial design in precision medicine: discovery, development and direction. Signal Transduct Target Ther 2024; 9:57. [PMID: 38438349 PMCID: PMC10912713 DOI: 10.1038/s41392-024-01760-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 03/06/2024] Open
Abstract
In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional "one-size-fits-all" trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the "Precision Pro", "Dynamic Precision", and "Intelligent Precision". This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.
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Affiliation(s)
- Xiao-Peng Duan
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Bao-Dong Qin
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiao-Dong Jiao
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Ke Liu
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhan Wang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yuan-Sheng Zang
- Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai, China.
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Luo X, He X, Zhang X, Zhao X, Zhang Y, Shi Y, Hua S. Hepatocellular carcinoma: signaling pathways, targeted therapy, and immunotherapy. MedComm (Beijing) 2024; 5:e474. [PMID: 38318160 PMCID: PMC10838672 DOI: 10.1002/mco2.474] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 02/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a high mortality rate. It is regarded as a significant public health issue because of its complicated pathophysiology, high metastasis, and recurrence rates. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Traditional treatment methods such as surgical resection, radiotherapy, chemotherapy, and interventional therapies have limited therapeutic effects for HCC patients with recurrence or metastasis. With the development of molecular biology and immunology, molecular signaling pathways and immune checkpoint were identified as the main mechanism of HCC progression. Targeting these molecules has become a new direction for the treatment of HCC. At present, the combination of targeted drugs and immune checkpoint inhibitors is the first choice for advanced HCC patients. In this review, we mainly focus on the cutting-edge research of signaling pathways and corresponding targeted therapy and immunotherapy in HCC. It is of great significance to comprehensively understand the pathogenesis of HCC, search for potential therapeutic targets, and optimize the treatment strategies of HCC.
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Affiliation(s)
- Xiaoting Luo
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Xin He
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Xingmei Zhang
- Department of NeurobiologySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina
| | - Xiaohui Zhao
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Yuzhe Zhang
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Yusheng Shi
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Shengni Hua
- Department of Radiation OncologyZhuhai People's HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
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Kang M, Xue F, Xu S, Shi J, Mo Y. Effectiveness and safety of anlotinib with or without S-1 in the treatment of patients with advanced hepatocellular carcinoma in a Chinese population: a prospective, phase 2 study. Radiol Oncol 2023; 57:405-410. [PMID: 37494583 PMCID: PMC10476909 DOI: 10.2478/raon-2023-0036] [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: 02/16/2023] [Accepted: 06/15/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND The aim of the study was to observe the safety and efficacy of anlotinib (ANL) alone or combined with S-1 in the first-line treatment of advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS Fifty-four patients with untreated advanced HCC who could not be resected were randomly divided into the ANL group (n = 27) and ANL+S-1 group (n = 27). The ANL group was given 10 mg ANL orally once a day for 14 consecutive days, stopped for 1 week, and repeated every 21 days. The ANL+S-1 group was given 10 mg ANL once a day orally and 40 mg S-1 twice a day orally for 14 consecutive days, stopped for 1 week, repeated every 21 days. All patients were treated until the disease progressed or toxicity became unacceptable. For patients who could not tolerate adverse reactions, the ANL dose should be reduced to 8 mg per day. CT or MRI was reviewed every 6 weeks to evaluate the efficacy. RESULTS A total of 44 patients were included in the results analysis, including 22 patients in the ANL group and 22 patients in the ANL+S-1 group. In the ANL group, the objective response rate (ORR) was 4.5% (1/22), the disease control rate (DCR) was 77.3% (17/22), the median progression-free survival (PFS) was 4.2 months (95% CI: 3.6-6.0) and the median overall survival (mOS) was 7.0 months (95% CI: 6.3-9.0). In the ANL+S-1 group, the ORR was 18.2% (4/22), the DCR was 59.1% (13/22), the median PFS was 4.0 months (95% CI: 3.6-5.4) and the mOS was 6.0 months (95% CI: 5.5-7.4). There was no significant difference in ORR (p = 0.345) or DCR (p = 0.195) between the two groups. Adverse reactions were mainly hypertension, anorexia, fatigue, liver transaminase heightened and hand and foot skin reaction. CONCLUSIONS ANL monotherapy was effective in the treatment of advanced HCC, and adverse reactions have been able to tolerated.
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Affiliation(s)
- Mafei Kang
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Feng Xue
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Shengyuan Xu
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Jieqiong Shi
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
| | - Yunyan Mo
- Department of Medical Oncology, Affiliated Hospital of Guilin Medical University, Guangxi Guilin, China
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Xie S, Wang M, Zeng C, Ou Y, Zhao L, Wang D, Chen L, Kong F, Yi D. Research progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma. Front Oncol 2023; 13:1197698. [PMID: 37305582 PMCID: PMC10248438 DOI: 10.3389/fonc.2023.1197698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/16/2023] [Indexed: 06/13/2023] Open
Abstract
Hepatocellular carcinoma is a common gastrointestinal malignancy with a high mortality rate and limited treatment options. Molecularly targeted drugs combined with immune checkpoint inhibitors have shown unique advantages over single-agent applications, significantly prolonging patient survival. This paper reviews the research progress of molecular-targeted drugs combined with immune checkpoint inhibitors in the treatment of hepatocellular carcinoma and discusses the effectiveness and safety of the combination of the two drugs to provide a reference for the further application of molecular-targeted drugs combined with immune checkpoint inhibitors in clinical practice.
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Affiliation(s)
| | | | | | | | | | | | - Liwei Chen
- Department of Oncology, The First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Shreedhar Reddy T, Rai S, Kumar Koppula S. One‐Pot Synthesis of Isatin‐Pyrazole Hybrids as VEGFR‐2 Inhibitors and Molecular Docking Studies. ChemistrySelect 2023. [DOI: 10.1002/slct.202204327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- T. Shreedhar Reddy
- Department of Chemistry GITAM Deemed to be University, Hyderabad campus, Rudraram, Sangareddy Hyderabad 502329 Telangana India
- Medicinal Chemistry Division Aragen Life Sciences Pvt. Ltd., IDA Nachram Hyderabad 500076 India
| | - Sanjay Rai
- Medicinal Chemistry Division Aragen Life Sciences Pvt. Ltd., IDA Nachram Hyderabad 500076 India
| | - Shiva Kumar Koppula
- Department of Chemistry GITAM Deemed to be University, Hyderabad campus, Rudraram, Sangareddy Hyderabad 502329 Telangana India
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11
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Hagras M, Saleh MA, Ezz Eldin RR, Abuelkhir AA, Khidr EG, El-Husseiny AA, El-Mahdy HA, Elkaeed EB, Eissa IH. 1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies. J Enzyme Inhib Med Chem 2022; 37:380-396. [PMID: 34923885 PMCID: PMC8725909 DOI: 10.1080/14756366.2021.2015342] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/23/2021] [Accepted: 12/01/2021] [Indexed: 01/09/2023] Open
Abstract
In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (5, 8, 15, 16, 17, and 18) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.
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Affiliation(s)
- Mohamed Hagras
- Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Marwa A. Saleh
- Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Rogy R. Ezz Eldin
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Port Said University, Port Said, Egypt
| | | | - Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Ahmed A. El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Hesham A. El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Eslam B. Elkaeed
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia
| | - Ibrahim H. Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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12
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Design, Synthesis, and In Vitro Antiproliferative Screening of New Hydrazone Derivatives Containing cis-(4-Chlorostyryl) Amide Moiety. Symmetry (Basel) 2022. [DOI: 10.3390/sym14112457] [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] Open
Abstract
Hydrazones are regarded as a distinctive category of organic compounds because of their tremendous characteristics and potential uses in analytical, chemical, and medicinal chemistry. In the present study, a new series of Hydrazone Derivatives bearing cis-(4-chlorostyryl) amide moiety were designed and synthesized. In vitro cytotoxicity screening showed that compounds 3i, 3l, 3m, and 3n revealed potent anticancer activity against MCF-7 cancer cell line with IC50 values between 2.19–4.37 μM compared with Staurosporin as a reference compound. The antiproliferative activity of these compounds appears to be correlated well with their ability to inhibit the VEGFR-2 kinase enzyme. Activation of the damage response pathway leads to cellular cycle arrest at the G1 phase. Fluorochrome Annexin V/PI staining indicated that cell death proceeds through the apoptotic pathway mechanism. The mechanistic pathway was confirmed by a significant increase in the level of active caspase 9 compared with control untreated MCF-7 cells.
