Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines

Abstract.

Purpose: Arsenic compounds have been found to be effective in the treatment of acute promyelocytic leukemia through the downregulation of bcl-2 expression. Resistant ovarian cancer cells often overexpress bcl-2 or p53 proteins or both. We hypothesized that arsenic compounds, such as As₂O₃ and As₂S₃, could also be active against gynecological cancers resistant to conventional chemotherapy. Methods: We investigated the effects of these two arsenic compounds in vitro on ovarian cancer cell lines sensitive (OVCAR, GG, JAM) and resistant (CI80-13S) to cisplatin (CDDP) and on human cervical cancer cell lines (HeLa) in comparison with their effects on human fibroblasts (HF). A fluorometric assay based on measurements of fluorescein diacetate (FDA) in cells was used to determine cell viability. Apoptosis was assessed in terms of cell morphology, by flow cytometry and by a DNA fragmentation assay. Results: Treatment of each cell line with the As₂O₃ or As₂S₃ led to a marked dose-dependent decrease in cell growth. The IC₅₀ of the two compounds indicated a significantly greater cytotoxic effect against all the cancer cells tested than against the normal HF. At a clinically achievable concentration (2 µM), As₂O₃ selectively inhibited the growth and induced apoptosis in CI80-13S, OVCAR and HeLa cells but had no significant apoptotic effect on GG or JAM cells or HF. Following treatment with 5 µM As₂S₃, the CI80-13S, OVCAR and HeLa cells also exhibited growth inhibition and induction of apoptosis. Conclusions: Arsenic compounds (As₂O₃ and As₂S₃) can inhibit growth and induce apoptosis in human ovarian and cervical cancer cells at clinically achievable concentrations, indicating that As₂O₃ and As₂S₃ could be effective in the treatment of gynecological cancer.