Synergistic Effects of Sanglifehrin-Based Cyclophilin Inhibitor NV651 with Cisplatin in Hepatocellular Carcinoma

SIMPLE SUMMARY: Cyclophilins, one of the three families of proteins with peptidyl-prolyl isomerase activity, are overexpressed in several cancers, including hepatocellular carcinoma (HCC), and this overexpression is correlated with poor prognosis. Cyclophilins play an important role in cancer progression; this role includes mediating chemoresistance. In this study, the effect of cyclophilin inhibition in HCC cells was evaluated to find potential combination treatments. We demonstrated that the novel cyclophilin inhibitor, NV651, reduced cell division and DNA repair. In addition, the combination of NV651 and cisplatin, a DNA damage reagent, can be considered an interesting novel treatment therapy for HCC as it significantly increases cancer cell death compared with that caused by cisplatin alone. ABSTRACT: Hepatocellular carcinoma (HCC), commonly diagnosed at an advanced stage, is the most common primary liver cancer. Owing to a lack of effective HCC treatments and the commonly acquired chemoresistance, novel therapies need to be investigated. Cyclophilins—intracellular proteins with peptidyl-prolyl isomerase activity—have been shown to play a key role in therapy resistance and cell proliferation. Here, we aimed to evaluate changes in the gene expression of HCC cells caused by cyclophilin inhibition in order to explore suitable combination treatment approaches, including the use of chemoagents, such as cisplatin. Our results show that the novel cyclophilin inhibitor NV651 decreases the expression of genes involved in several pathways related to the cancer cell cycle and DNA repair. We evaluated the potential synergistic effect of NV651 in combination with other treatments used against HCC in cisplatin-sensitive cells. NV651 showed a synergistic effect in inhibiting cell proliferation, with a significant increase in intrinsic apoptosis in combination with the DNA crosslinking agent cisplatin. This combination also affected cell cycle progression and reduced the capacity of the cell to repair DNA in comparison with a single treatment with cisplatin. Based on these results, we believe that the combination of cisplatin and NV651 may provide a novel approach to HCC treatment.