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13
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Li N, Yang P, Fang J. Transarterial chemoembolization (TACE) plus apatinib vs. TACE alone for hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2022; 46:102022. [PMID: 36089248 DOI: 10.1016/j.clinre.2022.102022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/27/2021] [Accepted: 10/08/2021] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Transarterial chemoembolization (TACE) is a common therapy for hepatocellular carcinoma (HCC), while TACE-induced tumor angiogenesis would increase progression and metastasis risk. Besides, apatinib possesses the capability of inhibiting tumor angiogenesis. Thus, this study aimed to explore the efficacy and safety of TACE plus apatinib compared to TACE alone in HCC patients. METHODS Ninety-six intermediate-advanced HCC patients were retrospectively enrolled and classified into TACE plus apatinib group (N = 45) and TACE group (N = 51) based on the treatment. RESULTS Objective response rate (68.9% vs. 47.1%) was increased in TACE plus apatinib group than in TACE group (P = 0.031). However, no difference was found in disease-control rate between groups (95.6% vs. 86.3%) (P = 0.167). Progression-free survival (PFS) (median PFS (95% confidence interval (CI)): 20.0 (13.2-26.8) vs. 14.0 (8.3-19.7) months) was enhanced in TACE plus apatinib group compared with TACE group (P = 0.030), while no difference was found in overall survival between groups (P = 0.060). Additionally, multivariate Cox's analysis presented that TACE plus apatinib (vs. TACE alone) independently associated with prolonged PFS (P = 0.043, hazard ratio = 0.617). Regarding safety profile, no difference in liver function indexes (albumin, total bilirubin, alanine aminotransferase and aspartate aminotransferase) was found after treatment between two groups; meanwhile, only the incidence of hand-foot skin reaction (24.4% vs. 7.8%) was higher in TACE plus apatinib group compared to TACE group (P = 0.025), while no difference was found in other adverse events between two groups (all P > 0.05). CONCLUSION TACE plus apatinib illustrates a superior efficacy with tolerable safety than TACE alone in intermediate-advanced HCC patients.
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Affiliation(s)
- Ningjie Li
- Department of Radiology, Wuhan Sixth Hospital, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Ping Yang
- Department of Ultrasonography, Wuhan Sixth Hospital, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Jun Fang
- Department of Radiology, Wuhan Sixth Hospital, Affiliated Hospital of Jianghan University, Wuhan, China.
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14
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Zhang L, Cheng C, Li B, Chen J, Peng J, Cao Y, Yue Y, Mai X, Yu D. Combined clinical features and MRI parameters for the prediction of VEGFR2 in hepatocellular carcinoma patients. Front Oncol 2022; 12:961530. [PMID: 36313714 PMCID: PMC9608502 DOI: 10.3389/fonc.2022.961530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 10/03/2022] [Indexed: 01/17/2023] Open
Abstract
PURPOSE To develop a prediction model for estimating the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC) patients using clinical features and the contrast-enhanced MRI Liver Imaging Reporting and Data System (LI-RADS). METHODS A total of 206 HCC patients were subjected to preoperative contrast-enhanced MRI, radical resection, and VEGFR2 immunohistochemistry labeling. The intensity of VEGFR2 expression was used to split patients into either the positive group or the negative group. For continuous data, the Mann-Whitney U test was employed, and for categorical variables, the χ2 test was utilized. RESULTS VEGFR2-positivity was identified in 41.7% (86/206) of the patients. VEGFR2-positive HCCs were confirmed by higher serum alpha-fetoprotein (AFP) levels, larger tumor dimensions (either on MRI or upon final pathology), and a higher LI-RADS score (all p < 0.001). LI-RADS scores and AFP levels were independent predictors for high VEGFR2 expression. These two parameters were used to establish a VEGFR2-positive risk nomogram, which was validated to possess both good discrimination and calibration. The area under the curve was 0.830 (sensitivity 83.6%, specificity 72.5%) and the mean absolute error was 0.021. The threshold probabilities ranged between 0.07 and 0.95, and usage of the model contributed net benefits. CONCLUSION A nomogram including clinical features and contrast-enhanced MRI parameters was developed and was demonstrably effective at predicting VEGFR2 expression in HCC patients.
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Affiliation(s)
- Laizhu Zhang
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chunxiao Cheng
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Binghua Li
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun Chen
- Department of Pathology, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jin Peng
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yajuan Cao
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yang Yue
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiaoli Mai
- Department of Radiology, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Decai Yu
- Hepatobiliary and Pancreatic Center & Liver Transplantation Center, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
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15
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Liu ZY, Kan XF, Zhang LJ, Makamure J, Li Q, Zhao D, Zhou GF, Feng GS, Zheng CS, Liang B. Transarterial Chemoembolization Combined with Apatinib for Treatment of Advanced Hepatocellular Carcinoma: Analysis of Survival and Prognostic Factors. Curr Med Sci 2022; 42:1015-1021. [DOI: 10.1007/s11596-022-2620-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 06/21/2022] [Indexed: 11/29/2022]
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16
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Synergistic Lethality Effects of Apatinib and Homoharringtonine in Acute Myeloid Leukemia. JOURNAL OF ONCOLOGY 2022; 2022:9005804. [PMID: 36081666 PMCID: PMC9448536 DOI: 10.1155/2022/9005804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/05/2022] [Indexed: 11/26/2022]
Abstract
Purpose The significance of vascular endothelial growth factor receptor (VEGFR)-2 in numerous solid tumors and acute myeloid leukemia (AML) has been demonstrated, but Apatinib remains largely unexplored. In this study, whether Apatinib combined with homoharringtonine (HHT) kills AML cell lines and its possible mechanisms have been explored. Methods AML cell lines were treated with Apatinib and HHT in different concentrations with control, Apatinib alone, HHT alone, and Apatinib combined with HHT. The changes of IC50 were measured by CCK8 assay, and apoptosis rate, cell cycle, and the mitochondrial membrane potential in each group were measured by flow cytometry. Finally, the possible cytotoxicity mechanism was analyzed by Western blotting. Results Our results noted that Apatinib combined with HHT remarkably inhibited cell proliferation, reduced the capacity of colony-forming, and induced apoptosis and cell cycle arrest in AML cells. Mechanistically, Apatinib and HHT play a role as a suppressor in the expression of VEGFR-2 and the downstream signaling cascades, such as the PI3K, MAPK, and STAT3 pathways. Conclusion Our preclinical data demonstrate that Apatinib combined with HHT exerts a better antileukemia effect than Apatinib alone by inhibiting the VEGFR-2 signaling pathway, suggesting the potential role of Apatinib and HHT in the treatment of AML. This study provides clinicians with innovative combination therapies and new therapeutic targets for the treatment of AML.
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17
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Kamal MA, Mandour YM, Abd El-Aziz MK, Stein U, El Tayebi HM. Small Molecule Inhibitors for Hepatocellular Carcinoma: Advances and Challenges. Molecules 2022; 27:5537. [PMID: 36080304 PMCID: PMC9457820 DOI: 10.3390/molecules27175537] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 12/12/2022] Open
Abstract
According to data provided by World Health Organization, hepatocellular carcinoma (HCC) is the sixth most common cause of deaths due to cancer worldwide. Tremendous progress has been achieved over the last 10 years developing novel agents for HCC treatment, including small-molecule kinase inhibitors. Several small molecule inhibitors currently form the core of HCC treatment due to their versatility since they would be more easily absorbed and have higher oral bioavailability, thus easier to formulate and administer to patients. In addition, they can be altered structurally to have greater volumes of distribution, allowing them to block extravascular molecular targets and to accumulate in a high concentration in the tumor microenvironment. Moreover, they can be designed to have shortened half-lives to control for immune-related adverse events. Most importantly, they would spare patients, healthcare institutions, and society as a whole from the burden of high drug costs. The present review provides an overview of the pharmaceutical compounds that are licensed for HCC treatment and other emerging compounds that are still investigated in preclinical and clinical trials. These molecules are targeting different molecular targets and pathways that are proven to be involved in the pathogenesis of the disease.
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Affiliation(s)
- Monica A. Kamal
- The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo-GUC, Cairo 11835, Egypt
| | - Yasmine M. Mandour
- School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo 11578, Egypt
| | - Mostafa K. Abd El-Aziz
- The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo-GUC, Cairo 11835, Egypt
| | - Ulrike Stein
- Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Hend M. El Tayebi
- The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo-GUC, Cairo 11835, Egypt
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18
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New application of novel tetrazine derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents. Future Med Chem 2022; 14:1251-1266. [PMID: 35950486 DOI: 10.4155/fmc-2022-0054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: A novel series of s-tetrazine derivatives was designed as a new scaffold and synthesized efficiently as VEGFR-2 inhibitors for the first time. Methodology & results: The inhibitory activities of the new compounds were tested by MTT assay and enzyme assay, respectively. Western blot assay, cell apoptosis assay and cell migration assay were carried out to study the action mechanism of them. All the synthesized compounds showed evident VEGFR-2 inhibitory activities (IC50 in the range of 88.53-257.55 nM). Compounds 23h, 25d, 26e and 27c showed excellent anti-proliferative activities against the four tested cell lines and were better than sorafenib basically. Conclusion: Compounds with good activities based on this novel scaffold can be screened successfully.
