Arsenic trioxide-mediated cytotoxicity and apoptosis in prostate and ovarian carcinoma cell lines

Abstract

We studied the effect of arsenic trioxide (As2O3) on prostate and ovarian carcinoma cell lines. As2O3 has been shown to be effective in leukemia, and acute promyelocytic leukemia in particular, both in vitro and in vivo. As model cell lines, we used DU145 and PC-3 for prostate cancer and MDAH 2774 for ovarian cancer. New modalities of treatment are essential in these kinds of cancers, which produce a high death toll. The 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to evaluate cytotoxicity. Flow cytometric analysis and mono-oligo nucleosome detection-based ELISA were used to determine the apoptosis. Isobologram analysis was used to evaluate synergism and/or the additive effects of As2O3 and conventional chemotherapeutic agents. We clearly demonstrated that As2O3 has significant cytotoxic effect on both prostate and ovarian carcinoma cell lines. The dose range of As2O3 in all three cell lines was approximately 10(-6) M. The mechanism underlying cytotoxicity of As2O3 was shown to be apoptosis. The experiments by butylated hydroxyanisole showed that the cytotoxic effect of As2O3 was not through superoxide generation. There was no synergism, but the additive effects of As2O3 were demonstrated with cisplatin, adriamycin, and etoposide. We strongly suggest that As2O3 alone or in combination with conventional chemotherapeutic agents be evaluated further as a new agent for the treatment of prostate and ovarian cancers.