Treatment with a new benzimidazole derivative bearing a pyrrolidine side chain overcomes sorafenib resistance in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Currently, sorafenib is the standard first-line drug for patients with advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity of tumour cells to the drug, leading to acquired resistance. Therefore, developing new compounds to treat sorafenib resistance is urgently needed. Although benzimidazole and its derivatives have been reported to exert antimicrobial and antitumour effects, the anti-drug resistance potential of these molecules is still unknown. In this study, we established sorafenib-resistant (SR) cell lines and an acquired sorafenib resistance xenograft model. We showed that treatment with a benzimidazole derivative bearing a pyrrolidine side chain (compound 9a) inhibited the proliferation of SR cells by blocking the phosphorylation of AKT, p70S6 and the downstream molecule RPS6. In addition, caspase 3/PARP-dependent apoptotic signals were induced in 9a-treated cells. Regarding epithelial-mesenchymal transition (EMT) activities, 9a treatment significantly suppressed the migration of SR cells. In particular, the levels of EMT-related transcription factors (snail, slug and twist) and mesenchymal markers (vimentin and N-cadherin) were downregulated. In the acquired sorafenib resistance xenograft model, compound 9a administration decreased the growth of tumours with acquired sorafenib resistance and the expression of the HCC markers α-fetoprotein, glypican 3 and survivin. In conclusion, treatment with this compound may be a novel therapeutic strategy for patients with sorafenib resistance.

Treatment with a New Barbituric Acid Derivative Exerts Antiproliferative and Antimigratory Effects against Sorafenib Resistance in Hepatocellular Carcinoma

“…60434) cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Gibco BRL, Grand Island, NY, USA) with 10% heat-inactivated fetal bovine serum (FBS, HyClone, Logan, UT, USA) at 37 °C in a humidified atmosphere containing 5% CO 2 . Sorafenib-resistant Huh7 (Huh7-SR) and sorafenib-resistant Hep3B (Hep3B-SR) cells were cultured from parental cells under increasing concentrations of sorafenib [ 57 ].…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…Suk et al evaluated the activity of benzimidazole derivative 211 against sorafenib resistant HCC cell lines (Hep3B-SR and HuH7-SR) [ 183 ]. Compound 211 displayed significant antiproliferative effects against these two cell lines at a concentration of 25 µM.…”

Successful stories of drug repurposing for cancer therapy in hepatocellular carcinoma

“…However, with the use of the newly developed and approved multiple kinase inhibitors, the median overall survival still remains almost 1 year. Moreover, de novo resistance developing to sorafenib has been recently heavily reported impeding its beneficial clinical applications [ [23] , [24] , [25] , [26] ]. Resistance to sorafenib involves a cross talk between several pathways such as Janus kinase/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), and hypoxia-inducible pathways beside others [ 27 ].…”