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19
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Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer. Cell Death Dis 2022; 13:636. [PMID: 35864117 PMCID: PMC9304404 DOI: 10.1038/s41419-022-05079-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 01/21/2023]
Abstract
The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
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20
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Sun Y, Zhang W, Bi X, Yang Z, Tang Y, Jiang L, Bi F, Chen M, Cheng S, Chi Y, Han Y, Huang J, Huang Z, Ji Y, Jia L, Jiang Z, Jin J, Jin Z, Li X, Li Z, Liang J, Liu L, Liu Y, Lu Y, Lu S, Meng Q, Niu Z, Pan H, Qin S, Qu W, Shao G, Shen F, Song T, Song Y, Tao K, Tian A, Wang J, Wang W, Wang Z, Wu L, Xia F, Xing B, Xu J, Xue H, Yan D, Yang L, Ying J, Yun J, Zeng Z, Zhang X, Zhang Y, Zhang Y, Zhao J, Zhou J, Zhu X, Zou Y, Dong J, Fan J, Lau WY, Sun Y, Yu J, Zhao H, Zhou A, Cai J. Systemic Therapy for Hepatocellular Carcinoma: Chinese Consensus-Based Interdisciplinary Expert Statements. Liver Cancer 2022; 11:192-208. [PMID: 35949289 PMCID: PMC9218612 DOI: 10.1159/000521596] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/15/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China, it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. SUMMARY For more than a decade, sorafenib, a small-molecular-weight tyrosine kinase inhibitor (SMW-TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date, no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists, radiologists, pathologists, orthopedic surgeons, traditional Chinese medicine physicians, and interventional radiologists has reviewed the literature in order to develop updated treatment regimens. KEY MESSAGES Panel consensus statements for the appropriate use of new molecular -targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation, and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.
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Affiliation(s)
- Yongkun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhengqiang Yang
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Tang
- Department of GCP Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Jiang
- Department of Diagnostic Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Feng Bi
- Department of Medical Oncology, West China Hospital, Chengdu, China
| | - Minshan Chen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuqun Cheng
- The Six Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yihebali Chi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Han
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Huang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhen Huang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Liqun Jia
- Department of Oncology of Integrative Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Zhichao Jiang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Jin
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhengyu Jin
- Department of Radiology, Peking Union Medical College Hospital, Beijing, China
| | - Xiao Li
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyu Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Liang
- Department of Medical Oncology, Peking University International Hospital, Beijing, China
| | - Lianxin Liu
- Department of Hepatic Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yinying Lu
- Department of Comprehensive Liver Cancer Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shichun Lu
- Department of Hepatobiliary Surgery, First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Chinese PLA Medical School, Beijing, China
| | - Qinghua Meng
- Department of Clinical Care Medicine of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zuoxing Niu
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Jinan, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shukui Qin
- Department of Medical Oncology, PLA Cancer Centre of Nanjing Bayi Hospital, Nanjing, China
| | - Wang Qu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guoliang Shao
- Department of Interventional Radiology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China
| | - Feng Shen
- Department of Hepatic Surgery IV, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Tianqiang Song
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Yan Song
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Aiping Tian
- Department of Traditional Chinese Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianhua Wang
- Department of Interventional Radiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Wenling Wang
- Department of Radiology, The Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang, China
| | - Zhe Wang
- Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Liqun Wu
- Department of Hepatic Biliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, The Southwest Hospital of AMU, Chongqing, China
| | - Baocai Xing
- Department of Hepatobiliary and Pancreatic Surgery Unit I, Beijing Cancer Hospital, Beijing, China
| | - Jianming Xu
- Department of Gastrointestinal Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Huadan Xue
- Department of Radiology, Peking Union Medical College Hospital, Beijing, China
| | - Dong Yan
- Department of Interventional Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingping Yun
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhaochong Zeng
- Department of Radiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China
| | - Yanqiao Zhang
- Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianjun Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianguo Zhou
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Zhu
- Department of Interventional Radiology, Beijing Cancer Hospital, Beijing, China
| | - Yinghua Zou
- Department of Interventional Radiology, Peking University First Hospital, Beijing, China
| | - Jiahong Dong
- Department of Hepatopancreatobiliary Surgery, Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Jia Fan
- Department of Liver Surgery, Zhongshan Hospital Fudan University, Shanghai, China
| | - Wan Yee Lau
- Department of Hepatic Biliary Pancreatic Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Yan Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinming Yu
- Department of Radiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Taian, China
| | - Hong Zhao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianqiang Cai
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Ke W, Zhang L, Zhao X, Lu Z. p53 m 6A modulation sensitizes hepatocellular carcinoma to apatinib through apoptosis. Apoptosis 2022; 27:426-440. [PMID: 35503144 DOI: 10.1007/s10495-022-01728-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2022] [Indexed: 11/02/2022]
Abstract
Hepatocellular carcinoma (HCC) is insidious and prone to metastasis and recurrence. Currently, no effective treatment is available for HCC. Furthermore, HCC does not respond to various radio- and chemotherapies, and the molecular mechanism of treatment resistance is unclear. Here, we found that p53 n6-methyladenosine (m6A) played a decisive role in regulating HCC sensitivity to chemotherapy via the p53 activator RG7112 and the vascular endothelial growth factor receptor inhibitor apatinib. Our results reveal that p53 activation plays a crucial role in chemotherapy-induced apoptosis and reducing cell viability. Moreover, decreasing m6A methyltransferase (e.g., methyltransferase-like 3, METTL3) expression through chemotherapeutic drug combinations reduced p53 mRNA m6A modification. p53 mRNA m6A modification blockage induced by S-adenosyl homocysteine or siRNA-mediated METTL3 inhibition enhanced HCC sensitivity to chemotherapy. Importantly, we observed that downregulation of METTL3 and upregulation of p53 expression by oral administration of chemotherapy drugs triggered apoptosis and xenograft tumor growth inhibition in nude mice. Based on these findings, we hypothesize that a METTL3-m6A-p53 axis could be a potential target in HCC therapy.
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Affiliation(s)
- Weiwei Ke
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Linlin Zhang
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xiangxuan Zhao
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Zaiming Lu
- Department of Radiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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22
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Liu Q, Xu JY, Xu YH, Chen M, Deng LC, Wu JP, Zhou T, Zhang LQ, Tan J, Pu XX, Shang YL, Hua J, Li YQ, Cai W, Gu YL, Peng XC, Chan PC, Jabbour SK, Nam HS, Hua D. Efficacy and safety of apatinib as second or later-line therapy in extensive-stage small cell lung cancer: a prospective, exploratory, single-arm, multi-center clinical trial. Transl Lung Cancer Res 2022; 11:832-844. [PMID: 35693282 PMCID: PMC9186180 DOI: 10.21037/tlcr-22-313] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/18/2022] [Indexed: 11/26/2022]
Abstract
Background A paucity of strategies exist for extensive-stage small cell lung cancer (ES-SCLC) patients who fail the first-line chemotherapy. Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), which has been demonstrated to have active anti-tumor activity in ES-SCLC when used only or combined with PD-1 inhibitors or chemotherapy with good tolerance. However, the efficacy and safety of apatinib monotherapy is unclear in second-line or beyond treatment of ES-SCLC. Methods In this prospective, exploratory, single-arm, multi-center study, eligible patients were aged 18 years or older with histologically confirmed ES-SCLC, and had progressed on, or were intolerant to previous systemic treatment. Patients received apatinib 500 mg (orally qd, every 4 weeks a cycle). The efficacy was assessed after 1 cycle and then every 2 cycles based on computed tomography imaging per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (NCI-CTCAE 4.0). This study is registered in the Chinese Clinical Trial Registry, number ChiCTR-OPC-17013964. Results From 28 July 2017 to 21 June 2019, 62 patients were screened for eligibility, among whom 57 patients were available for efficacy and safety analysis. The objective response rate (ORR) was 14.3% and disease control rate (DCR) was 79.6%. The median PFS was 5.6 months [95% confidence interval (CI): 3.3-8.0 months] and the median overall survival (OS) was 11.2 months (95% CI: 7.5-24.0 months). Among the participants who received apatinib as second-line treatment, the median PFS and OS were 6.1 months (95% CI: 2.6-7.6 months) and 12.0 months (95% CI: 7.9 months to not reached), respectively. The most common AEs of all grades were anemia (36.8%), hypertension (33.3%), fatigue (31.6%), blood bilirubin increased (22.8%), elevated transaminase (19.3%), and hand-foot syndrome (17.54%). Grade 3 AEs included 2 (3.5%) cases of hypertension and 1 (1.8%) case of fatigue. No grade 4/5 AEs were observed. Conclusions Apatinib showed encouraging anti-tumor activity in pretreated ES-SCLC patients with tolerable toxicities. Further larger scale studies are warranted to demonstrate the efficacy of apatinib.
