Eicosapentaenoic acid enhanced apoptotic and oxidant effects of cisplatin via activation of TRPM2 channel in brain tumor cells.

Abstract

Cisplatin (CiSP) induced-overload Ca(2+) entry results in the increase of mitochondrial oxidative stress and apoptosis in the cancer cell. TRPM2 cation channel is gated by the cytosolic ADP-ribose (ADPR) and reactive oxygen species (ROS). The high content of polyunsaturated fatty acid (PUFA) in the brain is a main target of ROS. eicosapentaenoic acid (EPA) induces oxidant action via the enhance of PUFA content in the glioblastoma (DBTRG) cells. We hypothesized that a combination of CiSP and epa may offer a potential therapy in the DBTRG cell by exerting the antitumor, oxidant, and apoptotic actions and stimulating Ca(2+) influx and TRPM2 activity. In the DBTRG cells, we induced four groups as control, epa (30 μM for 24 h), CiSP (25 μM for 24 h), and CiSP + EPA. The CiSP-induced intracellular Ca(2+) responses to the TRPM2 activation were increased in the DBTRG cells from coming H(2)O(2) and ADPR. The responses were decreased in the cells by the inhibitions of TRPM2 (ACA and 2/APB) and PARP/1 (DPQ and PJ34). The incubation of epa further increased the intracellular Ca(2+) responses, mitochondria function, and the generation of ROS in the DBTRGs. After the treatment of EPA, lipid peroxidation, apoptosis, cell death, caspase -3, -8, and -9 levels were further increased in the DBTRG, although the levels of glutathione, glutathione peroxidase, cell numbers, and cell viability were further decreased in the cells. In summary, anticancer, apoptotic, and oxidant actions of CiSP were further increased via the activation of TRPM2 channel in the DBTRGs by the treatment of EPA. Hence, TRPM2 stimulation via epa could be used as an effective agent in the treatment of glioblastoma tumors with CiSP.