PO-235 Fenofibrate overcomes the drug-resistance of human prostate cancer cells

Introduction Microevolution of drug-resistant cancer cell populations is a serious obstacle for currently available cancer therapies. Reports on the inhibitory effects of fenofibrate (FF) on the growth, survival and invasiveness of prostate cancer cells suggest its potential for metronomic strategies of prostate cancer therapy. Therefore, we assessed the interference of FF with the drug-resistance of prostate cancer cells. Material and methods Additive effects of DCX/FF on the propagation, invasiveness and drug-resistance of native prostate cancer cells and of their invasive DCX-resistant variants (DU145_DCX20 and DU145_DCX50) were estimated with time-lapse and fluorescence microscopy. Flow-cytometric and cytofluorimetric tests were performed to assess the interference of FF with ATP production, pro-apoptotic and pro-autophagic pathways; and with the activity of ABC transporters. Results and discussions When administered alone, 2.5 nM DCX significantly attenuated the proliferation of native DU145 cells, but exerted no effect on the viability of DU145_DCX20 and DU145_DCX50 cells. FF (25 mM) sensitised these cells to DCX through PPARa/ROS-independent interference with intracellular ATP production and P-gp activity, as demonstrated by control assays with elacridar. Concomitantly, DCX/FF treatment considerably reduced neoplastic and invasive potential of drug-resistant DU145 cells via the activation of mTOR-sensitive suicidal autophagy signalling(s). Conclusion Our observations suggest that FF can be applied to reduce the effective doses of chemotherapeutic drugs, to attenuate their adverse effects and to inhibit the microevolution of drug-resistant cells induced by chemotherapy. Thus, it can be considered as an metronomic agent that can enhance the efficiency of long-term palliative prostate cancer treatment.