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Affiliation(s)
- Quan Liu
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Juan-Ying Xu
- Department of Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Ye-Hong Xu
- Department of Respiratory Medicine, Anhui Provincial Cancer Hospital, Hefei, China
| | - Meng Chen
- Department of Radiation Oncology, Xuzhou Central Hospital, Xuzhou, China
| | - Li-Chun Deng
- Department of Oncology, Jiangyin People’s Hospital, Wuxi, China
| | - Jian-Ping Wu
- Department of Oncology, Changshu No. 1 People’s Hospital, Suzhou, China
| | - Tong Zhou
- Department of Medical Oncology, Changzhou Tumor Hospital, Changzhou, China
| | - Li-Qin Zhang
- Department of Respiratory Medicine, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Jie Tan
- Department of Oncology, Suzhou Municipal Hospital, Suzhou, China
| | - Xing-Xiang Pu
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha, China
| | - Yu-Long Shang
- Department of Respiratory Medicine, Xuzhou Cancer Hospital, Xuzhou, China
| | - Jun Hua
- Cardio-Thoracic Surgery, The Second People’s Hospital of Wuxi, Wuxi, China
| | - Yuan-Qin Li
- Department of Respiratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wei Cai
- Department of Oncology, The First People’s Hospital of Wujiang, Suzhou, China
| | - Yu-Lan Gu
- Department of Oncology, Changshu No. 2 People’s Hospital, Suzhou, China
| | - Xing-Chen Peng
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Po-Chung Chan
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, China
| | - Salma K. Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
| | - Hae-Seong Nam
- Division of Pulmonology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Dong Hua
- Department of Oncology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China
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23
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Chi Y, Wang F, Zhang Y, Shan Z, Tao W, Lian Y, Xin D, Fan Q, Sun Y. Apatinib inhibits tumour progression and promotes antitumour efficacy of cytotoxic drugs in oesophageal squamous cell carcinoma. J Cell Mol Med 2022; 26:1905-1917. [PMID: 35315581 PMCID: PMC8980885 DOI: 10.1111/jcmm.17209] [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: 04/20/2020] [Revised: 12/26/2021] [Accepted: 12/31/2021] [Indexed: 12/12/2022] Open
Abstract
Apatinib, a highly selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), inhibits the angiogenesis of tumours. The function and mechanism of apatinib in oesophageal squamous cell carcinoma (ESCC) remain unknown. In present study, we found that the development of ESCC in patients was controlled by treatment of combination of apatinib and a chemotherapeutic drug. Moreover, apatinib efficiently promotes cell apoptosis, inhibits cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and activity of the Akt/mTOR pathway in ESCC cells. Western blot analysis showed that apatinib significantly increased vimentin protein levels, decreased Bcl2, matrix metalloproteinase 9 (MMP9), E-cadherin, p-Akt and p-mTOR protein levels in ESCC cells. Furthermore, apatinib enhanced chemosensitivity of cytotoxic drugs paclitaxel (TAX), 5-fluorouracil (5-FU) and cisplatin (DDP) by upregulating expression of vimentin protein, and downregulating expression of Bcl2, MMP9 and E-cadherin protein in vitro. Compared with single-agent groups, the combination of apatinib with each chemotherapeutic drug significantly repressed tumour growth and angiogenesis through blocking the expression of Ki67 and VEGFR-2 in vivo. Taken together, apatinib efficiently inhibits cell growth through blocking Bcl2 and Akt/mTOR pathway, and suppresses metastasis via inhibiting MMP9 and EMT in ESCC cells. Apatinib promoted antitumour effect of chemotherapeutic agents through promoting cell apoptosis and inhibiting EMT and angiogenesis in ESCC.
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Affiliation(s)
- Yanyan Chi
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feng Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yana Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengzheng Shan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weili Tao
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujin Lian
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dao Xin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingxia Fan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Sun
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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24
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Ju S, Wang W, Chen P, Li F, Li H, Wang M, Han X, Ren J, Duan X. Drug-eluting bead transarterial chemoembolization followed by apatinib is effective and safe in treating hepatocellular carcinoma patients with BCLC stage C. Clin Res Hepatol Gastroenterol 2022; 46:101859. [PMID: 34999249 DOI: 10.1016/j.clinre.2022.101859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/14/2021] [Accepted: 12/31/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The present study aimed to evaluate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) followed by apatinib in treating hepatocellular carcinoma (HCC) patients with Barcelona Clinic Liver Cancer (BCLC) stage C. METHODS Totally, 110 HCC patients with BCLC stage C treated with DEB-TACE followed by apatinib were consecutively enrolled. Treatment response (including complete response rate (CR), objective response rate (ORR) and disease control rate (DCR)), survival data (progression-free survival (PFS), overall survival (OS)), and adverse events were documented during the follow-up. RESULTS CR, ORR and DCR were 25.5%, 77.2% and 79.1% at 3 months, then were 29.1%, 59.1% and 71.0% at 6 months, respectively. Regarding survival, median PFS (95%CI) was 6.3 (5.0-7.7) months, meanwhile 1-year and 2-year PFS were 19.8% and 3.3%, respectively; median OS (95%CI) was 16.9 (10.2-23.7) months, then 1-year, 2-year and 3-year OS were 66.5%, 34.7% and 14.2%, respectively. Further subgroup analysis indicated that nodule size, Child-Pugh stage, Eastern Cooperative Oncology Group performance status score and level of portal vein invasion were negatively correlated with PFS or OS, which were further validated by univariate and multivariate Cox's regression analysis. Most adverse events by DEB-TACE and apatinib treatment were mild and well-tolerable. CONCLUSION DEB-TACE followed by apatinib is effective and safe in treating BCLC stage C HCC patients, indicating its role as an acceptable option in HCC management.
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Affiliation(s)
- Shuguang Ju
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Wenhui Wang
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Pengfei Chen
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Fangzheng Li
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Hao Li
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Manzhou Wang
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
| | - Jianzhuang Ren
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China.
| | - Xuhua Duan
- Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China.
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25
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Alsaedi AM, Almehmadi SJ, Farghaly TA, Harras MF, Khalil KD. VEGFR2 and hepatocellular carcinoma inhibitory activities of trisubstituted triazole derivatives. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2021.131832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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26
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Li N, Chen J. Efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) plus apatinib versus DEB-TACE alone in treating huge hepatocellular carcinoma patients. Ir J Med Sci 2022; 191:2611-2617. [PMID: 35083645 PMCID: PMC9671984 DOI: 10.1007/s11845-021-02884-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/07/2021] [Indexed: 12/11/2022]
Abstract
Background Apatinib, a tyrosine kinase inhibitor, inhibits angiogenesis under the tumor hypoxic environment induced by drug-eluting bead transarterial chemoembolization (DEB-TACE), which is hypothesized to have synergic effect with DEB-TACE in treating hepatocellular carcinoma (HCC) patients. This study aimed to evaluate the efficacy and safety of DEB-TACE plus apatinib in treating huge HCC patients. Methods Totally, 73 huge HCC patients (tumor size > 10 cm) were screened and divided into DEB-TACE plus apatinib group (N = 34) or DEB-TACE group (N = 39) based on the treatment they received. Their clinical response and adverse events were retrieved. The progression-free survival (PFS) and overall survival (OS) were calculated. Results DEB-TACE plus apatinib achieved a trend of higher objective response rate (64.7% vs. 43.6%, P = 0.071), but similar disease control rate (88.2% vs. 79.5%, P = 0.314) than DEB-TACE alone. Moreover, DEB-TACE plus apatinib reached an improved PFS (median (95%CI): 19.0 months (15.5–22.5) vs. 10.9 months (8.0–13.8), P = 0.025) and OS (median (95%CI): 25.1 months (20.3–29.9) vs. 13.7 months (9.8–17.6), P = 0.042) than DEB-TACE alone. After adjustment by multivariate Cox’s regression analyses, DEB-TACE plus apatinib (vs. DEB-TACE alone) was independently correlated with better PFS (HR: 0.420, P = 0.004) and OS (HR: 0.477, P = 0.022). Regarding safety, adverse events were mostly mild and manageable; also, they were of no difference between DEB-TACE plus apatinib and DEB-TACE alone (all P > 0.05). Conclusion DEB-TACE plus apatinib achieves prolonged PFS and OS, while similar adverse events occurrence compared to DEB-TACE alone in huge HCC treatment. Supplementary information The online version contains supplementary material available at 10.1007/s11845-021-02884-w.
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Affiliation(s)
- Ningjie Li
- Department of Radiology, Wuhan Sixth Hospital, Affiliated Hospital of Jianghan University, Wuhan, 430015, China
| | - Jiao Chen
- Department of Radiology, Edong Healthcare Group, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, No.141 Tianjin Raod, Huangshi, 435000, China.
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27
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Yuan S, Fu Q, Zhao L, Fu X, Li T, Han L, Qin P, Ren Y, Huo M, Li Z, Lu C, Yuan L, Gao Q, Wang Z. OUP accepted manuscript. Oncologist 2022; 27:e463-e470. [PMID: 35348754 PMCID: PMC9177116 DOI: 10.1093/oncolo/oyab068] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 11/15/2021] [Indexed: 11/25/2022] Open
Abstract
Background The prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study’s objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. Methods This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. Results Fifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred. Conclusion Apatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable. ClinicalTrials.gov Identifier NCT03383237
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Affiliation(s)
- Shumin Yuan
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Qiang Fu
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Lingdi Zhao
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Xiaomin Fu
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Tiepeng Li
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Lu Han
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Peng Qin
- Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Yingkun Ren
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Mingke Huo
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Zhimeng Li
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Chaomin Lu
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Long Yuan
- Department of General Surgery, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, People’s Republic of China
| | - Quanli Gao
- Corresponding author: Zibing Wang, MD, PhD, Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, People’s Republic of China. Tel: +1 8937621301; ; and Quanli Gao, MD, PhD.
| | - Zibing Wang
- Corresponding author: Zibing Wang, MD, PhD, Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou 450008, People’s Republic of China. Tel: +1 8937621301; ; and Quanli Gao, MD, PhD.
