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Islam MR, Rauf A, Alash S, Fakir MNH, Thufa GK, Sowa MS, Mukherjee D, Kumar H, Hussain MS, Aljohani ASM, Imran M, Al Abdulmonem W, Thiruvengadam R, Thiruvengadam M. A comprehensive review of phytoconstituents in liver cancer prevention and treatment: targeting insights into molecular signaling pathways. Med Oncol 2024; 41:134. [PMID: 38703282 DOI: 10.1007/s12032-024-02333-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 02/13/2024] [Indexed: 05/06/2024]
Abstract
Primary liver cancer is a type of cancer that develops in the liver. Hepatocellular carcinoma is a primary liver cancer that usually affects adults. Liver cancer is a fatal global condition that affects millions of people worldwide. Despite advances in technology, the mortality rate remains alarming. There is growing interest in researching alternative medicines to prevent or reduce the effects of liver cancer. Recent studies have shown growing interest in herbal products, nutraceuticals, and Chinese medicines as potential treatments for liver cancer. These substances contain unique bioactive compounds with anticancer properties. The causes of liver cancer and potential treatments are discussed in this review. This study reviews natural compounds, such as curcumin, resveratrol, green tea catechins, grape seed extracts, vitamin D, and selenium. Preclinical and clinical studies have shown that these medications reduce the risk of liver cancer through their antiviral, anti-inflammatory, antioxidant, anti-angiogenic, and antimetastatic properties. This article discusses the therapeutic properties of natural products, nutraceuticals, and Chinese compounds for the prevention and treatment of liver cancer.
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Affiliation(s)
- Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Anbar, 23561, Khyber Pakhtunkhwa, Pakistan.
| | - Shopnil Alash
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Md Naeem Hossain Fakir
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Gazi Kaifeara Thufa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Mahbuba Sharmin Sowa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka, 1216, Bangladesh
| | - Dattatreya Mukherjee
- Raiganj Government Medical College and Hospital, Pranabananda Sarani, Raiganj, 733134, West Bengal, India
| | - Harendra Kumar
- Dow University of Health Sciences, Mission Rd, New Labour Colony Nanakwara, Karachi, 74200, Sindh, Pakistan
| | - Md Sadique Hussain
- School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura, Jaipur, 302017, Rajasthan, India
| | - Abdullah S M Aljohani
- Department of Medical Biosciences, College of Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Muhammad Imran
- Chemistry Department, Faculty of Science, King Khalid University, P.O. Box 9004, 61413, Abha, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Rekha Thiruvengadam
- Center for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical & Technical Sciences (SIMATS), Saveetha University, Chennai, 600077, Tamil Nadu, India.
| | - Muthu Thiruvengadam
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul, 05029, South Korea
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Li P, Hu M, Liu M, Ren X, Liu D, Liu J, Yin J, Tan X, Cao G. The efficacy and safety of different systemic combination therapies on advanced hepatocellular carcinoma: a systematic review and meta-analysis. Front Oncol 2023; 13:1197782. [PMID: 37817769 PMCID: PMC10561006 DOI: 10.3389/fonc.2023.1197782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 09/04/2023] [Indexed: 10/12/2023] Open
Abstract
Background and aims Systemic combinations have recently brought significant therapeutic benefits for advanced hepatocellular carcinoma (aHCC). To design the most effective combination regimens, a systematic review (PROSPERO ID: CRD42022321949) was conducted to evaluate the efficacy and safety of systemic combinations on aHCC. Methods We retrieved all the studies from PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI) using the Medical Subject Headings (MeSH) terms until December 21, 2022. The effect indicators (hazard ratio [HR], relative risk [RR], and median) were pooled by a fixed- or random-effects model. A subgroup analysis was conducted according to types and specific therapies. Results In total, 88 eligible studies were selected from 7249 potential records. Each kind of combination treatment (chemotherapy plus chemotherapy, targeted plus immune checkpoint inhibitor (ICI) therapy, targeted plus chemotherapy, and targeted plus targeted therapy) had a better objective response rate (ORR) in patients with aHCC, compared to the monotherapy mostly with sorafenib (RR: 1.57 [1.44-1.71]; I 2 = 30%). Of those, targeted plus ICI therapy showed better therapeutic efficiency in overall survival (median: 15.02 [12.67-17.38]), progression-free survival (median: 7.08 [6.42-7.74]), and ORR (RR: 1.81 [1.55-2.13]), compared to the monotherapy. Specifically, Atezo plus Beva showed all those benefits. Our pooled result showed all the combinations had increased ≥3 Grade treatment-related adverse events (TrAEs), with an RR of 1.25 [95% CI: 1.15-1.36], compared to the monotherapy. Conclusion The systemic combinations, especially targeted plus ICI therapy, including Atezo plus Beva, significantly improve clinical outcomes but increase side effects in patients with aHCC. Future trials should concentrate on improvement in therapeutic efficiency and reduction of toxicity of targeted plus ICI therapy. Systematic review registration https://www.crd.york.ac.uk/prospero, identifier CRD42022321949.
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Affiliation(s)
- Ping Li
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Ming Hu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Mei Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Xiangyu Ren
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Donghong Liu
- Department of Hepatic Surgery, The Third Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Jiluo Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Xiaojie Tan
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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Yadav S. Advanced therapeutics avenues in hepatocellular carcinoma: a novel paradigm. Med Oncol 2023; 40:239. [PMID: 37442842 DOI: 10.1007/s12032-023-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and it poses a significant risk to patients health and longevity due to its high morbidity and fatality rates. Surgical ablation, radiotherapy, chemotherapy, and, most recently, immunotherapy have all been investigated for HCC, but none have yielded the desired outcomes. Several unique nanocarrier drug delivery techniques have been studied for their potential therapeutic implications in the treatment of HCC. Nanoparticle-based imaging could be effective for more accurate HCC diagnosis. Since its inception, nanomedicine has significantly transformed the approach to both the treatment and diagnostics of liver cancer. Nanoparticles (NPs) are being studied as a potential treatment for liver cancer because of their ability to carry small substances, such as treatment with chemotherapy, microRNA, and therapeutic genes. The primary focus of this study is on the most current discoveries and practical uses of nanomedicine-based diagnostic and therapeutic techniques for liver cancer. In this section, we had gone over what we know about metabolic dysfunction in HCC and the treatment options that attempt to fix it by targeting metabolic pathways. Furthermore, we propose a multi-target metabolic strategy as a viable HCC treatment option. Based on the findings given here, the scientists believe that smart nanomaterials have great promise for improving cancer theranostics and opening up new avenues for tumor diagnosis and treatment.
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Affiliation(s)
- Shikha Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Plot No.2, Sector 17-A, Yamuna Expressway, Gautam Buddhnagar, Greater Noida, Uttar Pradesh, 201310, India.
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Altalal A, Almomen A, Alkholief M, Binkhathlan Z, Alzoman NZ, Alshamsan A. Development and validation of a UPLC-MS/MS method for simultaneous detection of doxorubicin and sorafenib in plasma: Application to pharmacokinetic studies in rats. Saudi Pharm J 2023; 31:1317-1326. [PMID: 37323919 PMCID: PMC10267530 DOI: 10.1016/j.jsps.2023.05.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023] Open
Abstract
An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous quantitation of doxorubicin (DOX) and sorafenib (SOR) in rat plasma. Chromatographic separation was performed using a reversed-phase column C18 (1.7 μm, 1.0 × 100 mm Acquity UPLC BEH™). The gradient mobile phase system consisted of water containing 0.1% acetic acid (mobile phase A) and methanol (mobile phase B) with a flow rate of 0.40 mL/min over 8 min. Erlotinib (ERL) was used as an internal standard (IS). The quantitation of conversion of [M + H]+, which was the protonated precursor ion, to the corresponding product ions was performed using multiple reaction monitoring (MRM) with a mass-to-charge ratio (m/z) of 544 > 397.005 for DOX, 465.05 > 252.03 for SOR, and 394 > 278 for the IS. Different parameters were used to validate the method including accuracy, precision, linearity, and stability. The developed UPLC-MS/MS method was linear over the concentration ranges of 9-2000 ng/mL and 7-2000 ng/mL with LLOQ of 9 and 7 ng/mL for DOX and SOR, respectively. The intra-day and inter-day accuracy, expressed as % relative standard deviation (RSD%), was below 10% for both DOX and SOR in all QC samples that have drug concentrations above the LLOQ. The intra-day and inter-day precision, expressed as percent relative error (Er %), was within the limit of 15.0% for all concentrations above LLOQ. Four groups of Wistar rats (250-280 g) were used to conduct the pharmacokinetic study. Group I received a single intraperitoneal (IP) injection of DOX (5 mg/kg); Group II received a single oral dose of SOR (40 mg/kg), Group III received a combination of both drugs; and Group IV received sterile water for injection IP and 0.9% w/v sodium chloride solution orally to serve as a control. Non-compartmental analysis was used to calculate the different pharmacokinetic parameters. Data revealed that coadministration of DOX and SOR altered some of the pharmacokinetic parameters of both agents and resulted in an increase in the Cmax and AUC and reduction in the apparent clearance (CL/F). In conclusion, our newly developed method is sensitive, specific, and can reliably be used to simultaneously determine DOX and SOR concentrations in rat plasma. Moreover, the results of the pharmacokinetic study suggest that coadministration of DOX and SOR might cause an increase in exposure of both drugs.
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Affiliation(s)
- Alanoud Altalal
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Aliyah Almomen
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Musaed Alkholief
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Ziyad Binkhathlan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
- Nanobiotechnology Unit, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Nourah Z. Alzoman
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
| | - Aws Alshamsan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia
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Tian M, Fan D, Liu Z, Mu X, Tao Q, Yu C, Zhang S. Oral Supramolecular Adsorbent for Preventing Chemo-Induced Gastrointestinal Mucositis and Microbial Dysbiosis and for Enhancing Chemoimmunotherapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2205299. [PMID: 36189825 DOI: 10.1002/adma.202205299] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 09/20/2022] [Indexed: 06/16/2023]
Abstract
The addition of immune checkpoint blockade (ICB) to cytotoxic chemotherapy has emerged as the first-line treatment for multiple cancers. Paradoxically, cytotoxic chemotherapy may limit the therapeutic potential of ICB by significantly impairing the largest immune organ, the gastrointestinal (GI) tract, and driving gut microbial dysbiosis. Here, an orally administered polymeric adsorbent containing a supramolecular motif (named SPORA-SN9) is reported, which can selectively remove chemotherapeutics from the GI tract, thereby preventing chemotherapy-induced GI mucositis and microbial dysbiosis and providing better chemoimmunotherapy synergy. By theoretical design and experimental screening of the molecular recognition motifs, SPORA-SN9 exhibits superior complexation capacity for doxorubicin and irinotecan and high selectivity over a range of commonly used combinational medications. In mouse models of chemotherapy-induced GI mucositis, SPORA-SN9 protects the integrity of the GI tissues and the homeostasis of the gut microbiota. Finally, the addition of SPORA-SN9 enhances the efficacy of chemoimmunotherapy in tumor-bearing mice. SPORA-SN9 offers a translational approach for supramolecular chemistry to modulate complex biosystems by selectively removing target substrates from the GI tract.
