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Arsenic Trioxide-mediated Cytotoxicity and Apoptosis in Prostate and Ovarian Carcinoma Cell Lines

Departments of Medical Oncology and Hematology [R. U., U. A. S., C. S., B. K., S. B. O., E. G.], and Department of Immunology [E. T.], Ege University School of Medicine, 35100, Izmir, Turkey

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)-2,5diphenyl-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 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.

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