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28
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Alanazi MM, Alaa E, Alsaif NA, Obaidullah AJ, Alkahtani HM, Al-Mehizia AA, Alsubaie SM, Taghour MS, Eissa IH. Discovery of new 3-methylquinoxalines as potential anti-cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and in silico studies. J Enzyme Inhib Med Chem 2021; 36:1732-1750. [PMID: 34325596 PMCID: PMC8330740 DOI: 10.1080/14756366.2021.1945591] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 06/02/2021] [Accepted: 06/14/2021] [Indexed: 02/08/2023] Open
Abstract
There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1H)-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC50 range is 2.1 - 9.8 µM), comparing to sorafenib (IC50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC50 range is 2.9 - 5.4 µM), comparing to sorafenib (IC50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).
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Affiliation(s)
- Mohammed M. Alanazi
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Elwan Alaa
- Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Nawaf A. Alsaif
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahmad J. Obaidullah
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hamad M. Alkahtani
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdulrahman A. Al-Mehizia
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Sultan M. Alsubaie
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed S. Taghour
- Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Ibrahim H. Eissa
- Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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Li L, Li Y, Zou H. A novel role for apatinib in enhancing radiosensitivity in non-small cell lung cancer cells by suppressing the AKT and ERK pathways. PeerJ 2021; 9:e12356. [PMID: 34760374 PMCID: PMC8557687 DOI: 10.7717/peerj.12356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/30/2021] [Indexed: 12/12/2022] Open
Abstract
Background Radioresistance is still the major cause of radiotherapy failure and poor prognosis in patients with non-small cell lung cancer (NSCLC). Apatinib (AP) is a highly selective inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2). Whether and how AP affects radiosensitivity in NSCLC remains unknown. The present study aimed to explore the radiosensitization effect of AP in NSCLC and its underlying mechanism as a radiosensitizer. Methods The NSCLC cell lines A549 and LK2 were treated with AP, ionizing radiation (IR), or both AP and IR. Expression of VEGFR2 was analyzed by western blot and RT-PCR. Cell proliferation was measured using CCK-8 and colony formation assays. Apoptosis and cell cycle distribution in NSCLC cells were analyzed by flow cytometry. Nuclear phosphorylated histone H2AX foci immunofluorescence staining was performed to evaluate the efficacy of the combination treatment. Western blot was used to explore the potential mechanisms of action. Results AP inhibited cell proliferation in a dose- and time-dependent manner. Flow cytometry analysis indicated that AP significantly increased radiation-induced apoptosis. Colony formation assays revealed that AP enhanced the radiosensitivity of NSCLC cells. AP strongly restored radiosensitivity by increasing IR-induced G2/M phase arrest. AP effectively inhibited repair of radiation-induced DNA double-strand breaks. Western blot analysis showed that AP enhanced radiosensitivity by downregulating AKT and extracellular signal-regulated kinase (ERK) signaling. Conclusion Our findings suggest that AP may enhance radiosensitivity in NSCLC cells by blocking AKT and ERK signaling. Therefore, AP may be a potential clinical radiotherapy synergist and a novel small-molecule radiosensitizer in NSCLC. Our study fills a gap in the field of anti-angiogenic drugs and radiosensitivity.
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Affiliation(s)
- Lin Li
- The First Oncology Department, The Fourth Hospital of China Medical University, Shenyang, Liaoning, China.,Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yuexian Li
- Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Huawei Zou
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Yao H, Liu J, Zhang C, Shao Y, Li X, Yu Z, Huang Y. Apatinib inhibits glioma cell malignancy in patient-derived orthotopic xenograft mouse model by targeting thrombospondin 1/myosin heavy chain 9 axis. Cell Death Dis 2021; 12:927. [PMID: 34635636 PMCID: PMC8505401 DOI: 10.1038/s41419-021-04225-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/13/2022]
Abstract
We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy.
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Affiliation(s)
- Hui Yao
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Jiangang Liu
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Chi Zhang
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Yunxiang Shao
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China
| | - Xuetao Li
- Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, Jiangsu, China
| | - Zhengquan Yu
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China.
| | - Yulun Huang
- Department of Neurosurgery, the First Affiliated Hospital of Soochow University, No188, Shizi Street, Suzhou, 215007, Jiangsu, China.
- Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, Jiangsu, China.
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Wang H, Wang Z, Hou Z, Yang X, Zhu K, Cao M, Zhu X, Li H, Zhang T. The Neutrophil-to-Lymphocyte Ratio (NLR) Predicts the Prognosis of Unresectable Intermediate and Advanced Hepatocellular Carcinoma Treated with Apatinib. Cancer Manag Res 2021; 13:6989-6998. [PMID: 34522141 PMCID: PMC8434860 DOI: 10.2147/cmar.s311526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Patients with hepatocellular carcinoma (HCC) who might benefit most from anti-angiogenesis therapy remain unknown. In recent years, neutrophil-to-lymphocyte ratio (NLR), an indicator of inflammatory response, has received particular attention in HCC. Herein, we explored the prognostic value of pre-treatment NLR in individuals with unresectable intermediate and advanced hepatocellular carcinoma treated with apatinib, a second-line angiogenesis inhibitor. The findings of this study would assist in precision medicine and provide clinical decision support. Patients and Methods This is a retrospective study in which 171 HCC patients attending Tianjin Medical University Cancer Institute and Hospital and treated with apatinib between January 2016 and July 2018 were enrolled. The prognosis of the patients based on NLR signatures was then analyzed. Results Patients with a low pre-treatment NLR (NLR < 2.49) presented a significantly longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.043). Furthermore, a low pre-treatment NLR level could be used to predict a longer OS in patients with non-macrovascular invasion (P < 0.001). Independent of serum alpha-fetoprotein (AFP) levels, a low NLR level in this cohort of patients is associated with a longer OS. Conclusion Pre-treatment NLR predicts the prognosis of patients with unresectable intermediate and advanced HCC treated with apatinib.
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Affiliation(s)
- Huaqi Wang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Zhiwei Wang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Zhenyu Hou
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Xuejiao Yang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Keyun Zhu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Manqing Cao
- Department of Breast Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Xiaolin Zhu
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Huikai Li
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Ti Zhang
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital; Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.,Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
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Bouz G, Bouz S, Janďourek O, Konečná K, Bárta P, Vinšová J, Doležal M, Zitko J. Synthesis, Biological Evaluation, and In Silico Modeling of N-Substituted Quinoxaline-2-Carboxamides. Pharmaceuticals (Basel) 2021; 14:ph14080768. [PMID: 34451864 PMCID: PMC8399443 DOI: 10.3390/ph14080768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 07/29/2021] [Accepted: 08/02/2021] [Indexed: 11/29/2022] Open
Abstract
Despite the established treatment regimens, tuberculosis remains an alarming threat to public health according to WHO. Novel agents are needed to overcome the increasing rate of resistance and perhaps achieve eradication. As part of our long-term research on pyrazine derived compounds, we prepared a series of their ortho fused derivatives, N-phenyl- and N-benzyl quinoxaline-2-carboxamides, and evaluated their in vitro antimycobacterial activity. In vitro activity against Mycobacterium tuberculosis H37Ra (represented by minimum inhibitory concentration, MIC) ranged between 3.91–500 µg/mL, with most compounds having moderate to good activities (MIC < 15.625 µg/mL). The majority of the active compounds belonged to the N-benzyl group. In addition to antimycobacterial activity assessment, final compounds were screened for their in vitro cytotoxicity. N-(naphthalen-1-ylmethyl)quinoxaline-2-carboxamide (compound 29) was identified as a potential antineoplastic agent with selective cytotoxicity against hepatic (HepG2), ovarian (SK-OV-3), and prostate (PC-3) cancer cells lines. Molecular docking showed that human DNA topoisomerase and vascular endothelial growth factor receptor could be potential targets for 29.
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Zhang M, Li Y, Guo Y, Xu J. Arginine Regulates NLRP3 Inflammasome Activation Through SIRT1 in Vascular Endothelial Cells. Inflammation 2021; 44:1370-1380. [PMID: 33630211 DOI: 10.1007/s10753-021-01422-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/23/2020] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
L-arginine (Arg), a semi-essential amino acid, has recently been shown to attenuate inflammatory response during cardiovascular disease. NLRP3 inflammasome serves a central role in amplification of cellular inflammation. In this study, we aimed to confirm the modulatory effect of Arg on NLRP3 inflammasome and the underlying mechanisms in vascular endothelial cells (ECs). Arg suppressed NLRP3 inflammasome activation in ECs stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Moreover, treatment with Arg increased the expression of the deacetylase sirtuin 1 (SIRT1) in ECs. Importantly, knockdown of SIRT1 abolished the inhibitory potential of Arg on the activation of NLRP3 inflammasome. Further study indicated that Arg also alleviated LPS plus ATP-induced the generation of reactive oxygen species (ROS) in ECs. In addition, Arg may regulate NLRP3 inflammasome activation partly through suppression of ROS production. In combination, we speculate that Arg exerts an inhibitory effect on the activation of NLRP3 inflammasome in ECs, which may be partly mediated by SIRT1 and ROS.
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Affiliation(s)
| | - Yanxiang Li
- School of Pharmacy, Weifang Medical University, Weifang, China
- School of Pharmacy, Taizhou Polytechnic College, Taizhou, China
| | - Yujie Guo
- School of Medicine, Nantong University, Nantong, China.
| | - Jiashuo Xu
- School of Medicine, Nantong University, Nantong, China
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Blidisel A, Marcovici I, Coricovac D, Hut F, Dehelean CA, Cretu OM. Experimental Models of Hepatocellular Carcinoma-A Preclinical Perspective. Cancers (Basel) 2021; 13:3651. [PMID: 34359553 PMCID: PMC8344976 DOI: 10.3390/cancers13153651] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.