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Affiliation(s)
- Meng Tian
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Dongyue Fan
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhen Liu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Xin Mu
- School of Biomedical Engineering, ShanghaiTech University, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qianqian Tao
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Chunyang Yu
- School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Shiyi Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
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Contreras L, Rodríguez-Gil A, Muntané J, de la Cruz J. Broad Transcriptomic Impact of Sorafenib and Its Relation to the Antitumoral Properties in Liver Cancer Cells. Cancers (Basel) 2022; 14:cancers14051204. [PMID: 35267509 PMCID: PMC8909169 DOI: 10.3390/cancers14051204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/21/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related mortality worldwide. While ablation, resection and orthotopic liver transplantation are indicated at an early stage of the disease, Sorafenib (Sfb) is the current most administrated first-line treatment for advanced HCC, even though its therapeutic benefit is limited due to the appearance of resistance. Deep knowledge on the molecular consequences of Sfb-treatment is essentially required for optimizing novel therapeutic strategies to improve the outcomes for patients with advanced HCC. In this study, we analyzed differential gene expression changes in two well characterized liver cancer cell lines upon a Sfb-treatment, demonstrating that both lines responded similarly to the treatment. Our results provide valuable information on the molecular action of Sfb on diverse cellular fundamental processes such as DNA repair, translation and proteostasis and identify rationalization issues that could provide a different therapeutic perspective to Sfb. Abstract Hepatocellular carcinoma (HCC) is one of the most frequent and essentially incurable cancers in its advanced stages. The tyrosine kinase inhibitor Sorafenib (Sfb) remains the globally accepted treatment for advanced HCC. However, the extent of its therapeutic benefit is limited. Sfb exerts antitumor activity through its cytotoxic, anti-proliferative and pro-apoptotic roles in HCC cells. To better understand the molecular mechanisms underlying these effects, we used RNA sequencing to generate comprehensive transcriptome profiles of HepG2 and SNU423, hepatoblastoma- (HB) and HCC-derived cell lines, respectively, following a Sfb treatment at a pharmacological dose. This resulted in similar alterations of gene expression in both cell lines. Genes functionally related to membrane trafficking, stress-responsible and unfolded protein responses, circadian clock and activation of apoptosis were predominantly upregulated, while genes involved in cell growth and cycle, DNA replication and repair, ribosome biogenesis, translation initiation and proteostasis were downregulated. Our results suggest that Sfb causes primary effects on cellular stress that lead to upregulation of selective responses to compensate for its negative effect and restore homeostasis. No significant differences were found specifically affecting each cell line, indicating the robustness of the Sfb mechanism of action despite the heterogeneity of liver cancer. We discuss our results on terms of providing rationalization for possible strategies to improve Sfb clinical outcomes.
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Affiliation(s)
- Laura Contreras
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Seville, Spain; (L.C.); (A.R.-G.)
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, E-41012 Seville, Spain
| | - Alfonso Rodríguez-Gil
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Seville, Spain; (L.C.); (A.R.-G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), E-28029 Madrid, Spain
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, E-41009 Sevilla, Spain
| | - Jordi Muntané
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Seville, Spain; (L.C.); (A.R.-G.)
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, E-41009 Sevilla, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), E-28029 Madrid, Spain
- Correspondence: (J.M.); (J.d.l.C.); Tel.: +34-955-923-122 (J.M.); +34-923-126 (J.d.l.C.)
| | - Jesús de la Cruz
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, E-41013 Seville, Spain; (L.C.); (A.R.-G.)
- Departamento de Genética, Facultad de Biología, Universidad de Sevilla, E-41012 Seville, Spain
- Correspondence: (J.M.); (J.d.l.C.); Tel.: +34-955-923-122 (J.M.); +34-923-126 (J.d.l.C.)
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Choi YH, Zhang C, Liu Z, Tu MJ, Yu AX, Yu AM. A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine In Vivo Synergism. J Pharmacol Exp Ther 2021; 377:305-315. [PMID: 33712506 PMCID: PMC8140393 DOI: 10.1124/jpet.121.000584] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022] Open
Abstract
Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of in vivo pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered. Doxorubicin (Dox) and sorafenib (Sor) were used as model drugs whose PK data were obtained in mice and fit to two-compartment model. Xenograft tumor growth was biphasic in mice, and PD responses were described by three-compartment transit models. This PK-PD model revealed that Sor (contribution factor = 1.62) had much greater influence on overall tumor-growth inhibition than coadministered Dox (contribution factor = 0.644), which explains the mysterious clinical findings on remarkable benefits for patients with cancer when adding Sor to Dox treatment, whereas there were none when adding Dox to Sor therapy. Furthermore, the combination index method was integrated into this predictive PK-PD model for critical determination of in vivo pharmacologic synergism that cannot be correctly defined by the interaction factor in conventional models. In addition, this new PK-PD model was able to identify optimal dosage combination (e.g., doubling experimental Sor dose and reducing Dox dose by 50%) toward much greater degree of tumor-growth inhibition (>90%), which was consistent with stronger synergy (combination index = 0.298). These findings demonstrated the utilities of this new PK-PD model and reiterated the use of valid method for the assessment of in vivo synergism. SIGNIFICANCE STATEMENT: A novel pharmacokinetic (PK)-pharmacodynamic (PD) model was developed for the assessment of combination treatment by considering contributions from individual drugs, and combination index method was incorporated to critically define in vivo synergism. A greater contribution from sorafenib to tumor-growth inhibition than that of coadministered doxorubicin was identified, offering explanation for previously inexplicable clinical observations. This PK-PD model and strategy shall have broad applications to translational research on identifying optimal dosage combinations with stronger synergy toward improved therapeutic outcomes.
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Affiliation(s)
- Young Hee Choi
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
| | - Chao Zhang
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
| | - Zhenzhen Liu
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
| | - Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
| | - Ai-Xi Yu
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
| | - Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, University of California (UC) Davis School of Medicine, Sacramento, California (Y.H.C., C.Z., Z.L., M.-J.T., A.-M.Y.); College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.); and Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China (A.-X.Y.)
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LINC00978 promotes hepatocellular carcinoma carcinogenesis partly via activating the MAPK/ERK pathway. Biosci Rep 2021; 40:222177. [PMID: 32077915 PMCID: PMC7064789 DOI: 10.1042/bsr20192790] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/20/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Objective: To study the role of long non-coding RNA (lncRNA) LINC00978 in hepatocellular carcinoma (HCC) carcinogenesis. Materials and methods: LINC00978 expression level was measured by reverse transcription quantitative real-time PCR (RT-qPCR) in HCC tissues and adjacent healthy liver tissues from 49 HCC patients. MTT assay, colony forming assay, and flow cytometry were performed to evaluate the effects of shRNA-mediated LINC00978 knockdown on HCC cell proliferation, cell cycle progression, and apoptosis in vitro. Xenograft tumor model was performed to determine the effects of LINC00978 knockdown on HCC tumor growth in vivo. Western blot was used to assess the activation of signaling molecules in the apoptosis and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. Results: LINC00978 expression was significantly up-regulated in human HCC tissue relative to adjacent normal tissue, and LINC00978 high expression was correlated with poor HCC overall survival. LINC00978 was up-regulated in HCC cell lines. ShRNA-mediated LINC00978 knockdown significantly decreased HCC cell proliferation, and induced HCC cell cycle arrest and apoptosis in vitro. LINC00978 knockdown led to significant decrease in tumor xenograft size in vivo. Western blots revealed LINC00978 inhibition decreased ERK, p38, and c-Jun N-terminal kinase (JNK) phosphorylation in HCC cells. Conclusions: LINC00978 is highly expressed in human HCC tissue and correlates with poor HCC prognosis. LINC00978 promotes HCC cell proliferation, cell cycle progression, and survival, partially by activating the MAPK/ERK pathway. Our findings partially elucidated the roles of LINC00978 in HCC carcinogenesis, and identified a therapeutic target for HCC.
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Shing K, Kwok G, Chiu J, Cheung TT, Yau T. Sorafenib plus doxorubicin in advanced hepatocellular carcinoma patients: hope or hype? ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1695. [PMID: 33490207 PMCID: PMC7812207 DOI: 10.21037/atm-2020-130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Kit Shing
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Gerry Kwok
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Joanne Chiu
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Thomas Yau
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
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Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer 2020; 1873:188314. [PMID: 31682895 PMCID: PMC6981221 DOI: 10.1016/j.bbcan.2019.188314] [Citation(s) in RCA: 871] [Impact Index Per Article: 174.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 02/06/2023]
Abstract
Globally, liver cancer is the most frequent fatal malignancy; in the United States, it ranks fifth. Patients are often diagnosed with liver cancer in advanced stages, contributing to its poor prognosis. Of all liver cancer cases, >90% are hepatocellular carcinomas (HCCs) for which chemotherapy and immunotherapy are the best options for therapy. For liver cancer patients, new treatment options are necessary. Use of natural compounds and/or nanotechnology may provide patients with better outcomes with lower systemic toxicity and fewer side effects. Improved treatments can lead to better prognoses. Finally, in this review, we present some of the problems and current treatment options contributing to the poor outcomes for patients with liver cancer.
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Affiliation(s)
- David Anwanwan
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Santosh Kumar Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
| | - Shriti Singh
- Department of Kriya Sharir, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP 221 005, India
| | - Varma Saikam
- Department of Chemistry, Center for Therapeutics and Diagnostics, Georgia State University, Atlanta, GA 30302, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
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11
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Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check. Front Med 2019; 14:273-283. [PMID: 31863306 DOI: 10.1007/s11684-019-0728-2] [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: 07/21/2019] [Accepted: 10/12/2019] [Indexed: 02/06/2023]
Abstract
In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or anti-angiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.
