Inhibition of P-glycoprotein-mediated docetaxel efflux sensitizes ovarian cancer cells to concomitant docetaxel and SN-38 exposure

Abstract

The first-line treatment of ovarian cancer is based on cytoreductive surgery and the use of anticancer drugs. The main disadvantage in the usage of anticancer drugs is the wide capacity of cancer cells to acquire a resistance to chemotherapeutic agents and therefore new treatment strategies have to be developed and tested. In this study, the responses of seven ovarian carcinoma cell lines to docetaxel and a camptothecin derivative, SN-38, were evaluated. We further studied the expression of P-glycoprotein (P-gp), the best described mechanism of drug resistance, in these cells and the effect of treatment with a specific P-gp inhibitor (PGP-4008). Simultaneous treatment with docetaxel and SN-38 (docetaxel+SN-38) had an antagonistic growth effect that was not dependent on the administration schedule. Both drugs alone or in combination induced G2M cell cycle arrest. Docetaxel was a more potent inducer of apoptosis than SN-38, but simultaneous treatment with docetaxel+SN-38 decreased the proportion of apoptotic cells to the same level observed after exposure to SN-38 alone. SN-38 increased P-gp expression in all cell lines. PGP-4008 enhanced docetaxel-mediated growth inhibition and apoptosis, but it did not have an effect when used simultaneously with SN-38. When cells were treated with docetaxel, SN-38, and PGP-4008 simultaneously, the growth was inhibited more efficiently and the proportion of apoptotic cells was higher than that without PGP-4008. Thus, treatment of ovarian cancer cells with docetaxel+SN-38 may have antagonistic effects. The simultaneous administration of a P-gp inhibitor may prevent docetaxel efflux, thereby sensitizing cells to docetaxel and other chemotherapeutic agents.