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Affiliation(s)
- Alexandru Blidisel
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
| | - Iasmina Marcovici
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Dorina Coricovac
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Florin Hut
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
| | - Cristina Adriana Dehelean
- Faculty of Pharmacy, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania;
- Research Center for Pharmaco-Toxicological Evaluations, Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania
| | - Octavian Marius Cretu
- Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, RO-300041 Timișoara, Romania; (A.B.); (F.H.); (O.M.C.)
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Song J, Guan Z, Song C, Li M, Gao Z, Zhao Y. Apatinib suppresses the migration, invasion and angiogenesis of hepatocellular carcinoma cells by blocking VEGF and PI3K/AKT signaling pathways. Mol Med Rep 2021; 23:429. [PMID: 33846786 PMCID: PMC8047914 DOI: 10.3892/mmr.2021.12068] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy worldwide with poor prognosis and high metastasis and recurrence rates. Although apatinib has been demonstrated to have potential antitumor activity in multiple solid tumors, the underlying mechanism of apatinib in HCC treatment remains to be elucidated. In the present study, apatinib were used to treat HCC cells transfected with or without VEGFR2 overexpression vectors. The proliferation of HCC cells was detected by MTT assay. The migration and invasion of HCC cells were detected by wound healing assay and Transwell assay. The ability of angiogenesis of HCC cells were detected by tube formation assay. The related protein expression levels were detected by western blotting. The present study aims to investigate the effect and potential mechanism of apatinib on the migration, invasion and angiogenesis of HCC cells. It was found that apatinib treatment significantly inhibited the proliferation, migration and invasion of Hep3b cells and suppressed angiogenesis in HUVECs. In addition, apatinib inhibited the epithelial‑mesenchymal transition of Hep3b cells by increasing the expression of the epithelial hallmarks E‑cadherin and α‑catenin and decreased the expression of the mesenchymal hallmarks N‑cadherin and vimentin. These effects were associated with the downregulation of VEGF and VEGFR2 and suppression of the PI3K/AKT signaling pathway. Thus, apatinib inhibited cell migration, invasion and angiogenesis by blocking the VEGF and PI3K/AKT pathways, supporting an effective therapeutic strategy in the treatment of HCC.
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Affiliation(s)
- Jifu Song
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
| | - Zhibin Guan
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
| | - Chao Song
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
| | - Maojiang Li
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
| | - Zhiwei Gao
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
| | - Yongli Zhao
- Department of Radiotherapy, Qingdao Jiaozhou City Central Hospital, Jiaozhou, Qingdao 266300, P.R. China
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Wang J, Wang J, Wang J, Qian Z, Xu W, Hang X. Combination treatment for advanced hepatocellular carcinoma with portal vein tumour thrombus: A case report. J Int Med Res 2021; 49:300060521994406. [PMID: 33596694 PMCID: PMC7897824 DOI: 10.1177/0300060521994406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We present a case of a 43-year-old man with advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombus. Initially, transcatheter arterial chemoembolization (TACE) was performed. Although alpha-fetoprotein (AFP) levels decreased, circulating tumour DNA (ctDNA) levels showed an upward trend, and abdominal magnetic resonance imaging (MRI) showed that tumours in the portal vein had increased. Based on ctDNA profiling, apatinib and anti-programmed cell death protein 1 (anti-PD-1) antibodies and were sequentially administered. Approximately three months later, intrahepatic tumours had significantly diminished and AFP and ctDNA levels had reduced. The response was sustained at the 23-month follow-up and the patient was in good health. Combination treatment of TACE, apatinib and anti-PD-1 antibodies was effective, and profiling of ctDNA fragmentation may be beneficial in the therapeutic management of patients with HCC.
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Affiliation(s)
- Jianrong Wang
- Department of Infectious Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Junxue Wang
- Department of Infectious Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jianzhu Wang
- Pharmaceutical College of Taizhou Vocational and Technical College, Taizhou, China
| | - Ziliang Qian
- Prophet Genomics Inc, 1229 Briarcreekct, San Jose, CA, USA
| | - Wensheng Xu
- Department of Infectious Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiaofeng Hang
- Department of Infectious Diseases, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Li H, Zhou L, Zhou J, Li Q, Ji Q. Underlying mechanisms and drug intervention strategies for the tumour microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:97. [PMID: 33722297 PMCID: PMC7962349 DOI: 10.1186/s13046-021-01893-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/24/2021] [Indexed: 02/08/2023]
Abstract
Cancer occurs in a complex tissue environment, and its progression depends largely on the tumour microenvironment (TME). The TME has a highly complex and comprehensive system accompanied by dynamic changes and special biological characteristics, such as hypoxia, nutrient deficiency, inflammation, immunosuppression and cytokine production. In addition, a large number of cancer-associated biomolecules and signalling pathways are involved in the above bioprocesses. This paper reviews our understanding of the TME and describes its biological and molecular characterization in different stages of cancer development. Furthermore, we discuss in detail the intervention strategies for the critical points of the TME, including chemotherapy, targeted therapy, immunotherapy, natural products from traditional Chinese medicine, combined drug therapy, etc., providing a scientific basis for cancer therapy from the perspective of key molecular targets in the TME.
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Affiliation(s)
- Haoze Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lihong Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Sun T, Ren Y, Kan X, Chen L, Zhang W, Yang F, Zheng C. Advanced Hepatocellular Carcinoma With Hepatic Arterioportal Shunts: Combination Treatment of Transarterial Chemoembolization With Apatinib. Front Mol Biosci 2020; 7:607520. [PMID: 33344507 PMCID: PMC7746797 DOI: 10.3389/fmolb.2020.607520] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/13/2020] [Indexed: 01/11/2023] Open
Abstract
Object: This study aimed to compare the efficacy and safety of transarterial chemoembolization (TACE) combining with apatinib (TACE-apatinib) and TACE-alone for patients with advanced hepatocellular carcinoma (HCC) with hepatic arterioportal shunts (APS). Materials and Methods: This retrospective study evaluated the medical records of patients with advanced HCC with APS who underwent TACE-apatinib or TACE-alone from June 2015 to January 2019. The occlusion of the shunt was performed during the TACE procedure. The time to tumor progression (TTP) and overall survival (OS) of study patients were evaluated. The modified Response Evaluation Criteria in solid tumors (mRECIST) was used to evaluate the treatment response. The apatinib-related adverse events were recorded. Results: Fifty-eight patients were included in this study. Twenty-seven patients underwent the treatment of TACE-apatinib, and 31 received TACE-alone treatment. The median overall survival (OS) and median time of tumor progression (TTP) in the TACE-apatinib group were significantly longer than those of the TACE-alone group (OS: 12.0 vs. 9.0 months, P = 0.000; TTP: 9.0 vs. 5.0 months, P = 0.041). Multivariate analysis revealed that TACE-apatinib was a protective factor for OS, and there was no independent risk factor for TTP. In the TACE-apatinib group, the grade 3 apatinib-related adverse events occurred in four patients. Conclusion: TACE-apatinib was an efficacious and safe treatment for patients with advanced HCC with APS, and apatinib improved the efficacy of TACE in the treatment of these patients.
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Affiliation(s)
- Tao Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yanqiao Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xuefeng Kan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Lei Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Weihua Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Fan Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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Liu X, Zheng Q, Yu Q, Hu Y, Cheng Y, Shao Z, Chen L, Ding W, Gao D. Apatinib regulates the growth of gastric cancer cells by modulating apoptosis and autophagy. Naunyn Schmiedebergs Arch Pharmacol 2020; 394:1009-1018. [DOI: 10.1007/s00210-020-02018-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 11/05/2020] [Indexed: 12/22/2022]
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Zhang XH, Cao MQ, Li XX, Zhang T. Apatinib as an alternative therapy for advanced hepatocellular carcinoma. World J Hepatol 2020; 12:766-774. [PMID: 33200015 PMCID: PMC7643208 DOI: 10.4254/wjh.v12.i10.766] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/02/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma (HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.
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Affiliation(s)
- Xi-Hao Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China
| | - Man-Qing Cao
- Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China
| | - Xiu-Xiu Li
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China
- Digestive Department, Shanxi Province Tumor Hospital, Taiyuan 030013, Shanxi Province, China
| | - Ti Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin 300060, China
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
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Cui Y, Cao Y, Cao M, Chen X, Liu G, Chen H. Efficacy and safety of apatinib monotherapy in metastatic renal cell carcinoma (mRCC) patients: A single-arm observational study. Urol Oncol 2020; 38:936.e1-936.e6. [PMID: 32839081 DOI: 10.1016/j.urolonc.2020.07.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Antiangiogenic treatments play an important role in the therapeutic strategy for metastatic renal cell carcinoma. Apatinib is an oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. We aimed to assess the efficacy and safety of apatinib therapy in metastatic renal cell carcinoma patients. METHODS Between January 2018 and November 2018, we enrolled 53 metastatic renal cell carcinoma patients. Apatinib was administered at an initial dose of 500 mg once daily. The disease control rate, objective response rate, progression-free survival, and adverse events were reviewed and evaluated. FINDINGS Among the 53 patients, 14 achieved partial response and 31 achieved stable disease. Thus, the disease control rate was 84.9% and the objective response rate was 26.4%. The median progression-free survival was 11.2 months (95% confidence interval: 9.884-12.574). Most of the adverse events (AEs) were at grade 1 or 2, and the main grade 3 AEs were hypertension (5.7%), anemia (3.8%), and thrombocytopenia (3.8%). INTERPRETATION Apatinib showed promising efficacy and manageable toxicity in metastatic renal cell carcinoma patients, giving potent evidence to conduct further clinical trials.
