Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel

Abstract

Metronomic agents reduce the effective doses and adverse effects of cytostatics in cancer chemotherapy. Therefore, they can enhance the treatment efficiency of drug-resistant cancers. Cytostatic and anti-angiogenic effects of fenofibrate (FF) suggest that it can be used for the metronomic chemotherapy of drug-resistant prostate tumors. To estimate the effect of FF on the drug-resistance of prostate cancer cells, we compared the reactions of naïve and drug-resistant cells to the combined treatment with docetaxel (DCX)/mitoxantrone (MTX) and FF. FF sensitized drug-resistant DU145 and PC3 cells to DCX and MTX, as illustrated by their reduced viability and invasive potential observed in the presence of DCX/MTX and FF. The synergy of the cytostatic activities of both agents was accompanied by the inactivation of P-gp-dependent efflux, dysfunction of the microtubular system, and induction of polyploidy in DCX-resistant cells. Chemical inhibition of PPARα- and reactive oxygen species (ROS)-dependent pathways by GW6471 and N-acetyl-L-cysteine, respectively, had no effect on cell sensitivity to combined DCX/FF treatment. Instead, we observed the signs of adenosine triphosphate (ATP) deficit and autophagy in DCX/FF-treated drug-resistant cells. Furthermore, the cells that had been permanently propagated under DCX- and DCX/FF-induced stress did not acquire DCX/FF-resistance. Instead, relatively slow proliferation of DCX-resistant cells was efficiently inhibited by FF. Collectively, our observations show that FF reduces the effective doses of DCX by interfering with the drug resistance and energy metabolism of prostate cancer cells. Concomitantly, it impairs the chemotherapy-induced microevolution and expansion of DCX/FF-resistant cells. Therefore, FF can be applied as a metronomic agent to enhance the efficiency of palliative chemotherapy of prostate cancer.

CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations

“…This is illustrated by the inhibition of their motility ( Figure 5A), proliferation ( Figure 5B), and by the induction of their apoptosis under DCX/FF stress. Concomitant disorganization of microtubular cytoskeleton ( Figure 5C) could be ascribed to the FF-induced inhibition of P-gp, 22 as also determined for DU145wt and DU145_DCX20 cells (cf. Figure 3B).…”

“…We have previously shown the interference of FF with the drug resistance of prostate cancer cells. 22 Analyses of the cytostatic effects of combined DCX/FF treatment on the progenies of CD44 + SCL cells demonstrated the attenuating effect of FF on their DCX-resistance ( Figure 3A). This is illustrated by the inhibition of DU145, nSCL_DU145, and dcxSCL_DU145 cell motility immediately after DCX/FF administration.…”

“…To trace this adaptation process in vitro, we intermittently exposed DU145 cells to DCX administered at increasing concentrations. 22 Thus, the microevolution of drug-resistant DU145 lineages was induced (DU145_DCX20 and DU_DCX50). They displayed considerably higher DCX-resistance than dcxSCL_DU145 cells, as illustrated by negligible DCX effects on their motility and proliferation ( Figure 2B).…”

“…We have recently shown that fenofibrate (FF)-based metronomic regimens interfere with the drug resistance and malignancy of prostate cancer cells, while reducing adverse effects of chemotherapeutics. 22 FF is commonly used to improve high:low-density lipoprotein ratio in hyperlipidemia. 23 The peroxisome-proliferator activated receptor-α and reactive oxygen species-dependent signaling systems "canonically" mediate its biological activity.…”

“…25,26 Interference of FF with cancer cell expansion and systemic dissipation 27 is accompanied by its effects on cancer "stroma," including vascular cells, 24,28 and cellular energy metabolism. 22,29,30 Thus, FF interferes with drug-resistance systems and sensitizes drug-resistant prostate cancer cells to chemotherapy.…”