Arsenic trioxide as a novel anticancer agent against human transitional carcinoma--characterizing its apoptotic pathway.
Arsenic trioxide (As(2)O(3)) 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 As(2)O(3) resistant). The As(2)O(3)-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(2)O(3) alone, more significant apoptotic events were observed in the combined treatment of As(2)O(3) and non-toxic concentrations of BSO (up to 10 microM). These included the accumulation of sub-G(1) 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, As(2)O(3) in the presence of BSO may be an active agent against both chemonaive and cisplatin-resistant transitional carcinomas. The As(2)O(3)-mediated cytotoxicity appeared to go through the conventional apoptotic pathway. Our results have clinical implications and warrant further investigation.
Pu
Yeong-Shiau
YS
Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan 100, ROC. yspu@ha.mc.ntu.edu.tw
Hour
Tzyh-Chyuan
TC
Chen
Jun
J
Huang
Chao-Yuan
CY
Guan
Jing-Yi
JY
Lu
Shiu-Hui
SH
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D004273:DNA, Neoplasm; D010087:Oxides; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin; D000077237:Arsenic Trioxide