Differential Combined Effect of COX Inhibitors on Cell Survival Suppressed by Sorafenib in the HepG2 Cell Line

Yagi, Kenta; Kawasaki, Yoichi; Nakamura, Hiroko; Miura, Taro; Takeda, Tatsuaki; Esumi, Satoru; Matsunaga, Hisashi; Kitamura, Yoshihisa; Sendo, Toshiaki

doi:10.1248/bpb.b13-00963

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…Our results highlight the potential to use diclofenac in combination with sorafenib in HCC. Consistent with our findings, the additive effect of various NSAIDs in combination with sorafenib was demonstrated in vitro in the HCC cell line HepG2 [34]. Of note, the efficacy of sorafenib/diclofenac combination treatment is not limited to HCC, as a synthetic lethal screening with small molecule inhibitors demonstrated a synergistic cytotoxicity between sorafenib and diclofenac in melanoma cell lines [12].…”

Section: Discussionsupporting

confidence: 83%

Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress

Duval

Troquier

Silva

et al. 2019

Cancers

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Sorafenib is the first developed systemic treatment for advanced forms of hepatocellular carcinoma, which constitutes the most frequent form of primary liver cancers and is a major global health burden. Although statistically significant, the positive effect of sorafenib on median survival remains modest, highlighting the need to develop novel therapeutic approaches. In this report, we introduce diclofenac, a nonsteroidal anti-inflammatory drug, as a potent catalyzer of sorafenib anticancer efficacy. Treatment of three different hepatocellular cancer cells (Huh-7, HepG2, and PLC-PRF-5) with sorafenib (5 µM, 24 h) and diclofenac (100 µM, 24 h) significantly increased cancer cell death compared to sorafenib or diclofenac alone. Anti-oxidant compounds, including N-acetyl-cysteine and ascorbic acid, reversed the deleterious effects of diclofenac/sorafenib co-therapy, suggesting that the generation of toxic levels of oxidative stress was responsible for cell death. Accordingly, whereas diclofenac increased production of mitochondrial oxygen reactive species, sorafenib decreased concentrations of glutathione. We further show that tumor burden was significantly diminished in mice bearing tumor xenografts following sorafenib/diclofenac co-therapy when compared to sorafenib or diclofenac alone. Taken together, these results highlight the anticancer benefits of sorafenib/diclofenac co-therapy in hepatocellular carcinoma. They further indicate that combining sorafenib with compounds that increase oxidative stress represents a valuable treatment strategy in hepatocellular carcinoma.

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Section: Discussionsupporting

confidence: 83%

Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress

Duval

Troquier

Silva

et al. 2019

Cancers

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“…It has been reported that sorafenib is efficiently transported by ABCG2 (15). However, there is a certain controversy regarding the transport effect of ABCB1; certain studies reported that sorafenib was moderately transported by ABCB1 (16), while other studies reported that sorafenib inhibited ABCB1 but did not appear to be ABCB1 substrates in vitro and cancer cells transfected with ABCC2 (also called MRP2) had increased resistance to sorafenib, which suggested that sorafenib is a substrate for ABCC2 (17,18). The present study demonstrated that CSN5 silencing downregulated the expression of these ABC family transporters.…”

Section: Discussionmentioning

confidence: 99%

CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells

Wang

Qian

Zhao

et al. 2015

Molecular Medicine Reports

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Hepatocellular carcinoma (HCC) is one of the most common tumor types, and is the third leading cause of cancer mortalities worldwide. A large number of patients with HCC are diagnosed at a late stage when the curative treatment of surgical resection and liver transplantation are no longer applicable. Sorafenib has been proved to improve overall survival in advanced HCC; however, drug resistance is common. The present study reported that the CSN5 is correlated with sorafenib resistance of the HCC cell line HepG2/S. Following silencing of CSN5, resistance to sorafenib was reversed, and multi-drug‑resistance proteins, including as adenosine triphosphate binding cassette (ABC)B1, ABCC2 and ABCG2 as well as CDK6, cyclin D1 and B‑cell lymphoma 2 were downregulated. In addition, it was demonstrated that the integrin beta-1, transforming growth factor‑β1 and nuclear factor‑κB pathways were modified by CSN5.

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“…Combination treatment of sorafenib and DCF was effective against all cell lines, regardless of genotypic status. A different research group also investigated the in vitro activity of sorafenib and a number of COX inhibitors, including DCF, in the HepG2 hepatocellular carcinoma (HCC) cell line [ 28 ]. The results showed that DCF treatment at a concentration of 50 μg/mL significantly reduced proliferation ( P < 0.01).…”

Section: Pre-clinical Evidence In Cancer - In Vitro mentioning

confidence: 99%

Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent

Pantziarka¹,

Sukhatme²,

Bouche³

et al. 2016

ecancer

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Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper.

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Differential Combined Effect of COX Inhibitors on Cell Survival Suppressed by Sorafenib in the HepG2 Cell Line

Cited by 9 publications

References 46 publications

Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress

Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress

CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells

Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent

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