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12
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Gao Y, Wang P, Cheng J, Sun Y, Hu B, Guo W, Zhou K, Yin Y, Li Y, Wang J, Huang J, Qiu S, Zhou J, Fan J, Yang X. Chemotherapeutic perfusion of portal vein after tumor thrombectomy and hepatectomy benefits patients with advanced hepatocellular carcinoma: A propensity score-matched survival analysis. Cancer Med 2019; 8:6933-6944. [PMID: 31566899 PMCID: PMC6853833 DOI: 10.1002/cam4.2556] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/08/2019] [Accepted: 08/30/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Portal vein tumor thrombus (PVTT) is a common complication in hepatocellular carcinoma (HCC), signaling dismal outcomes. This study was conducted to evaluate the survival benefit of postoperative portal vein perfusion chemotherapy (PVC) in patients with HCC and PVTT. METHODS A retrospective review was conducted in 401 consecutive patients with HCC and PVTT who underwent hepatic resection between January 2009 and December 2015 and 67 patients received adjuvant postoperative PVC. A propensity score matching (PSM) was used to match patients with and without PVC at a ratio of 1:1. RESULTS After PSM, the median time to recurrence (TTR) and overall survival (OS) were significantly longer in PVC group compared with control group (12.3 vs 5.8 months, P = .001; 19.0 vs 13.4 months, P = .037; respectively). At 1, 2, 3, and 5 years, the cumulative recurrence rates in PVC group were 48.1%, 86.5%, 92.3% ,96.2%, respectively, with OS rates of 63.8%, 37.9%, 24.4%, 18.3%, respectively; whereas cumulative recurrence rates of 76.6%, 91.5%, 94.3%, and 97.2%, respectively and OS rates of 55.4%, 23.0%, 12.4%, and 12.4%, respectively were recorded for the control group. In multivariate analysis, postoperative PVC emerged as a significant predictor for TTR (hazard ratio [HR], 0.523; P = .001) and OS (HR, 0.591; P = .010). PVC could reduce early recurrence (≤1 year) rate after surgical resection (40.3% vs 64.2%, P = .006) and clinical outcomes were further enhanced by adding sorafenib to postoperative PVC. CONCLUSIONS Compared with surgical resection alone, postoperative adjuvant PVC treatment boosts survival and reduces early tumor recurrences in patients surgically treated for HCC and PVTT.
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Affiliation(s)
- Yang Gao
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Peng‐Xiang Wang
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Jian‐Wen Cheng
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Yun‐Fan Sun
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Bo Hu
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Wei Guo
- Department of Laboratory MedicineZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Kai‐Qian Zhou
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Yue Yin
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Yuan‐Cheng Li
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Jian Wang
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Jun‐Feng Huang
- Department of Intensive Care MedicineZhongshan HospitalFudan UniversityShanghaiChina
| | - Shuang‐Jian Qiu
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Jian Zhou
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Jia Fan
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
| | - Xin‐Rong Yang
- Department of Liver Surgery & TransplantationLiver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiP. R. China
- Key Laboratory of Carcinogenesis and Cancer InvasionMinistry of EducationShanghaiP. R. China
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13
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Hulin A, Stocco J, Bouattour M. Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma. Clin Pharmacokinet 2019; 58:983-1014. [PMID: 31093928 DOI: 10.1007/s40262-019-00740-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The management of hepatocellular carcinoma (HCC) is based on a multidisciplinary decision tree. Treatment includes loco-regional therapy, mainly transarterial chemoembolization, for intermediate-stage HCC and systemic therapy with oral tyrosine kinase inhibitors (TKIs) for advanced HCC. Transarterial chemoembolization involves hepatic intra-arterial infusion with either conventional procedure or drug-eluting-beads. The aim of the loco-regional procedure is to deliver treatment as close as possible to the tumor both to embolize the tumor area and to enhance efficacy and minimize systemic toxicity of the anticancer drug. Pharmacokinetic studies applied to transarterial chemoembolization are rare and pharmacodynamic studies even rarer. However, all available studies lead to the same conclusions: use of the transarterial route lowers systemic exposure to the cytotoxic drug and leads to much higher tumor drug concentrations than does a similar dose via the intravenous route. However, reproducibility of the procedure remains a major problem, and no consensus exists regarding the choice of anticancer drug and its dosage. Systemic therapy with TKIs is based on sorafenib and lenvatinib as first-line treatment and regorafenib and cabozantinib as second-line treatment. Clinical use of TKIs is challenging because of their complex pharmacokinetics, with high liver metabolism yielding both active metabolites and their common toxicities. Changes in liver function over time with the progression of HCC adds further complexity to the use of TKIs. The challenges posed by TKIs and the HCC disease process means monitoring of TKIs is required to improve clinical management. To date, only partial data supporting sorafenib monitoring is available. Results from further pharmacokinetic/pharmacodynamic studies of these four TKIs are eagerly awaited and are expected to permit such monitoring and the development of consensus guidelines.
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Affiliation(s)
- Anne Hulin
- APHP, Laboratory of Pharmacology, GH Henri Mondor, EA7375, University Paris Est Creteil, 94010, Creteil, France
| | - Jeanick Stocco
- APHP, HUPNVS, Department of Clinical Pharmacy and Pharmacology, Beaujon University Hospital, 92110, Clichy, France
| | - Mohamed Bouattour
- APHP, HUPNVS, Department of Digestive Oncology, Beaujon University Hospital, 92110, Clichy, France.
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14
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Bajbouj K, Shafarin J, Hamad M. Estrogen-dependent disruption of intracellular iron metabolism augments the cytotoxic effects of doxorubicin in select breast and ovarian cancer cells. Cancer Manag Res 2019; 11:4655-4668. [PMID: 31213891 PMCID: PMC6536718 DOI: 10.2147/cmar.s204852] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/16/2019] [Indexed: 01/10/2023] Open
Abstract
Introduction: Increased iron content in cancer cells is associated with resistance to chemotherapy. Recent studies have demonstrated that estrogen (E2) suppresses hepcidin synthesis and enhances intracellular iron efflux. Herein, we investigated whether E2-driven intracellular iron efflux renders cancer cells more susceptible to doxorubicin (Dox)-induced cytotoxicity. Methods: Breast, ovarian, and liver cancer cell lines treated with E2, Dox, or a combination of both were assessed for intracellular iron status, mitochondrial function, cell cycle, and apoptosis. Results: E2+Dox treatment in MCF7, SKOV3 and MDA-MB231 cells resulted in enhanced apoptosis compared with Dox-treated cells. Expression of γH2AX was significantly higher and that of survivin significantly lower in E2+Dox-treated cells than Dox-treated cells. At 48 hours, E2+Dox had induced a significant increase in the percentage of sub-G1 apoptotic cells, increased CHK1 expression, and decreased cyclin D1, CDK4, and CDK6 expression. Ferroportin and ferritin expression was significantly higher and that of TfR1 significantly lower in E2+Dox-treated cells than Dox-treated cells. Intracellular iron content was significantly reduced in E2+Dox-treated cells at 48 hours posttreatment. Lastly, E2+Dox-treated cells showed higher levels of mitochondrial membrane hyperpolarization than Dox-treated cells. Conclusion: These findings suggest that E2 disrupts intracellular iron metabolism in such a way that increases cell susceptibility to Dox-induced cytotoxicity.
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Affiliation(s)
- Khuloud Bajbouj
- Sharjah Institute for Medical Research, Sharjah, United Arab Emirates
| | - Jasmin Shafarin
- Sharjah Institute for Medical Research, Sharjah, United Arab Emirates
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, Sharjah, United Arab Emirates.,Department of Medical Laboratory Sciences, University of Sharjah, Sharjah, United Arab Emirates
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15
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Zhang X, Wang K, Wang M, Yang G, Ye X, Wu M, Cheng S. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. Oncotarget 2018; 8:29416-29427. [PMID: 28177886 PMCID: PMC5438741 DOI: 10.18632/oncotarget.15075] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/09/2017] [Indexed: 02/07/2023] Open
Abstract
Background The benefits of transarterial chemoembolization plus sorafenib (TACE-S) in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remain controversial. We compared the effectiveness and safety of TACE-S and TACE for HCC with PVTT. Methods The Cochrane Library, PubMed, EMBASE, Chinese National Knowledge Infrastructure, VIP, Wan Fang, and Sino Med databases were systematically searched for studies of HCC with PVTT treated using TACE-S. Two authors independently extracted study outcomes, including overall survival (OS), time to progression (TTP), objective response (tumor response) and adverse events (AEs). Results Eight high-quality, retrospective studies with 1091 patients (TACE-S=356, TACE=735) were included in the review. Five retrospective studies with 973 patients (TACE-S=238, TACE=735) were included in the meta-analysis. The objective response rate (ORR, OR=3.59, 95% CI=1.74–7.39; I2=21%, P=0.0005) and disease control rate (DCR, OR=4.72, 95% CI=1.75–12.72; I2=56%, P=0.002) favored TACE-S. TACE-S significantly increased 6-month OS (OR=3.47; 95% CI=2.47–4.89; I2=0%, P < 0.00001) and 1-year OS (OR=3.10; 95% CI=2.22–4.33; I2=41%, P < 0.00001). The hazard ratio (HR) for OS (HR=0.62; 95% CI=0.51–0.75; I2=30%, P < 0.00001) also indicated that TACE-S was superior to TACE. TACE-S with PVTT had better outcomes in the first-order portal vein branch and lower-order portal vein branches than in the main portal vein and upper branches to superior mesenteric vein. The most common AEs were hand-foot skin reaction (HFSR, 178; 73%), diarrhea (142; 58%) and alopecia (76; 31%); AEs of grade 3/4 were rare. Conclusions TACE-S may improve OS, ORR, TTP and DCR for HCC patients with PVTT compared to TACE.
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Affiliation(s)
- XiuPing Zhang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University. Shanghai, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University. Shanghai, China
| | - Meng Wang
- Department of Medical Statistical, Second Military Medical University, Shanghai, China
| | - Guang Yang
- Company 5 of Student Brigade, Second Military Medical University, Shanghai, China
| | - XiaoFei Ye
- Department of Medical Statistical, Second Military Medical University, Shanghai, China
| | - MengChao Wu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University. Shanghai, China
| | - ShuQun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University. Shanghai, China
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16
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Design and synthesis of thienopyrimidine urea derivatives with potential cytotoxic and pro-apoptotic activity against breast cancer cell line MCF-7. Eur J Med Chem 2018; 143:1807-1825. [DOI: 10.1016/j.ejmech.2017.10.075] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/28/2017] [Accepted: 10/28/2017] [Indexed: 01/16/2023]
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17
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Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer 2017; 1868:564-570. [PMID: 29054475 DOI: 10.1016/j.bbcan.2017.10.002] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/04/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.
