Silibinin sensitizes CD133+ hepatocellular carcinoma cells to cisplatin treatment through suppression of OPA1

Abstract

Background: Drug resistance is still a major obstacle during the cisplatin-based chemotherapy of hepatocellular carcinoma (HCC). Recently, studies have indicated that the population of CD133+ cancer cells is partially responsible for the failure of cancer treatment. However, the potential mechanisms are still unclear.Methods: CD133+ HepG2 and Huh7 cells were sorted via flow cytometry. CCK-8 assay was used to detect the cytotoxicity of cisplatin and silibinin against HCC cells. Western blot assay was performed to detect the protein expression, cleavage of caspases and release of cytochrome c from mitochondria into cytosol. Flow cytometry analysis was used to measure the apoptotic rate of CD133+ HepG2 and Huh7 cells.Results: CD133+ HepG2 and Huh7 cells were observed to exhibit obvious resistance against cisplatin. However, co-treatment with silibinin significantly reduced the cisplatin resistance of CD133+ HepG2 and Huh7 cells. Furthermore, although CD133+ HepG2 and Huh7 cells were resistant to cisplatin-induced apoptosis, co-treatment with silibinin enhanced the cisplatin-induced apoptosis through promoting the release of cytochrome c from mitochondria into cytosol. In the mechanism research, we proved that silibinin inhibited the expression of OPA1 in CD133+ HepG2 and Huh7 cells. Under the stress of cisplatin, silibinin promoted the collapse of mitochondria and increased the release of cytochrome c. As a result, caspases-dependent apoptosis was induced in CD133+ HepG2 and Huh7 cells which were co-treated with cisplatin and silibinin.Conclusion: Silibinin sensitizes CD133+ HCC cells to cisplatin-induced apoptosis through suppression of OPA1.