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Open AccessArticle

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

1
Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
2
Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
3
Department of Transplantology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, 265 Wielicka Str., 30-663 Kraków, Poland
4
Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków; and Proteomics and Mass Spectrometry Laboratory, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland
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Department of Clinical Immunology, Institute of Paediatrics, Faculty of Medicine, Jagiellonian University Medical College, 265 Wielicka Str., 30-663 Kraków, Poland
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(1), 77; https://doi.org/10.3390/cancers11010077
Received: 29 November 2018 / Revised: 31 December 2018 / Accepted: 8 January 2019 / Published: 11 January 2019
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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. View Full-Text
Keywords: fenofibrate; chemotherapy; prostate cancer; drug-resistance; cancer microevolution fenofibrate; chemotherapy; prostate cancer; drug-resistance; cancer microevolution
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Luty, M.; Piwowarczyk, K.; Łabędź-Masłowska, A.; Wróbel, T.; Szczygieł, M.; Catapano, J.; Drabik, G.; Ryszawy, D.; Kędracka-Krok, S.; Madeja, Z.; Siedlar, M.; Elas, M.; Czyż, J. Fenofibrate Augments the Sensitivity of Drug-Resistant Prostate Cancer Cells to Docetaxel. Cancers 2019, 11, 77.

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