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Affiliation(s)
- Leilei Niu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Liping Liu
- Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China
| | - Shengli Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianwei Ren
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China.
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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18
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Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model. PLoS One 2017; 12:e0181944. [PMID: 28829785 PMCID: PMC5567696 DOI: 10.1371/journal.pone.0181944] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.
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19
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Li J, Liu W, Zhu W, Wu Y, Wu B. Transcatheter hepatic arterial chemoembolization and sorafenib for hepatocellular carcinoma: a meta-analysis of randomized, double-blind controlled trials. Oncotarget 2017; 8:59601-59608. [PMID: 28938663 PMCID: PMC5601759 DOI: 10.18632/oncotarget.19334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 07/06/2017] [Indexed: 12/11/2022] Open
Abstract
We performed a meta-analysis of transcatheter hepatic arterial chemoembolization (TACE) combined with sorafenib for hepatocellular carcinoma (HCC), which included 4 double-blind, randomized controlled trials (RCTs) that investigated the effects of TACE combined with sorafenib (experimental groups) on time to disease progression (TTP), overall survival (OS), and various sorafenib-related adverse events, compared to those in the placebo (control) groups. A total of 877 HCC cases from 14 countries, including China and the USA, were included in our meta-analysis. The TTP increased significantly in the experimental groups (hazard ration [HR]: 0.82; 95% CI: 0.69–0.97; p = 0.02), but OS did not improve significantly (HR: 0.97; 95% CI: 0.72–1.29; p = 0.82), compared with the control groups. The risks of hand and foot skin reactions (HFSR), rash, fatigue, and diarrhea were significantly greater in the experimental groups (p < 0.05 for all), compared to those in the control groups, whereas the risk of nausea was statistically similar (p > 0.05). Among these, the risk of HFSR was highest (risk ratio [RR]: 5.93; 95% CI: 2.00–17.53; p = 0.001), and a subgroup analysis of studies that lacked significant heterogeneity in the HFSR data showed a higher risk of HFSR (RR: 10.96; 95% CI: 5.54–21.69; p < 0.05). In conclusion, although TACE plus sorafenib increases TTP, it does not improve OS. Therefore, the risk of the adverse events of TACE plus sorafenib should be considered as a potential therapeutic limitation.
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Affiliation(s)
- Jun Li
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Wenhui Liu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Wenhua Zhu
- Department of Oncology, Chinese 309th Hospital of PLA, Beijing 100091, China
| | - Yinqiao Wu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
| | - Benyan Wu
- Department of Gastroenterology, Chinese PLA General Hospital, Beijing 100853, China
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20
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Sui J, Cui Y, Cai H, Bian S, Xu Z, Zhou L, Sun Y, Liang J, Fan Y, Zhang X. Synergistic chemotherapeutic effect of sorafenib-loaded pullulan-Dox conjugate nanoparticles against murine breast carcinoma. NANOSCALE 2017; 9:2755-2767. [PMID: 28155940 DOI: 10.1039/c6nr09639e] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
pH-Sensitive pullulan-doxorubicin conjugates encapsulating sorafenib (P-Dox/S) nanoparticles were developed as a synergistic combinatorial delivery system against murine breast carcinoma. The nanoparticles can encapsulate Dox and sorafenib with ultra-high loading capacity (65.34 wt%) through chemical conjugation and physical loading, whereas can remain stable under physiological conditions and gradually release Dox and sorafenib with the decreasing pH. These conjugates can be effectively internalized and clearly suppress 4T1 cell growth in vitro. Furthermore, research data of in vivo animal models revealed that the synergistic combinatorial P-Dox/S nanoparticles heavily accumulated in solid tumor tissue sites to maximize therapeutic efficacy; they also significantly inhibited solid tumor growth, even remarkably reduced solid tumor volume in comparison to the initial volume, and obviously diminished adverse effects. The anti-tumor therapeutic effect obviously outperformed the delivery of combinational chemotherapy of free drugs or single drug-loaded P-Dox nanoparticles at the same concentration. These promising results indicate the high-efficiency synergistic chemotherapeutic effects of these nanoparticles. Combinational chemotherapy using P-Dox/S nanoparticles has important potential in the clinical treatment of malignancy for overcoming drug resistance and heterogeneity.
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Affiliation(s)
- Junhui Sui
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Yani Cui
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Hanxu Cai
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Shaoquan Bian
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Zhiyi Xu
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Ling Zhou
- Cancer Center, West China hospital, Sichuan University, 37 Guoxue Lane, Chengdu 610064, China
| | - Yong Sun
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Jie Liang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Yujiang Fan
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
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21
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Liao Y, Zheng Y, He W, Li Q, Shen J, Hong J, Zou R, Qiu J, Li B, Yuan Y. Sorafenib therapy following resection prolongs disease-free survival in patients with advanced hepatocellular carcinoma at a high risk of recurrence. Oncol Lett 2017; 13:984-992. [PMID: 28356989 PMCID: PMC5351299 DOI: 10.3892/ol.2016.5525] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Accepted: 05/13/2016] [Indexed: 01/27/2023] Open
Abstract
Sorafenib is the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC); however, its therapeutic value in patients with HCC following resection remains controversial. The current retrospective study was undertaken to assess the effects of sorafenib treatment following surgical resection in patients with advanced HCC disease who were at a high risk for recurrence. Between July 2010 and July 2013, a consecutive cohort of 42 patients with advanced HCC and at a high risk of recurrence (i.e., those with portal vein tumor thrombosis, adjacent organ involvement or tumor rupture) who underwent resection were analyzed. The patients were categorized into the sorafenib group (n=14) or the best supportive care (BSC) group (n=28). Although the histological grade, Barcelona Clinic Liver Cancer Stage, tumor size, nodule number and proportion of patients with high serum α-fetoprotein levels were comparable between the sorafenib and BSC groups, those receiving sorafenib following resection had significantly longer disease-free survival (DFS) of 5.2 months [95% confidence interval (CI), 1.2-9.2 months] compared with the BSC group [1.8 months (95% CI, 0.6-3.0 months)]. No differences in overall survival were noted between the groups. Furthermore, no drug-related adverse events resulted in discontinuation of sorafenib therapy. Univariate log-rank analysis revealed that sorafenib treatment (P=0.002) and treatment prior to resection (P=0.012) were significantly associated with longer DFS; however, sorafenib therapy (P=0.027) and tumor size (P=0.028) were associated with longer DFS by multivariate analysis. Furthermore, sorafenib was well-tolerated and improved DFS in patients with advanced HCC who underwent hepatic resection. Thus, tumor resection followed by sorafenib therapy may represent an effective therapeutic strategy for patients with advanced HCC. This possibility should be confirmed in larger, multicenter studies.
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Affiliation(s)
- Yadi Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Yun Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Wei He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Qijiong Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Jingxian Shen
- Department of Medical Imaging and Interventional Center, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Jian Hong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Ruhai Zou
- Department of Ultrasound, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Jiliang Qiu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Binkui Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
- Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
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22
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Schmid I, von Schweinitz D. Pediatric hepatocellular carcinoma: challenges and solutions. J Hepatocell Carcinoma 2017; 4:15-21. [PMID: 28144610 PMCID: PMC5248979 DOI: 10.2147/jhc.s94008] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (α-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%–90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable – individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine.
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Affiliation(s)
| | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
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23
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Xu Y, Zhao Y, Xu Y, Guan Y, Zhang X, Chen Y, Wu Q, Zhu G, Chen Y, Sun F, Wang J, Yu Y. Blocking inhibition to YAP by ActinomycinD enhances anti-tumor efficacy of Corosolic acid in treating liver cancer. Cell Signal 2017; 29:209-217. [DOI: 10.1016/j.cellsig.2016.11.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 11/01/2016] [Accepted: 11/01/2016] [Indexed: 01/02/2023]
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24
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Zerkoune L, Lesieur S, Putaux JL, Choisnard L, Gèze A, Wouessidjewe D, Angelov B, Vebert-Nardin C, Doutch J, Angelova A. Mesoporous self-assembled nanoparticles of biotransesterified cyclodextrins and nonlamellar lipids as carriers of water-insoluble substances. SOFT MATTER 2016; 12:7539-7550. [PMID: 27714323 DOI: 10.1039/c6sm00661b] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Soft mesoporous hierarchically structured particles were created by the self-assembly of an amphiphilic deep cavitand cyclodextrin βCD-nC10 (degree of substitution n = 7.3), with a nanocavity grafted by multiple alkyl (C10) chains on the secondary face of the βCD macrocycle through enzymatic biotransesterification, and the nonlamellar lipid monoolein (MO). The effect of the non-ionic dispersing agent polysorbate 80 (P80) on the liquid crystalline organization of the nanocarriers and their stability was studied in the context of vesicle-to-cubosome transition. The coexistence of small vesicular and nanosponge membrane objects with bigger nanoparticles with inner multicompartment cubic lattice structures was established as a typical feature of the employed dispersion process. The cryogenic transmission electron microscopy (cryo-TEM) images and small-angle X-ray scattering (SAXS) structural analyses revealed the dependence of the internal organization of the self-assembled nanoparticles on the presence of embedded βCD-nC10 deep cavitands in the lipid bilayers. The obtained results indicated that the incorporated amphiphilic βCD-nC10 building blocks stabilize the cubic lattice packing in the lipid membrane particles, which displayed structural features beyond the traditional CD nanosponges. UV-Vis spectroscopy was employed to characterize the nanoencapsulation of a model hydrophobic dimethylphenylazo-naphthol guest compound (Oil red) in the created nanocarriers. In perspective, these dual porosity carriers should be suitable for co-encapsulation and sustained delivery of peptide, protein or siRNA biopharmaceuticals together with small molecular weight drug compounds or imaging agents.
