Cisplatin Kills Ovarian Cancer Cells by Causing Mitochondrial Oxidative Stress and Death Through the TRPV1 Channel Stimulation: The Role of Eicosapentaenoic Acid

INTRODUCTION: Cisplatin (Cisp) causes excessive Ca2+ and Zn2+ influxes mediated by TRPV1 channel stimulation and produces a high concentration of mitochondrial (mROS) and cytosolic (cROS) free reactive oxygen radicals. In clinical trials, it can be used in combination with other adjuvant medicinal agents to enhance the safety and efficacy of Cisp. Although contradictory findings exist, eicosapentaenoic acid (EPA) as an adjuvant has been shown to suppress the proliferation of ovarian cancer cells. We assessed the effects of EPA and Cisp incubations on oxidant levels, Zn2+, lysosomal injury, and apoptotic markers in the OVCAR-3 ovarian cancer cell line by activating TRPV1. METHODS: Five groups were induced in the cells: control, Cisp (25 μM for 24h), EPA (100 μM for 24h), Cisp + EPA, and Cisp + TRPV1 antagonist (100 M capsazepine, CPZ). RESULTS: Compared with control cells, Cisp mediated upregulation of Ca2+ entry and TRPV1 current density via TRPV1 stimulation in the cells. Cisp-mediated TRPV1 activation includes increases in mROS and cROS, mitochondrial dysfunction, and decreases in glutathione, glutathione peroxidase, OVCAR-3 viability, and number. In response to capsaicin, Cisp-mediated TRPV1 stimulation causes mitochondrial Ca2+ and Zn2+ overload, followed by increases in caspase-3/-8/-9, lysosomal injury, and apoptosis; however, these effects were less pronounced in the Cisp + EPA and Cisp + CPZ groups. DISCUSSION: The tumor cell death effect of Cisp was decreased due to the suppression of TRPV1 caused by the CPZ and EPA incubations. Cisp via TRPV1 activation may therefore be an additional therapeutic approach to increase the susceptibility of ovarian tumor cells to mROS-dependent cell death. CONCLUSION: We observed that Cisp kills OVCAR-3 cells by stimulating TRPV1; even when the channel is blocked, Cisp retains anti-cancer effects. Cisp and TRPV1 stimulators together may provide an alternative method of killing ovarian cancer cells.