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Affiliation(s)
- Yan Cui
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China
| | - Yuxuan Cao
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China
| | - Muyang Cao
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China
| | - Xueting Chen
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China
| | - Guobin Liu
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China
| | - Hui Chen
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, P.R. China.
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Xie DY, Ren ZG, Zhou J, Fan J, Gao Q. 2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr 2020; 9:452-463. [PMID: 32832496 DOI: 10.21037/hbsn-20-480] [Citation(s) in RCA: 324] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Importance Approximately half of newly-diagnosed hepatocellular carcinoma (HCC) cases in the world occur in China, with hepatitis B virus (HBV) infection being the predominant risk factor. Recently, the guidelines for the management of Chinese HCC patients were updated. Objective The past decade has witnessed a great improvement in the management of hepatocellular carcinoma (HCC). This study reviews the recommendations in the 2019 Chinese guidelines and makes comparison with the practices from the Western world. Evidence Review The updated recommendations on the surveillance, diagnosis, and treatment algorithm of HCC in the 2019 Chinese guidelines were summarized, and comparisons among the updated Chinese guidelines, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines were made. Findings Besides imaging and pathological diagnoses, novel biomarkers like the seven-micro-RNA panel are advocated for early diagnoses and therapeutic efficacy evaluation in the updated Chinese guidelines. The China liver cancer (CNLC) staging system, proposed in the 2017 guidelines, continues to be the standard model for patient classification, with subsequent modifications and updates being made in treatment allocations. Compared to the Barcelona Clinic Liver Cancer (BCLC) system, the CNLC staging system employs resection, transplantation, and transarterial chemoembolization (TACE) for more progressed HCC. TACE in combination with other regional therapies like ablation or with systemic therapies like sorafenib are also encouraged in select patients in China. The systemic treatments for HCC have evolved considerably since lenvatinib, regorafenib, carbozantinib, ramucirumab and immune checkpoint inhibitors (ICIs)were first prescribed as first-line or second-line agents. Conclusions and Relevances Novel biomarkers, imaging and operative techniques are recommended in the updated Chinese guideline. More aggressive treatment modalities are suggested for more progressed HBV-related HCC in China.
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Affiliation(s)
- Di-Yang Xie
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
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Yu X, Fan H, Jiang X, Zheng W, Yang Y, Jin M, Ma X, Jiang W. Apatinib induces apoptosis and autophagy via the PI3K/AKT/mTOR and MAPK/ERK signaling pathways in neuroblastoma. Oncol Lett 2020; 20:52. [PMID: 32788939 PMCID: PMC7416412 DOI: 10.3892/ol.2020.11913] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 05/27/2020] [Indexed: 02/07/2023] Open
Abstract
The clinical outcome of neuroblastoma (NB) has significantly improved in the last 30 years for patients with localized disease; however, the overall survival (OS) for patients with metastasis remains poor. Apatinib, a selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, which was discovered to be highly associated with metastasis, has been reported to exert antitumor effects in numerous types of cancer. However, the effect of apatinib in NB remains relatively unknown. The present study aimed to investigate the antitumor effects of apatinib in NB cells in vitro. The results revealed that apatinib inhibited cell viability and colony formation, whilst inducing cell cycle arrest and the apoptosis of NB cells. Additionally, apatinib inhibited the migration and invasion of NB cells, in addition to promoting the autophagy of NB cells. Western blotting demonstrated that the protein expression levels of phosphorylated (p)-AKT, p-mTOR and p-P70S6K, and downstream molecules associated with the cell cycle and apoptosis, such as cyclin D1 and the Bcl-2/Bax ratio of NB cells, were significantly decreased following treatment with apatinib. In addition, western blotting and immunofluorescence assays identified that the expression level of microtubule-associated protein 1A/1B-light chain 3-II, which is expressed in autophagosomes, was upregulated following apatinib treatment. In conclusion, the findings of the present study suggested that apatinib may induce apoptosis and autophagy via the PI3K/AKT/mTOR and mitogen-activated protein kinase/ERK signaling pathways in NB cells. Thus, apatinib may be a potential antitumor agent for the clinical treatment of NB.
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Affiliation(s)
- Xiying Yu
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Hongjun Fan
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, P.R. China
| | - Xingran Jiang
- Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Wei Zheng
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Yanan Yang
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Mei Jin
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, P.R. China
| | - Xiaoli Ma
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Discipline of Pediatrics, Ministry of Education, MOE Key Laboratory of Major Diseases in Children, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, P.R. China
| | - Wei Jiang
- Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.,Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
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Zhang Y, Huang G, Miao H, Song Z, Zhang X, Fan W, Wang Y, Li J, Chen Y. Apatinib treatment may improve survival outcomes of patients with hepatitis B virus-related sorafenib-resistant hepatocellular carcinoma. Ther Adv Med Oncol 2020; 12:1758835920937422. [PMID: 32754228 PMCID: PMC7378719 DOI: 10.1177/1758835920937422] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 06/04/2020] [Indexed: 12/15/2022] Open
Abstract
AIMS This study aimed to (a) assess the effectiveness and safety of apatinib as a subsequent treatment for patients with sorafenib-resistant hepatocellular carcinoma (HCC), and (b) identify the clinical factors influencing their treatment outcomes. METHODS The electronic medical records of consecutive patients with newly diagnosed advanced HCC treated with first-line sorafenib from 2015 to 2017 were retrospectively reviewed. Patients who were confirmed to have primary resistance to sorafenib were enrolled in this study. The outcomes of patients treated with apatinib were compared with those of patients who received supportive care. The primary endpoint was overall survival (OS). RESULTS A total of 92 patients with sorafenib-resistant advanced HCC (84 men and 8 women; mean age, 51.9 years) were included. All patients had an etiology of hepatitis B. The median OS in the overall cohort was 5.0 months [95% confidence interval (CI): 3.9, 6.0]. Of 92 patients, 58 (63.0%) were treated with apatinib, and 34 (37.0%) received supportive care. Apatinib treatment was associated with longer survival times than supportive care for patients with sorafenib-resistant advanced HCC (median OS: 7.0 versus 4.0 months, p < 0.001). The results of the multivariate analysis demonstrated that liver tumor load [hazard ratio (HR): 3.653, 95% CI: 2.047, 5.965, p < 0.001] and extrahepatic spread (HR: 0.303, 95% CI: 0.231, 0.778, p = 0.003) were independent predictors of OS after apatinib treatment. CONCLUSION This study showed that subsequent apatinib treatment may improve survival outcomes compared with supportive care for patients with sorafenib-resistant, advanced hepatitis B virus (HBV)-related HCC, especially for patients who have a lower liver tumor load and extrahepatic spread.
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Affiliation(s)
- Yingqiang Zhang
- Department of Radiology, The Seventh Affiliated
Hospital, Sun Yat-sen University, Shenzhen, China
| | - Guihua Huang
- Digestive Medicine Center, The Seventh
Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Hongfei Miao
- Division of Vascular and Interventional
Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical
University, Guangzhou, China
| | - Ze Song
- Department of Oncology, The Seventh Affiliated
Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiaoying Zhang
- Health Management Center, The Seventh Affiliated
Hospital, Sun Yat-sen University, Shenzhen, China
| | - Wenzhe Fan
- Department of Interventional Oncology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yu Wang
- Department of Interventional Oncology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaping Li
- Department of Interventional Oncology, The First
Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road, Guangzhou,
510080, P.R. China
| | - Yong Chen
- Division of Vascular and Interventional
Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical
University, 1838 North Guangzhou Avenue, Guangzhou, 510515, P.R. China
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Ma Y, Yu J, Li Q, Su Q, Cao B. Addition of docosahexaenoic acid synergistically enhances the efficacy of apatinib for triple-negative breast cancer therapy. Biosci Biotechnol Biochem 2019; 84:743-756. [PMID: 31889475 DOI: 10.1080/09168451.2019.1709789] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The current study aimed to investigate the antitumor and antiangiogenesis effects of apatinib in triple-negative breast cancer in vitro and also whether the combination of docosahexaenoic acid (DHA) and apatinib is more effective than apatinib monotherapy. The cell counting kit-8 assay was used to measure cell proliferation. Flow cytometry was utilized to determine the cell apoptosis rate. A wound healing assay was utilized to assess cell migration. Western blot analysis was carried out to determine the effects of apatinib and DHA on Bcl-2, BAX, cleaved caspase-3, caspase-3, phosphorylated protein kinase B (p-Akt), and Akt expression. DHA in combination with apatinib showed enhanced inhibitory effects on cell proliferation and migration compared with apatinib or DHA monotherapy. Meanwhile, DHA combined with apatinib strongly increased the cell apoptosis percentage. DHA was observed to enhance the antitumor and antiangiogenesis effects of apatinib via further downregulation of p-Akt expression.Abbreviations: FITC: fluorescein isothiocyanate; PI: propidium iodide.