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Affiliation(s)
- Leïla Zerkoune
- Institut Galien Paris-Sud, CNRS UMR 8612, Univ. Paris-Sud, Université Paris-Saclay, LabEx LERMIT, 5 rue J.-B. Clément, 92296 Châtenay-Malabry cedex, France.
| | - Sylviane Lesieur
- Institut Galien Paris-Sud, CNRS UMR 8612, Univ. Paris-Sud, Université Paris-Saclay, LabEx LERMIT, 5 rue J.-B. Clément, 92296 Châtenay-Malabry cedex, France.
| | - Jean-Luc Putaux
- Université Grenoble Alpes, Centre de Recherches sur les Macromolécules Végétales (CERMAV), F-38000 Grenoble, France and CNRS, CERMAV, F-38000 Grenoble, France
| | - Luc Choisnard
- Université Grenoble Alpes, Département de Pharmacologie Moléculaire (DPM), F-38000 Grenoble, France and CNRS UMR 5063, DPM, F-38000 Grenoble, France
| | - Annabelle Gèze
- Université Grenoble Alpes, Département de Pharmacologie Moléculaire (DPM), F-38000 Grenoble, France and CNRS UMR 5063, DPM, F-38000 Grenoble, France
| | - Denis Wouessidjewe
- Université Grenoble Alpes, Département de Pharmacologie Moléculaire (DPM), F-38000 Grenoble, France and CNRS UMR 5063, DPM, F-38000 Grenoble, France
| | - Borislav Angelov
- Institute of Physics, ELI Beamlines, Academy of Sciences of the Czech Republic, Na Slovance 2, CZ-18221 Prague, Czech Republic
| | | | - James Doutch
- Diamond Light Source Ltd., Didcot, Oxfordshire OX11 0DE, UK
| | - Angelina Angelova
- Institut Galien Paris-Sud, CNRS UMR 8612, Univ. Paris-Sud, Université Paris-Saclay, LabEx LERMIT, 5 rue J.-B. Clément, 92296 Châtenay-Malabry cedex, France.
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25
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iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 12:1303-11. [PMID: 26964482 DOI: 10.1016/j.nano.2016.01.017] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 01/26/2016] [Accepted: 01/29/2016] [Indexed: 11/21/2022]
Abstract
The combination of doxorubicin (DOX) with sorafenib (SOR) has proven an effective strategy to enhance anti-hepatocellular carcinoma (HCC) efficacy. However, respective in vivo pharmacokinetic profiles and different endocytosis capacities of these two drugs greatly hinder their current application. Herein, the tumor-targeting peptide iRGD decorated lipid-polymer hybrid nanoparticles (NPs) with a shell-core structure were developed for co-delivery of DOX and SOR (DOX+SOR/iRGD NPs). After the drug ratio was optimized, the stabilized DOX+SOR/iRGD NPs were prepared. Through the iRGD-integrin recognition, DOX+SOR/iRGD NPs showed synergistic cytotoxicity, pro-apoptotic ability and enhanced internalization rate in human liver cancer HepG2 cells. In vivo pharmacokinetic result demonstrated that an extended circulation and bioavailability of DOX+SOR/iRGD NPs than free drugs. More importantly, DOX+SOR/iRGD NPs significantly enhanced antitumor efficiency in HCC xenograft mouse models. Overall, this study describes a promising nanoparticulate drug co-delivery strategy to combine clinical anticancer drugs and enhance anti-HCC efficacy.
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26
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Zhou X, Wang Y, Lee WYW, Or PMY, Wan DCC, Kwan YW, Yeung JHK. Miltirone Is a Dual Inhibitor of P-Glycoprotein and Cell Growth in Doxorubicin-Resistant HepG2 Cells. JOURNAL OF NATURAL PRODUCTS 2015; 78:2266-2275. [PMID: 26339922 DOI: 10.1021/acs.jnatprod.5b00516] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Miltirone (1), an abietane-type diterpene quinone isolated from Salvia miltiorrhiza, possesses anticancer activity in p-glycoprotein (P-gp)-overexpressing human cancer cells. Results of the current study suggest a dual effect of miltirone on P-gp inhibition and apoptotic induction in a human hepatoma HepG2 cell line and its P-gp-overexpressing doxorubicin-resistant counterpart (R-HepG2). Miltirone (1) elicited a concentration-dependent cytotoxicity, with a similar potency (EC50 ≈ 7-12 μM), in HepG2 and R-HepG2 cells. Miltirone (1) (1.56-6.25 μM) produced synergistic effects on doxorubicin (DOX)-induced growth inhibition of R-HepG2 (synergism: 0.3 < combination index < 0.5). Molecular docking studies illustrated that miltirone (1) interacted with the active site of P-gp with a higher binding affinity than DOX, suggesting that it was a P-gp inhibitor. Flow cytometric analysis confirmed miltirone (1) as a competitive inhibitor of P-gp. At non-necrotic concentrations (1.56-25 μM), miltirone (1) activated caspase-dependent apoptotic pathways and triggered the generation of reactive oxygen species (ROS) and ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways (e.g., p38 MAPK, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular regulated kinase 1/2) in both HepG2 and R-HepG2 cells. Thus, we conclude that miltirone (1) is a dual inhibitor of P-gp and cell growth in human drug-resistant hepatoma cells.
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Affiliation(s)
- Xuelin Zhou
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - Yan Wang
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - Wayne Y W Lee
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - Penelope M Y Or
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - David C C Wan
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - Yiu Wa Kwan
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
| | - John H K Yeung
- School of Biomedical Sciences, ⊥Department of Orthopaedics & Traumatology, Faculty of Medicine, ‡Institute of Chinese Medicine, and §State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong , Hong Kong, People's Republic of China
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27
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Cuestas ML, Oubiña JR, Mathet VL. Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement. World J Pharmacol 2015; 4:96-116. [DOI: 10.5497/wjp.v4.i1.96] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/02/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and the third most common cause of cancer-related death in the world. The main risk factor worldwide for this type of malignancy is chronic hepatitis caused by hepatitis B virus and hepatitis C virus infections. Advances in early detection and treatment have improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have revealed that there is an 8-mo median survival rate in patients, approximately 20% of whom survive one year while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy is due, among other mechanisms, to several members of the ATP-Binding Cassette protein family involved in drug transport being overexpressed. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript intends to provide further insight into the etiology and molecular mechanisms related to HCC development and the latest therapeutic approaches to treat this malignancy. The development of effective delivery systems of antitumor drugs able to target the liver parenchyma is also assessed. Finally, the prospects in the development of more efficient drug therapies to overcome multidrug resistance are also examined.
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28
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Cao H, Wang Y, He X, Zhang Z, Yin Q, Chen Y, Yu H, Huang Y, Chen L, Xu M, Gu W, Li Y. Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma. Mol Pharm 2015; 12:922-31. [PMID: 25622075 DOI: 10.1021/mp500755j] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Herein, we first reported the codelivery of sorafenib and curcumin by directed self-assembled nanoparticles (SCN) to enhance the therapeutic effect on HCC. SCN was formed by employing the hydrophobic interactions among the lipophilic structure in sorafenib, curcumin, and similar hydrophobic segments of polyethylene glycol derivative of vitamin E succinate (PEG-VES), which comprised uniform spherical particles with particle size of 84.97 ± 6.03 nm. SCN presented superior effects over sorafenib, curcumin, and their physical mixture (Sora + Cur) on enhancing in vitro cytotoxicity and cell apoptosis in BEL-7402 cells and Hep G2 cells, and antiangiogenesis activities in tube formation and microvessel formation from aortic rings. Moreover, the tissue concentration of sorafenib and curcumin in gastrointestinal tract and major organs were significantly improved after their coassembly into SCN. In particular, in BEL-7402 cells induced tumor xenograft, SCN treatment displayed the obviously enhanced inhibitory effect on tumor progression over free drug monotherapy or their physical mixture, with significantly increased antiproliferation and antiangiogenesis capability. Thereby, the codelivered nanoassemblies of sorafenib and curcumin provided a promising strategy to enhance the combinational therapy of HCC.
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Affiliation(s)
- Haiqiang Cao
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China
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Chen Y, Angelova A, Angelov B, Drechsler M, Garamus VM, Willumeit-Römer R, Zou A. Sterically stabilized spongosomes for multidrug delivery of anticancer nanomedicines. J Mater Chem B 2015; 3:7734-7744. [DOI: 10.1039/c5tb01193k] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
SAXS patterns of drug-loaded lipid nanocarriers stabilized by polysorbate P80 (left); cryo-TEM image of BAI-BJO-spongosomes-2 (right).
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Affiliation(s)
- Yiyin Chen
- East China University of Science and Technology
- Shanghai
- China
| | - Angelina Angelova
- CNRS UMR8612 Institut Galien Paris-Sud
- Univ Paris Sud
- LabEx LERMIT
- Châtenay-Malabry
- F-92296 France
| | - Borislav Angelov
- Institute of Macromolecular Chemistry
- Academy of Sciences of the Czech Republic
- 16206 Prague
- Czech Republic
| | - Markus Drechsler
- Laboratory for Soft Matter Electron Microscopy
- Bayreuth Institute of Macromolecular Research (BIMF)
- University of Bayreuth
- D-95440 Bayreuth
- Germany
| | - Vasil M. Garamus
- Helmholtz-Zentrum Geesthacht
- Centre for Materials and Coastal Research
- D-21502 Geesthacht
- Germany
| | - Regine Willumeit-Römer
- Helmholtz-Zentrum Geesthacht
- Centre for Materials and Coastal Research
- D-21502 Geesthacht
- Germany
| | - Aihua Zou
- East China University of Science and Technology
- Shanghai
- China
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Hsieh SC, Tsai JP, Yang SF, Tang MJ, Hsieh YH. Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 2014; 46:2809-22. [PMID: 25245054 DOI: 10.1007/s00726-014-1838-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/10/2014] [Indexed: 12/28/2022]
Abstract
Metformin has been shown to exert anti-cancer activities in several cancer cells and animal models. However, the molecular mechanisms of its anti-metastatic activities remain poorly understood and warrant further investigation. The aims of this study were to evaluate the ability of metformin to inhibit the migration and invasion of hepatocellular carcinoma (HCC) cells and identify its effects on signaling pathways. Our data indicate that metformin inhibits the migration and invasion of human HCC cells. Metformin was also found to significantly inhibit the expression and secretion of MMP-9 and uPA in HCC cells, and suppress the phosphorylation of ERK1/2 and JNK1/2. Treatment with an ERK1/2 inhibitor (PD98059) or JNK1/2 inhibitor (SP600125) enhanced the inhibitory effects of metformin on the migration and invasion of HCC cells. Moreover, metformin-induced inhibition of MMP-9 and uPA promoter activity also blocked the nuclear translocation of NF-κB and its binding to the MMP-9 and uPA promoters, and these suppressive effects were further enhanced by PD98059 or SP600125. Moreover, metformin markedly enhanced the anti-metastatic effects of sorafenib. In conclusion, metformin inhibits the migration and invasion of HCC cells by suppressing the ERK/JNK-mediated NF-κB-dependent pathway, and thereby reducing uPA and MMP-9 expression. Additionally, combination treatment with metformin and sorafenib yielded synergistic inhibitory effects in suppressing cell migration and invasion of HCC cells. These findings provide insight into the molecular mechanisms involved in the anti-metastatic effects of metformin, as well as its ability to enhance the chemosensitivity of HCC cells to sorafenib.
