Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

Chang, Hui-Ju

doi:10.4254/wjh.v7.i16.2029

Cited by 8 publications

(12 citation statements)

References 117 publications

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“…As high doses of the drug have not shown efficacy in arresting tumor progression in long term, and side effects are a critical factor in survival, it is necessary to find strategies to increase chemosensitivity toward sorafenib. For instance, metformin, histone deacetylase inhibitors, CXC chemokine receptor 2, or cyclooxygenase 2 inhibitors, in combination with sorafenib, reduce metastasis, proliferation, or cell viability and increase apoptosis both in vitro and in vivo studies . Moreover, preclinical and clinical research have proven that sorafenib addition to conventional chemotherapy increases benefits in the treatment of different cancers …”

Section: Discussionmentioning

confidence: 99%

“…Although results obtained from these clinical studies have shown survival benefits, the efficacy of sorafenib treatment is frequently transient, and the activation of compensatory pathways in response to drug administration leads to tumor‐acquired resistance, having a negative impact on the therapeutic outcome . Therefore, overcoming acquired resistance is required to potentiate cytotoxic effects of sorafenib, and the combination with other molecules could be a manageable approach to reduce adaptive response of tumor cells to the action of the drug …”

Section: Introductionmentioning

confidence: 99%

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Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy

Prieto-Domínguez

Ordóñez

Fernández

et al. 2016

Journal of Pineal Research

116

141

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Effects of sorafenib in hepatocellular carcinoma (HCC) are frequently transient due to tumor-acquired resistance, a phenotype that could be targeted by other molecules to reduce this adaptive response. Because melatonin is known to exert antitumor effects in HCC cells, this study investigated whether and how melatonin reduces resistance to sorafenib. Susceptibility to sorafenib (10 nM to 50 μM) in the presence of melatonin (1 and 2 mM) was assessed in HCC cell lines HepG2, HuH7 and Hep3B. Cell viability was reduced by sorafenib from 1 μM in HepG2 or HuH7 cells, and 2.5 μM in Hep3B cells. Co-administration of melatonin and sorafenib exhibited a synergistic cytotoxic effect on HepG2 and HuH7 cells, while Hep3B cells displayed susceptibility to doses of sorafenib that had no effect when administrated alone. Co-administration of 2.5 μM sorafenib and 1 mM melatonin induced apoptosis in Hep3B cells, increasing PARP hydrolysis and BAX expression. We also observed an early colocalization of mitochondria with lysosomes, correlating with the expression of mitophagy markers PINK1 and Parkin and a reduction of mitofusin-2 and mtDNA compared with sorafenib administration alone. Moreover, increased reactive oxygen species production and mitochondrial membrane depolarization were elicited by drug combination, suggesting their contribution to mitophagy induction. Interestingly, Parkin silencing by siRNA to impair mitophagy significantly reduced cell killing, PARP cleavage and BAX expression. These results demonstrate that the pro-oxidant capacity of melatonin and its impact on mitochondria stability and turnover via mitophagy increase sensitivity to the cytotoxic effect of sorafenib.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy

Prieto-Domínguez

Ordóñez

Fernández

et al. 2016

Journal of Pineal Research

116

141

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“…In addition to sorafenib and bevacizumab, there are a number of additional targeted molecular agents against HCC currently in various clinical trial phases, such as sunitinib and linifanib [60,79,80]. However, only few of these new drugs have been reported to be used in combination with RFA so far.…”

Section: Rfa-combined Multimodal Therapiesmentioning

confidence: 99%

Radiofrequency ablation-combined multimodel therapies for hepatocellular carcinoma: Current status

2016

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Radiofrequency ablation (RFA) is widely accepted as a first-line interventional oncology approach for hepatocellular carcinoma (HCC) and has the advantages of high treatment efficacy and low complication risk. Local control rates equivalent to hepatic resection can be reached by RFA alone when treating small HCCs (<2 cm) in favorable locations. However, local tumor progression and recurrence rates with RFA monotherapy increase sharply when treating larger lesions (>3 cm). To address this clinical problem, recent efforts have focused on multimodel management of HCC by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy. The combination strategy indeed leads to better outcomes in comparison to RFA alone. In this article, we review the current status of RFA-combined multimodal therapies in the management of HCC.

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“…Sorafenib is a standard therapy for advanced HCC because the survival benefits have been demonstrated in two randomized, placebo‐controlled, double‐blind phase III clinical trials . Thereafter, most randomized studies of the new multikinase inhibitors, sunitinib, brivanib, and linifanib, or a combination of sorafenib and erlotinib did not reveal a better survival benefit or tolerability compared with sorafenib monotherapy . Recently, regorafenib, lenvatinib, and cabozantinib have shown survival benefits .…”

Section: Introductionmentioning

confidence: 99%

Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib

Adachi

Nouso

Miyahara³

et al. 2018

J of Gastro and Hepatol

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Background and Aim Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one‐time measurements before treatment. Methods We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated. Results Among six significant risk factors for overall survival in univariate analyses, high angiopoietin‐2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin‐2 at the time of progressive disease was a marker of short post‐progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression‐free survival except the presence of hepatitis B virus surface antigen. Conclusions Predictions of overall survival and post‐progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin‐2, in patients with HCC treated with sorafenib.

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Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

Cited by 8 publications

References 117 publications

Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy

Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy

Radiofrequency ablation-combined multimodel therapies for hepatocellular carcinoma: Current status

Monitoring serum proangiogenic cytokines from hepatocellular carcinoma patients treated with sorafenib

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