Arsenic Trioxide as a Novel Anticancer Agent against Human Transitional Carcinoma - Characterizing Its Apoptotic Pathway

Arsenic trioxide (As2O3) has been shown to be an active agent against acute promyelocytic leukemia. Little Is known about its therapeutic efficacy In human transitional carcinomas. In this study, the arsenic- mediated apoptotic pathway In transitional carcinoma cells was Investigated. Three bladder transitional carcinoma cell lines were used, Including a parental sensitive line and two resistant daughter lines ( cisplatin and As2O3 resistant). The As2O3- mediated cytotoxicity to the three cell lines was studied in vitro in the presence or absence of buthionine sulfoximine( BSO), a chemotherapy modulator. In results, although a lesser extent of apoptosis was seen in cells treated with As 2O 3 alone, more significant apoptotic events were observed in the combined treatment of As2O3 and non-toxic concentrations of BSO (up to 10 muM). These Included the accumulation of sub-G, fractions and Internucleosomal DNA breakdown, which were preceded by production of reactive oxygen species, loss of mitochondrial membrane potential and activation of caspase-3. In conclusion, As2O3 in the presence of BSO may be an active agent against both chemonaive and cisplatin-resistant transitional carcinomas. The As2O3-mediated cytotoxicity appeared to go through the conventional apoptotic pathway. Our results have clinical implications and warrant further Investigation. [(C) 2002 Lippincott Williams Wilkins]