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Affiliation(s)
- Shu-Ching Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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31
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Surgical treatment of extrahepatic recurrence of hepatocellular carcinoma. Langenbecks Arch Surg 2014; 399:1057-64. [PMID: 25030500 DOI: 10.1007/s00423-014-1230-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 07/10/2014] [Indexed: 12/20/2022]
Abstract
PURPOSE The purpose of this study was to clarify the clinicopathological features of extrahepatic hepatocellular carcinoma (HCC) recurrence after hepatectomy in order to schedule optimal treatment strategies for better long-term outcomes. METHODS A cohort of 206 patients who had undergone curative hepatectomy for HCC was analysed; 133 patients had developed relapse. Among them, 101 patients had intrahepatic recurrence only (IHR), and 32 patients had extrahepatic recurrence (EHR). Clinicopathological and survival data were compared between the two groups. RESULTS The overall survival rate after hepatectomy was better in the IHR than in the EHR group (p<0.0001). The recurrence-free interval after hepatectomy was significantly shorter in the EHR than in the IHR group (258 vs. 487 days, p<0.0043). Patients in the EHR group were more likely to have a high PIVKA II, a large tumour, and microscopic portal vein invasion when compared with patients in the IHR group. Microscopic portal vein invasion was the most important independent risk factor for EHR after hepatectomy (p=0.0295). Patients with more than two risk factors for EHR showed poor prognosis in comparison with patients without any risk factors (p<0.001). In the EHR group, patients who underwent repeated resection had significantly better survival than patients receiving only the best supportive care (539 vs. 133 days, p=0.0098). Furthermore, among EHR patients with concomitant IHR, patients with controllable IHR had significantly better survival than those with uncontrollable IHR (524 vs. 147 days, p=0.0131). CONCLUSIONS EHR of HCC was associated with early recurrence, and risk factors for the occurrence of EHR included the presence of high PIVKA II, large tumours, and microscopic portal vein invasion. Resection of recurrent tumour and local control of concomitant IHR may improve the prognosis of EHR patients.
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Harding JJ, Abou-Alfa GK. Treating advanced hepatocellular carcinoma: How to get out of first gear. Cancer 2014; 120:3122-30. [PMID: 24898783 DOI: 10.1002/cncr.28850] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 04/03/2014] [Accepted: 04/23/2014] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma is a common malignancy with a poor prognosis. Sorafenib is the only systemic therapy known to improve the overall survival of patients with advanced disease. The clinical benefit of sorafenib is modest and the mechanistic basis for its activity is unknown. Four phase 3 clinical trials have failed to improve on sorafenib in the frontline setting and no agent has been shown to impact outcomes after sorafenib failure. Several factors have contributed to this recent stall in drug development but new approaches hold promise and currently are being investigated. This review will focus on the current pipeline of experimental therapeutics for patients with advanced hepatocellular carcinoma and shed a light on scientific limitations that hamper the advancement of new therapies for this disease, and ways around it.
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Affiliation(s)
- James J Harding
- Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, New York
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Abstract
The multikinase inhibitor sorafenib, which inhibits targets related to tumor cell proliferation and angiogenesis, was the first systemic agent to demonstrate a significant improvement in the overall survival for patients with advanced hepatocellular carcinoma (HCC) in two large randomized controlled Phase III trials. Together with its manageable safety profile (mainly diarrhea, hand-foot skin reaction and fatigue), sorafenib was approved for the treatment of patients with (unresectable) HCC in 2007. Since then, sorafenib has been established as the standard of care in Child-Pugh A patients with advanced HCC or in those ineligible for or after failure of locoregional therapies in the intermediate stage of the disease. This article summarizes current knowledge and future perspectives regarding the use of sorafenib in patients with HCC.
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Affiliation(s)
- Marcus Alexander Wörns
- First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Peter Robert Galle
- First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
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Abdel-Rahman O, Fouad M. Sorafenib-based combination as a first line treatment for advanced hepatocellular carcinoma: a systematic review of the literature. Crit Rev Oncol Hematol 2014; 91:1-8. [PMID: 24457121 DOI: 10.1016/j.critrevonc.2013.12.013] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 12/04/2013] [Accepted: 12/18/2013] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Advanced HCC is a distinct disease entity with limited approved treatment options and grave prognosis. So, we will explore in this systematic review the value of using sorafenib-based combination in this poor prognosis subset of HCC. METHODS PubMed, Medline, the Cochrane Library, trip database and Google Scholar were searched using the terms "Hepatocellular carcinoma" OR "Hepatoma" or "Liver cancer" AND "systemic anticancer therapy" AND "Sorafenib" and specifying only English literature. Outcomes of interest included progression free survival and overall survival (PFS and OS), tumor response, and toxicities. RESULTS A total of 17 potentially relevant trials was identified, of which 9 studies were excluded. Hence, eight trials involving 272 patients were included. Median PFS was reported in 6 out of the 8 trials ranging from 3.7 to 7.5 months. Median OS was reported in 6 out of the 8 studies ranging from 7.4 to 40.1 months. The DCR was reported in the 8 studies, ranging from 48.7% to 76%. Frequently reported Grade 3/4 toxicities were increased AST/ALT, fatigue, hypertension, hand foot skin reaction and diarrhea. However, some chemotherapy-specific side effects were noted in some studies. CONCLUSIONS The current evidence from the available clinical trials suggests that sorafenib-based combination with some anticancer agents (especially mTOR inhibitors) could be a more effective and tolerable treatment for advanced HCC in the future. However, such sorafenib-based combination cannot be recommended outside the setting of clinical trials.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | - Mona Fouad
- Medical Microbiology and Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Vogl TJ, Lee C. Doxorubicin -eluting beads in the treatment of liver carcinoma. Expert Opin Pharmacother 2013; 15:115-20. [PMID: 24215628 DOI: 10.1517/14656566.2014.855719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
INTRODUCTION Doxorubicin and especially doxorubicin-eluting beads (DEBs) have become an intensive study subject in the locoregional therapy of liver carcinoma over the past 6 years. Since sorafenib has become the new standard in the treatment of advanced liver carcinoma and has been combined with DEB in clinical studies to evaluate safety and efficacy, it has shown promising results. Thus, the authors have investigated the evidence that DEB is a potential drug in the treatment of intermediate liver carcinoma, even in combination with systemic therapies. AREAS COVERED Evaluation of published articles in English using metadatabase such as PubMed. EXPERT OPINION Since there is no standard therapy regimen in the locoregional transarterial treatment of intermediate liver carcinoma, DEBs were designed to offer an attempt to homogenize the use of cytostatic and embolic agents. The development of so-called doxorubicin-eluting beads in the past few years is an effort to minimize systemic toxicity and increase local drug concentration. In the therapy of liver carcinoma, doxorubicin should not be systemically administered due to its high toxicity. Clinical trials indicate that the administration of DEB is safe and effective for the treatment of liver carcinoma and can even be combined with systemic drugs such as sorafenib.
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Affiliation(s)
- Thomas J Vogl
- J.W Goethe-University Hospital, Department of Diagnostic and Interventional Radiology , Theodor-Stern-Kai 7, 60590 Frankfurt/Main , Germany +0049 69 6301 7277 ; +0049 69 6301 7258 ;
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Welker MW, Trojan J. Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety. Cancer Manag Res 2013; 5:337-47. [PMID: 24204170 PMCID: PMC3804539 DOI: 10.2147/cmar.s35029] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety.
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Affiliation(s)
| | - Joerg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany
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Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol 2013; 14:e283-8. [PMID: 23725711 DOI: 10.1016/s1470-2045(13)70161-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The recommendation of sorafenib as standard of care in advanced hepatocellular carcinoma has lent support to the increased use of antiangiogenic therapies. However, in three phase 3 randomised trials that compared other antiangiogenics with sorafenib, results did not show superiority or non-inferiority of the new therapies. The 10-month median overall survival shown in these studies for patients given sorafenib might be a ceiling for single-agent antiangiogenic therapy. Strategies to increase survival time include combination therapies that pair antiangiogenic treatment with biological therapy or chemotherapy. The combination of sorafenib and erlotinib was not superior to sorafenib alone, which suggests no positive interaction between antiangiogenics and tyrosine kinase inhibitors in the treatment of advanced hepatocellular carcinoma. A combination of sorafenib and doxorubicin is being assessed in a randomised phase 3 trial. Differences in patient outcome with sorafenib because of disease cause and the ethnic origin of patients suggest that sorafenib's multitarget capacity, including RAF kinase inhibition, might be important. MET inhibitors cabozantinib and tivantinib are drugs that might also bypass the so-called antiangiogenic ceiling and have led to selective treatment of patients that overexpress MET with these drugs. Although this intense period of research activity has not yet resulted in significant improvements in survival for patients with advanced hepatocellular carcinoma, we are certainly closer to a customised treatment, which should increase the antiangiogenic survival ceiling.
