In ovarian cancer maraviroc potentiates the antitumoral activity and further inhibits the formation of a tumor-promoting microenvironment by trabectedin

Abstract

Ovarian cancer (OC) is the fifth most frequent cause of cancer-related death in women. Chemotherapy agent trabectedin, affecting cancer cells and tumor microenvironment, has been approved for the treatment of relapsed platinum-sensitive OC patients. CCR5-antagonist maraviroc inhibits tumor growth, metastasis, and enhances the antitumoral activity of DNA-damaging drugs. Here, we found that OC cells expressed CCR5 receptor but did not secret CCR5-ligands. Maraviroc treatment did not affect OC cell viability, but strongly potentiated the antiproliferative activity, apoptosis induction, cell cycle blockage, DNA damage, and ROS formation by trabectedin. In A2780cis cisplatin-resistant cells, the cross-resistance to trabectedin was overcame by the combination with maraviroc. Maraviroc enhanced trabectedin cytotoxicity in OC 3Dimensional spheroids and THP-1-monocytes. Both maraviroc and trabectedin interact with drug efflux pump MDR1/P-gp, overexpressed in recurrent OC patients. Maraviroc increased trabectedin intracellular accumulation and the MDR1-inhibitor verapamil, like maraviroc, increased trabectedin cytotoxicity. In OC tumor xenografts the combination with maraviroc further reduced tumor growth, angiogenesis, and monocyte infiltration by trabectedin. In conclusion, this study offers a preclinical rationale for the use of maraviroc as new option to improve trabectedin activity in relapsed chemoresistant OC patients.

Keywords

• Ovarian cancer
• CCR5-antagonist maraviroc
• Trabectedinm MDR1/P-glycoprotein
• Tumor microenvironment