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Affiliation(s)
- Yingjie Ma
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Junxian Yu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China
| | - Qin Li
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Qiang Su
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Bangwei Cao
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
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Liu J, Xie S, Duan X, Chen J, Zhou X, Li Y, Li Z, Han X. Assessment of efficacy and safety of the transcatheter arterial chemoembolization with or without apatinib in the treatment of large hepatocellular carcinoma. Cancer Chemother Pharmacol 2019; 85:69-76. [PMID: 31813003 DOI: 10.1007/s00280-019-04004-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 11/26/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE The goal of this study was to assess the clinical efficacy and safety of the transcatheter arterial chemoembolization (TACE) in combination with apatinib or TACE treatment alone in patients with large hepatocellular carcinoma (HCC). METHODS A total of 82 patients with large HCC were consecutively enrolled between January 2016 and December 2017. Of the 82 patients, 34 underwent the combined treatment, while 48 underwent TACE alone. The treatment response was assessed at first month and third month after TACE therapy, and the survival rate at median follow-up time was also compared between the two treatment groups. Furthermore, progression-free survival (PFS), overall survival (OS) and treatment-related complications were assessed and compared. RESULTS Patients treated with TACE + apatinib presented with better objective response rate and disease control rate compared to those who only underwent TACE. Median OS as well as median PFS was longer in the TACE plus apatinib group compared to the TACE alone group. Multivariate Cox's regression analysis further illustrated that TACE plus apatinib compared to TACE alone was an independent protective factor for PFS and OS. CONCLUSION TACE combined with apatinib is a safe and promising treatment approach for patients with large HCC.
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Affiliation(s)
- Juanfang Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | - Shanshan Xie
- Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | - Xuhua Duan
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China.,Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | - Jianjian Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | | | - Yahua Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | - Zhaonan Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1, East Jian She Road, Zhengzhou, 450052, Henan, People's Republic of China.
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Liao J, Jin H, Li S, Xu L, Peng Z, Wei G, Long J, Guo Y, Kuang M, Zhou Q, Peng S. Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:454. [PMID: 31694662 PMCID: PMC6836669 DOI: 10.1186/s13046-019-1419-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 09/09/2019] [Indexed: 12/24/2022]
Abstract
Background Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. Methods Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. Results Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. Conclusions Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.
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Affiliation(s)
- Junbin Liao
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Huilin Jin
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shaoqiang Li
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Lixia Xu
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.,Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhenwei Peng
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.,Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.,Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Guangyan Wei
- Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jianting Long
- Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yu Guo
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ming Kuang
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.,Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Qi Zhou
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. .,Department of General Surgery, Huiya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, 516081, Guangdong, China.
| | - Sui Peng
- Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. .,Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. .,Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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Wei Y, Liu J, Yan M, Zhao S, Long Y, Zhang W. Effectiveness and Safety of Combination Therapy of Transarterial Chemoembolization and Apatinib for Unresectable Hepatocellular Carcinoma in the Chinese Population: A Meta-Analysis. Chemotherapy 2019; 64:94-104. [PMID: 31569090 DOI: 10.1159/000502510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND The combination of transarterial chemoembolization (TACE) and apatinib has been used in the treatment of intermediate or advanced hepatocellular carcinoma (HCC). However, its effectiveness and safety are also argued. METHODS Eligible studies were collected from a computer search of literatures published from the database establishment to May 2019 in PubMed, Web of Science, EMBASE, Ovid, the Cochrane Library, Wanfang Database, China National Knowledge Infrastructure, and China Biology Medicine Disc. The objective response rate (ORR), the disease control rate (DCR), survival rate (SR), and the incidences of treatment-related adverse effects (AEs) were collected as the relevant outcomes. Data were analyzed through fixed/random effects of meta-analysis models with RevMan 5.3 software. RESULTS Eight randomized controlled clinical trials comprising 528 patients and 4 cohort studies comprising 226 patients were eventually included. Compared to the control group treated with TACE solely, combination therapy group, in which intermediate or advanced HCC patients were treated with TACE and apatinib, significantly enhanced ORR (relative risk [RR] 2.06, 95% CI 1.63-2.61, p < 0.001), DCR (RR 1.65, 95% CI 1.24-2.20, p < 0.001), and whole SRs of 6-month (RR 1.52, 95% CI 1.08-2.14, p = 0.02), 1-year (RR 1.52, 95% CI 1.25-1.84, p < 0.001), and 2-year (RR 1.84, 95% CI 1.34-2.54, p < 0.001). The incidence of hand foot syndrome, proteinuria, hypertension, and diarrhea was significantly increased in the combination therapy group compared with the control group (p < 0.05), and the incidence of nausea and vomiting, fever, and myelosuppression, respectively, was similar in 2 groups (p > 0.05). CONCLUSIONS The combination therapy of TACE and apatinib can enhance the clinical effectiveness better than TACE solely in patients with intermediate or advanced HCC, while increase in the AEs is usually tolerable.
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Affiliation(s)
- Yan Wei
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, Xi'an, China.,Department of Outpatient, 986th Military Hospital, Xi'an, China
| | - Jianjun Liu
- Department of Outpatient, 986th Military Hospital, Xi'an, China
| | - Min Yan
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Shuguang Zhao
- Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, Xi'an, China
| | - Yong Long
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
| | - Weilu Zhang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China,
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Phan C, Zheng Z, Wang J, Wang Q, Hu X, Tang G, Bai H. Enhanced antitumour effect for hepatocellular carcinoma in the advanced stage using a cyclodextrin-sorafenib-chaperoned inclusion complex. Biomater Sci 2019; 7:4758-4768. [PMID: 31509117 DOI: 10.1039/c9bm01190k] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular tumour characterized by tumour-driven neovascularization. The degrees of blood oxygen saturation (DBOS), microvessel density (MVD) and tumour size (TS) are indicators in identifying the development stage of HCC. Herein, we proposed an HCC staging model using HepG2 tumour-bearing mice based on DBOS, MVD and TS. According to the patterns of these three criteria, HCC was classified into four stages: early, intermediate, advanced and end stages. The advanced stage was characterized by MVD of 50-90 (number per mm2), DBOS of 12-16% and TS of 250-600 mm3, which poses a critical challenge in HCC therapy. In order to efficiently control and treat HCC in the advanced stage, we developed a cyclodextrin (CD)-based chaperoned inclusion complex using Sorafenib (Sor), β-CD and γ-CD (SCD) via the co-crystallization method. The structural study manifested that CDs could encapsulate Sor with the hydrophobic cavities at a 1 : 1 stoichiometry ratio. The crystallographic analysis indicated that Sor-β-CD presented a diagonal stacking pattern, while Sor-γ-CD possessed a channel-type structure. The resultant chaperoned inclusion complexes significantly improved the solubility, dissolution rate and drug release of Sor, leading to superior pharmacokinetics, biodistribution and biosafety through oral administration. The antitumour effect was then evaluated on a mouse model with advanced HCC through oral administration and intratumour injection. The treatment involving the oral administration of SCDs showed a promising therapeutic effect on advanced HCC, which efficiently blocked angiogenesis and inhibited tumour progression. For the treatments using intratumour injections, only Sor-γ-CD exhibited a satisfactory anti-tumour effect with reduction in TS, MVD and DBOS. The enhanced therapeutic performance of Sor-γ-CD was attributed to its channel-type structure, which had an impact on the dissociation and release of the drug. Thus, Sor-γ-CD can be used as a potential pro-drug for clinical medicine and basic research to treat HCC.
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Affiliation(s)
- Chiuyen Phan
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Ziyang Zheng
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Jianwei Wang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Qiwen Wang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Xiurong Hu
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Guping Tang
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
| | - Hongzhen Bai
- Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
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Mossenta M, Busato D, Baboci L, Cintio FD, Toffoli G, Bo MD. New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:E1086. [PMID: 31370258 PMCID: PMC6721310 DOI: 10.3390/cancers11081086] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/22/2019] [Accepted: 07/29/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant role in the generation and maintenance of an immunosuppressive tumor microenvironment. Several therapeutic options for HCC treatment are based on the inhibition of angiogenesis, both in the early/intermediate stages of the disease and in the late stages of the disease. Conventional treatment options employing antiangiogenic approaches provide for the starving of tumors of their blood supply to avoid the refueling of oxygen and nutrients. An emerging alternative point of view is the normalization of vasculature leading to enhance tumor perfusion and oxygenation, potentially capable, when proposed in combination with other treatments, to improve delivery and efficacy of other therapies, including immunotherapy with checkpoint inhibitors. The introduction of novel biomarkers can be useful for the definition of the most appropriate dose and scheduling for these combination treatment approaches. The present review provides a wide description of the pharmaceutical compounds with an antiangiogenic effect proposed for HCC treatment and investigated in clinical trials, including antibodies and small-molecule kinase inhibitors.
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Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Lorena Baboci
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
| | - Federica Di Cintio
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy.
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
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