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Affiliation(s)
- Ghassan K Abou-Alfa
- Section of Gastrointestinal Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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In-vitro growth inhibition of chemotherapy and molecular targeted agents in hepatocellular carcinoma. Anticancer Drugs 2013. [PMID: 23187461 DOI: 10.1097/cad.0b013e32835ba289] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and challenging malignant disease. The prognosis is poor in patients with advanced disease. Although sorafenib prolongs survival in these patients, improvement remains modest. We used doxorubicin and sorafenib as controls and screened eight new agents including ixabepilone, gefitinib, cetuximab, brivanib, dasatinib, sunitinib, BMS-690514, and BMS-536924 against nine HCC cell lines and evaluated their interactions. We studied growth inhibition of 10 drugs against nine HCC cell lines. Single-agent activity was tested using an MTS assay. Combination studies were carried out in both resistant and sensitive cells to determine the combination index. The IC50 of each agent varied widely among nine cell lines. Ixabepilone was more potent than doxorubicin. HT-17 cells were more sensitive to gefitinib and cetuximab than the other eight cell lines. BMS-536924 showed good efficacy (IC50 ≤ 1 µmol/l) on all three α-fetoprotein (AFP)-producing cell lines (HepG2, Hep3B, Huh-7). Three cell lines showed moderate sensitivity to dasatinib (IC50 ≤ 1 µmol/l). Dasatinib showed the most frequent and strongest synergism with ixabepilone, gefitinib, brivanib, BMS-690514, or BMS-536924. Ixabepilone, sorafenib, brivanib, dasatinib, and BMS-536924 are active against HCC cell lines. The heterogeneity of the sensitivity of each cell line emphasizes the need for individualized treatment. The sensitivity to BMS-536924 is closely associated with the production of AFP. AFP may be a biomarker predicting response to the insulin-like growth factor-1 receptor inhibitor in HCC patients. Additional studies are warranted. The synergism between dasatinib and other agents also provides future research directions to understand drug resistance and improve outcome.
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Duffy A, Wilkerson J, Greten TF. Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies. Hepatology 2013; 57:1068-77. [PMID: 23112096 PMCID: PMC3584189 DOI: 10.1002/hep.26120] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 10/11/2012] [Indexed: 12/13/2022]
Abstract
UNLABELLED The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with antiangiogenic agents. We performed a systematic review and meta-analysis of antiangiogenic studies in HCC from 1995 to 2011. For nonrandomized studies we compared bleeding risk with other HCC single-arm studies that did not include an antiangiogenic agent. To separate disease-specific factors we also performed a comparison analysis with renal cell cancer (RCC)) studies that evaluated sorafenib. Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.04, 3.0) but not grade 3-5 events in both HCC and RCC (OR 1.46; 95% CI 0.9, 2.36; P=0.45). When comparing the risk of bleeding in single-arm phase 2 studies evaluating antiangiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. CONCLUSION This analysis of both randomized and nonrandomized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower-grade events and similar in magnitude to the risk encountered in RCC.
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Affiliation(s)
- Austin Duffy
- Gastrointestinal Malignancy Section, Medical Oncology Branch, National Cancer Institute
| | - Julia Wilkerson
- Experimental Therapeutics Section, Medical Oncology Branch, National Cancer Institute
| | - Tim F. Greten
- Gastrointestinal Malignancy Section, Medical Oncology Branch, National Cancer Institute
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Yagublu V, Caliskan N, Lewis AL, Jesenofsky R, Gasimova L, Löhr JM, Keese M. Treatment of experimental pancreatic cancer by doxorubicin-, mitoxantrone-, and irinotecan-drug eluting beads. Pancreatology 2012; 13:79-87. [PMID: 23395574 DOI: 10.1016/j.pan.2012.11.305] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 11/07/2012] [Accepted: 11/08/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Peritoneal carcinomatosis is a common cause of death in pancreatic cancer patients. In this metastatic stage of the disease, few patients show a sustained response to therapy. In the palliative situation, targeted and compartment restricted delivery of drugs offers the opportunity to focus drugs directly to the tumor site, which is a prerequisite for avoiding toxic side effects. Here, we demonstrate the therapeutic efficiency of biocompatible polyvinyl-alcohol hydrogel drug eluting beads (DEBs) containing doxorubicin, mitoxantrone and irinotecan in vitro and in vivo in a syngenic model of experimental pancreatic cancer. METHODS Panc02 murine pancreatic carcinoma cells were exposed to doxorubicin, mitoxantrone and irinotecan DEBs and free compounds. The effect on cell proliferation and apoptosis induction was compared. Using this cell line, peritoneal carcinomatosis was induced in C57 black6 mice. Mortality, tumor load and therapy-associated weight loss were compared after treatment of tumor-bearing mice with DEBs or free compounds. RESULTS In vitro treatment with DEBs decreases tumor cell proliferation and induces apoptosis. The effect is less pronounced than with corresponding doses of the free drug. Repeated applications of the free drugs in vivo, however, induce significantly higher lethality and weight loss than corresponding doses of DEBs. No relevant differences in antitumoral activity were observed. Using computer tomography and HE-histology after subcutaneous and intraperitoneal injection of radiopaque beads no systemic spread of the beads could be found. CONCLUSION DEBs show the advantage of delivering potent cytotoxic activity to the intraperitoneal tumor manifestation while maintaining a low systemic toxicity.
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Affiliation(s)
- Vugar Yagublu
- Surgical Clinic, University Medicine Mannheim, Mannheim, Germany
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Liapi E, Geschwind JFH. Combination of local transcatheter arterial chemoembolization and systemic anti-angiogenic therapy for unresectable hepatocellular carcinoma. Liver Cancer 2012; 1:201-15. [PMID: 24159585 PMCID: PMC3760461 DOI: 10.1159/000343835] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The pathophysiologic complexity of hepatocellular carcinoma (HCC) and underlying hepatic cirrhosis, make optimal treatment choice a clinical challenge. The radical change in the treatment algorithm of patients with advanced unresectable HCC over the past 7 years, with the introduction of anti-angiogenic agents in patients with only preserved liver function reflect this challenge. Even though data from studies on the combination of transcatheter arterial chemoembolization and anti-angiogenic agents demonstrate a survival advantage in selected patients, this combination is not straightforward. In this review, we'll examine current data of administering anti-angiogenic therapy in combination with transcatheter arterial chemoembolization and critically evaluate the progress and gaps in current knowledge.
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Affiliation(s)
| | - Jean-Francois H. Geschwind
- Division of Vascular and Interventional Radiology, Johns Hopkins University School of Medicine, Interventional Radiology Center, Baltimore, Maryland, USA
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Xie B, Wang DH, Spechler SJ. Sorafenib for treatment of hepatocellular carcinoma: a systematic review. Dig Dis Sci 2012; 57:1122-9. [PMID: 22451120 PMCID: PMC3596114 DOI: 10.1007/s10620-012-2136-1] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 03/02/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND Sorafenib, a drug that inhibits Raf serine/threonine kinases mediating cell proliferation and receptor tyrosine kinases involved in angiogenesis, is approved for treatment of advanced hepatocellular carcinoma. AIMS To explore the efficacy and safety of sorafenib for treating advanced HCC, and to identify clinical factors that might affect that efficacy and safety. METHODS We conducted a systematic review using the PRISMA guidelines to identify prospective studies on sorafenib used alone or in combination with systemic and/or loco regional anti-tumor therapy for treating advanced HCC. RESULTS We identified 21 prospective trials of sorafenib treatment alone (7) or combined with other treatment (14). In randomized, placebo-controlled trials, sorafenib prolonged overall survival by 2.3-2.8 months, extended the time to tumor progression by 1.4-2.7 months, and increased disease control by 11-19 %. OS and DCRs were lowest for studies with the highest percentage of hepatitis B patients. Most studies reported major side effects (diarrhea, fatigue, and hand-foot syndrome) in <15 % of patients, with greater incidence in patients with advanced cirrhosis and those treated with sorafenib in combination with 5-FU drugs. CONCLUSIONS Treatment with sorafenib results in statistically significant, but clinically modest, improvements in OS, TTP, and DCR. For patients with hepatitis B, response seems to be poorer than for those with hepatitis C. The frequency of hand-foot syndrome seems to be higher when sorafenib is used in advanced cirrhosis and is combined with 5-FU drugs. It is not clear that sorafenib combined with other treatments is more effective than sorafenib alone.
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MESH Headings
- Antineoplastic Protocols
- Benzenesulfonates/administration & dosage
- Benzenesulfonates/adverse effects
- Carcinoma, Hepatocellular/complications
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Proliferation/drug effects
- Chemoembolization, Therapeutic/methods
- Hand-Foot Syndrome
- Hepatitis, Viral, Human/complications
- Humans
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis/complications
- Liver Neoplasms/complications
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/etiology
- Neovascularization, Pathologic/metabolism
- Niacinamide/analogs & derivatives
- Phenylurea Compounds
- Protein Kinase Inhibitors/administration & dosage
- Protein Kinase Inhibitors/adverse effects
- Pyridines/administration & dosage
- Pyridines/adverse effects
- Randomized Controlled Trials as Topic
- Receptor Protein-Tyrosine Kinases/metabolism
- Sorafenib
- Treatment Outcome
- raf Kinases/metabolism
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Affiliation(s)
- Bingru Xie
- Department of Medicine, VA North Texas Healthcare System, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, Kammer B, Kontny U, Leuschner I, Scheel-Walter HG, Scheurlen W, Werner S, Wiesel T, von Schweinitz D. Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. Pediatr Blood Cancer 2012; 58:539-44. [PMID: 21922643 DOI: 10.1002/pbc.23295] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Accepted: 07/06/2011] [Indexed: 01/14/2023]
Abstract
PURPOSE Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m(2) /day, doxorubicin 2 × 30 mg/m(2) /day) in combination with sorafenib in pediatric HCC patients. PATIENTS AND METHODS Clinical data of 12 patients (7-16 years), 7 with unresectable tumor, were retrospectively assessed. RESULTS In total 6/12 (50%) patients are in complete remission after a median follow-up of 20 months (4 with PLADO/sorafenib/resection, 2 with liver transplantation after local relapse). Of the seven patients with unresectable tumor, PLADO/sorafenib resulted in partial response (PR) in four, stable disease (SD) in two, and progression in one. Three are alive in CR after complete resection after 12 (alternative therapy after two cycles PLADO/sorafenib), 12 and 18 months (six cycles PLADO/sorafenib), respectively. All four patients with elevated alpha-fetoprotein levels had a marked drop after two cycles. Of the five patients with primary complete tumor resection one is alive disease-free at 27 months. Four had local or metastatic relapses (13, 7, 12, and 13 months), two of whom were rescued by liver transplantation (CR after 25 and 32 months). The main toxicity attributable to sorafenib was a hand-foot skin reaction (HFSR) in seven patients. CONCLUSION Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib.
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Affiliation(s)
- Irene Schmid
- Department of Pediatric Hematology and Oncology, Children's Hospital of the Ludwig-Maximilians-University, Munich, Germany.
