Novel Cyclophilin Inhibitor Decreases Cell Proliferation and Tumor Growth in Models of Hepatocellular Carcinoma

SIMPLE SUMMARY: Cyclophilins, a family of proteins with peptidyl prolyl isomerase activity, have been found to be overexpressed in several cancers, including hepatocellular carcinoma (HCC), and their expression is correlated to a poor prognosis. Cyclophilins play an important role in proliferation and cancer resistance in HCC. In this study, we evaluated the potential capacity of cyclophilin inhibitors as a treatment against HCC. We showed that our selected cyclophilin inhibitor, NV651, was able to decrease cell proliferation in vitro and induce an accumulation of cells in the G(2)/M phase due to a mitotic block. We could also confirm its capacity to decrease tumor growths in mice and its safety in vitro as well as in vivo. ABSTRACT: Hepatocellular carcinoma (HCC), the most common primary liver cancer, is usually diagnosed in its late state. Tyrosine kinase inhibitors such as sorafenib and regorafenib are one of the few treatment options approved for advanced HCC and only prolong the patient’s life expectancy by a few months. Therefore, there is a need for novel effective treatments. Cyclophilins are intracellular proteins that catalyze the cis/trans isomerization of peptide bonds at proline residues. Cyclophilins are known to be overexpressed in HCC, affecting therapy resistance and cell proliferation. In the present study, we explored the potential of cyclophilin inhibitors as new therapeutic options for HCC in vitro and in vivo. Our results showed that the novel cyclophilin inhibitor, NV651, was able to significantly decrease proliferation in a diverse set of HCC cell lines. The exposure of HCC cells to NV651 caused an accumulation of cells during mitosis and consequent accumulation in the G(2)/M phase of the cell cycle. NV651 reduced tumor growth in vivo using an HCC xenograft model without affecting the body weights of the animals. The safety aspects of NV651 were also confirmed in primary human hepatocytes without any cytotoxic effects. Based on the results obtained in this study, we propose NV651 as a potential treatment strategy for HCC.