Reversion of MultiDrugResistance (MDR) phenotype by new steroids derivatives, in vitro (resistant human tumor cell line) and in vivo (xenografts models)
The chemoresistance of cancer is characterized by a pleitropic resistance to multiple drugs. This mechanism is partly caused by the overexpression of “ATP Binding Cassette” transporters (Pgp, MRP1, BCRP…). Known inhibitors of these transporters such as cyclosporin A, verapamil and RU486 rather toxic at high doses. In this study, many steroid derivatives synthesized in the laboratory (from progesterone or bile acid precursor) to bind and inhibit ABC transporters, specifically the transport by Pgp or BCRP. Several of these synthetic derivatives were able to completely restore the sensivity of the resistant cells compared to cysclosporine A in vitro. In addition, the efficient of these derivatives could, in vivo significantly reduce tumor growth of xenografts on mice and increase survival time of mice. This study opens a route for development of new steroid derivatives with low toxicity, having the ability to reverse the MDR phenotype and restore sensitivity of cancer cells to the chemotherapeutic agents use, with a perspective at clinical use