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Ansari D, Andersson R. Radiofrequency ablation or percutaneous ethanol injection for the treatment of liver tumors. World J Gastroenterol 2012; 18:1003-1008. [PMID: 22416173 PMCID: PMC3296972 DOI: 10.3748/wjg.v18.i10.1003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Revised: 12/26/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023] Open
Abstract
The liver is a common location of both primary and secondary malignancies. For unresectable liver cancer, many local ablative therapies have been developed. These include e.g., percutaneous ethanol injection (PEI), percutaneous acetic acid injection, radiofrequency ablation (RFA), cryoablation, microwave ablation, laser-induced thermotherapy, and high-intensity focused ultrasound. RFA has recently gained interest and is the most widely applied thermoablative technique. RFA allows more effective tumor control in fewer treatment sessions compared with PEI, but with a higher rate of complications. However, there are certain circumstances where PEI therapy represents a better strategy to control liver tumors than RFA, especially in situations where RFA is difficult, for example when large vessels surround the tumor. In the context of hepatocellular carcinoma (HCC), both RFA and PEI are feasible and of benefit in non-operable patients. RFA seems superior to PEI in HCC > 2 cm, and the combination of interventions may be of benefit in selected patients. Liver resection is superior to RFA for patients with HCC meeting the Milan criteria, but RFA can be employed in tumors ≤ 3 cm and where there is an increased expected operative mortality. In addition, some lines of evidence indicate that RFA and PEI can be employed as a bridge to liver transplantation. The use of RFA in colorectal liver metastases is currently limited to unresectable disease and for patients unfit for surgery. The aim of this article is to summarize the current status of RFA in the management of liver tumors and compare it to the cheap and readily available technique of PEI.
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Asghar U, Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J Hepatol 2012; 56:686-95. [PMID: 21971559 DOI: 10.1016/j.jhep.2011.07.031] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Revised: 07/25/2011] [Accepted: 07/28/2011] [Indexed: 02/07/2023]
Abstract
Hepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2-3 months in selected patients. Cytotoxic chemotherapy has been used for over 30 years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Here, we summarise the past and current data that constitute the evidence base for chemotherapy in HCC, review the causes of chemoresistance and suggest strategies to overcome these barriers.
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Affiliation(s)
- Uzma Asghar
- Department of Oncology, UCL Medical School, Royal Free Campus, London, UK
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Sieghart W, Pinter M, Reisegger M, Müller C, Ba-Ssalamah A, Lammer J, Peck-Radosavljevic M. Conventional transarterial chemoembolisation in combination with sorafenib for patients with hepatocellular carcinoma: a pilot study. Eur Radiol 2012; 22:1214-23. [PMID: 22215073 DOI: 10.1007/s00330-011-2368-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2011] [Revised: 11/21/2011] [Accepted: 11/22/2011] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To investigate the safety of transarterial chemoembolisation (TACE) in combination with sorafenib in patients with hepatocellular carcinoma (HCC). METHODS Patients with Child-Pugh A/B liver function, ECOG performance status 0-2 and HCC treatable with TACE received continuous sorafenib 800 mg/day, and TACE with doxorubicin (75, 50 and 25 mg/m(2) according to serum bilirubin: <1.5, 1.5-3, and >3 mg/dL) and lipiodol 2 weeks after sorafenib initiation and repeated every 4 weeks. RESULTS Fifteen patients were included (Child-Pugh A/B, n = 12/3; Barcelona Clinic Liver Cancer-A/B/C, n = 1/9/5; ECOG 0/2, n = 14/1). Median time on sorafenib was 5.2 months (2.6-7.4 months); median number of TACE sessions was 3. Common adverse events were abdominal pain (n = 14), weight loss (n = 13), alopecia (n = 12), fatigue (n = 12) and hyperbilirubinaemia (n = 11). There were 32 serious adverse events (grade ≥ 3); 9/10-unscheduled hospital admissions and 4/5 deaths were considered TACE-related. The study was stopped prematurely because of safety concerns. At 6 months, 2 and 5 patients had complete or partial responses; 1 had stable disease. Median overall survival was 10.6 months (95% CI: 5.2-16 months). CONCLUSION These findings do not support use of an intensive, high-dose doxorubicin-based TACE regimen in combination with sorafenib in this study population. KEY POINTS • Transarterial chemoembolisation (TACE) is widely used in patients with hepatocellular carcinoma (HCC) • Various antiangiogenic and other agents have been used to augment this treatment • We tested lipiodol-TACE with bilirubin-adjusted doxorubicin dosing in combination with sorafenib • This trial was stopped prematurely because of safety reasons • Our safety results do not support the combination of sorafenib with this TACE regimen.
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Affiliation(s)
- Wolfgang Sieghart
- Department of Gastroenterology/Hepatology, Medical University of Vienna, Währinger Gürtel, 18-20, 1090 Vienna, Austria
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Manov I, Pollak Y, Broneshter R, Iancu TC. Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by sorafenib - the role of extracellular signal-regulated kinase counteraction. FEBS J 2011; 278:3494-507. [DOI: 10.1111/j.1742-4658.2011.08271.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Abou-Alfa GK, Saltz LB. Doxorubicin and sorafenib for treatment of advanced hepatocellular cancer. Gastroenterology 2011; 141:e19-20; author reply e20-1. [PMID: 21794834 DOI: 10.1053/j.gastro.2011.04.063] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Accepted: 04/28/2011] [Indexed: 12/02/2022]
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Wang ML, Miao F, Tang YH, Zhao XS, Zhong J, Yuan F. Special diaphragm-like strictures of small bowel unrelated to non-steroidal anti-inflammatory drugs. World J Gastroenterol 2011; 17:3596-604. [PMID: 21987606 PMCID: PMC3180016 DOI: 10.3748/wjg.v17.i31.3596] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2010] [Revised: 01/22/2011] [Accepted: 01/29/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To summarize clinical, endoscopic, radiologic and pathologic features of special diaphragm-like strictures found in small bowel, with no patient use of non-steroidal anti-inflammatory drugs (NSAIDs).
METHODS: From January 2000 to December 2009, 5 cases (2 men and 3 women, with a mean age of 41.6 years) were diagnosed as having diaphragm-like strictures of small bowel on imaging, operation and pathology. All the patients denied the use of NSAIDs. The clinical, endoscopic, radiologic and pathologic findings in these 5 patients were retrospectively reviewed from the hospital database. Images of capsule endoscopy (CE) and small bowel follow-through (SBFT) obtained in 3 and 3 patients, respectively, and images of double-balloon enteroscopy and computed tomography enterography (CTE) obtained in all 5 patients were available for review.
RESULTS: All patients presented with long-term (2-16 years) symptoms of gastrointestinal bleeding and varying degrees of anemia. There was only one stricture in four cases and three lesions in one case, and all the lesions were located in the middle or distal segment of ileum. Circumferential stricture was shown in the small bowel in three cases in the CE image, but the capsule was retained in the small bowel of 2 patients. Routine abdomen computed tomography scan showed no other abnormal results except gallstones in one patient. The lesions were shown as circumferential strictures accompanied by dilated small bowel loops in the small bowel on the images of CTE (in all 5 cases), SBFT (in 2 cases) and double-balloon enteroscopy (in all cases). On microscopy, a chronic inflammatory infiltrate and circumferential diaphragm were found in all lesions.
CONCLUSION: Diaphragm-like strictures of small bowel might be a special consequence of unclear damaging insults to the intestine, having similar clinical, endoscopic, radiologic and pathologic features.
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Ganslmayer M, Zimmermann A, Zopf S, Herold C. Combined inhibitors of angiogenesis and histone deacetylase: efficacy in rat hepatoma. World J Gastroenterol 2011; 17:3623-9. [PMID: 21987609 PMCID: PMC3180019 DOI: 10.3748/wjg.v17.i31.3623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Revised: 03/07/2011] [Accepted: 03/14/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the antitumoral effect of combined inhibitors of angiogenesis and histone deacetylases in an experimental rat hepatoma model. METHODS MH7777A hepatoma cells were injected into the liver of male Buffalo rats. After 7 d treatment with the vascular endothelial growth factor receptor antagonist PTK787/ZK222584 (PTK/ZK), the histone deacetylase inhibitor MS-275, tamoxifen (TAM) and/or retinoic acid was initiated (n ≥ 8 animals/group). Natural tumor development was shown in untreated control groups (control 1 with n = 12, control 2 with n = 8). The control groups were initiated at different time points to demonstrate the stability of the hepatoma model. For documentation of possible side effects, we documented any change in body weight, loss of fur and diarrhea. After 21 d treatment, the rats were euthanized. Main target parameters were tumor size and metastasis rate. Additionally, immunohistochemistry for the proliferating cell nuclear antigen (PCNA) and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay were performed. RESULTS The control groups developed large tumor nodules with extrahepatic tumor burden in the lung and abdominal organs (control 1: 6.18 cm(3) ± 4.14 cm(3) and control 2: 8.0 cm(3) ± 4.44 cm(3) 28 d after tumor cell injection). The tumor volume did not differ significantly in the control groups (P = 0.13). As single agents MS-275 and PTK/ZK reduced tumor volume by 58.6% ± 2.6% and 48.7% ± 3.2% vs control group 1, which was significant only for MS-275 (P = 0.025). The combination of MS-275 and PTK/ZK induced a nearly complete and highly significant tumor shrinkage by 90.3% ± 1% (P = 0.005). Addition of TAM showed no further efficacy, while quadruple therapy with retinoic acid increased antitumoral efficacy (tumor reduction by 93 ± 1%) and side effects. PCNA positive cells were not significantly reduced by the single agents, while dual therapy (MS-275 and PTK/ZK) and quadruple therapy reduced the PCNA-positive cell fraction significantly by 9.1 and 20.6% vs control 1 (P < 0.05). The number of TUNEL-positive cells, markers for ongoing apoptosis, was increased significantly by the single agents (control 1: 6.9%, PTK/ZK: 11.4%, MS-275: 12.2% with P < 0.05 vs control 1). The fraction of TUNEL-positive cells was upregulated highly significantly by dual therapy (18.4%) and quadruple therapy (24.8%, P < 0.01 vs control 1). For the proliferating (PCNA positive) and apoptotic cell fraction, quadruple therapy was significantly superior to dual therapy (P = 0.01). CONCLUSION Combined PTK/ZK and MS-275 were highly effective in this hepatoma model. Quadruple therapy enhanced the effects microscopically, but not macroscopically. These results should be investigated further.
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