Arsenic compounds induce cytotoxicity and apoptosis in cisplatin-sensitive and -resistant gynecological cancer cell lines.
OBJECTIVE
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 microM), 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 microM 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.
Du
Y H
YH
Department of Pharmacy, National University of Singapore, Singapore.
Ho
P C
PC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use*; D048429:Cell Size / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010087:Oxides / Q000627:therapeutic use*; D013440:Sulfides / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D013440:Sulfides; C058317:arsenic disulfide; D002945:Cisplatin; D000077237:Arsenic Trioxide