Methylseleninic acid potentiates apoptosis induced by chemotherapeutic drugs in prostate cancer cells through enhancing caspase activation

4933

The chemotherapy of advanced hormone refractory prostate cancer is severely compromised by drug resistance and dose limiting toxicity. Here we tested whether selenium could enhance the apoptosis potency of selected chemotherapeutic drugs in DU145 and PC3 human androgen-independent prostate cancer cells. Exponentially growing cells were exposed to low doses of selenium and/or the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN38), the topoisomerase II inhibitor etoposide or the microtubule drug paclitaxel/taxol. Apoptosis was measured by ELISA for histone-associated DNA fragments, by flow cytometric analysis of sub-G1 fraction, and by immunobloting the caspase cleaved poly(ADP-ribose)polymerase. Our results show that the methylselenol precursor methylseleninic acid (MSeA) increased the apoptosis potency of SN38, etoposide or paclitaxel by several folds higher than the expected sum of the apoptosis induced by MSeA and each drug alone in both cell lines. Mechanistically, the combination treatment did not further enhance the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 that was induced by each drug in DU145 cells. The JNK inhibitor SP600125 substantially decreased the activation of caspases and apoptosis induced by MSeA combination with the drugs. The caspase-8 inhibitor zIETDfmk completely abolished apoptosis and caspase-9 and caspase-3 cleavage, whereas the caspase-9 inhibitor zLEHDfmk significantly decreased caspase-3 cleavage and apoptosis but had no effect on caspase-8 cleavage. None of these caspase inhibitors abolished JNK1/2 phosphorylation. In contrast to MSeA, selenite did not show any enhancing effect on the apoptosis induced by these drugs. In conclusion, MSeA enhanced apoptosis induced by cancer therapeutic drugs in DU145 cells primarily through interactions between MSeA and JNK-dependent targets to amplify what appeared to be a caspase-8-initiated activation cascade. The results suggest, to our knowledge, for the first time a novel use of methyl selenium for improving the chemotherapy of prostate cancer. Grant supports: CA92231 and CA95642 from NCI and DAMD17-02-1-0007 from DOD.