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Arsenic trioxide as a novel anticancer agent against human transitional carcinoma--characterizing its apoptotic
Yeong-Shiau Pu1, Tzyh-Chyuan Hour, Jun Chen
1Department 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
Abstract:
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.
Insights
Arsenic trioxide combined with buthionine sulfoximine enhances apoptosis in transitional carcinoma cells. This combination therapy shows promise against both drug-sensitive and cisplatin-resistant bladder cancers.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Arsenic trioxide (As(2)O(3)) is effective against acute promyelocytic leukemia.
- Therapeutic efficacy of As(2)O(3) in human transitional carcinomas is not well understood.
Purpose of the Study:
- Investigate the arsenic-mediated apoptotic pathway in transitional carcinoma cells.
- Evaluate the efficacy of As(2)O(3) with buthionine sulfoximine (BSO) in chemoresistant cell lines.
Main Methods:
- Utilized three bladder transitional carcinoma cell lines (sensitive and resistant to cisplatin and As(2)O(3)).
- Assessed As(2)O(3)-mediated cytotoxicity in vitro, with and without BSO.
- Analyzed apoptotic events, reactive oxygen species production, mitochondrial membrane potential, and caspase-3 activation.
Main Results:
- As(2)O(3) alone induced some apoptosis, but combined treatment with non-toxic BSO concentrations significantly increased apoptotic events.
- Observed accumulation of sub-G(1) fractions and DNA fragmentation.
- Apoptosis was preceded by increased reactive oxygen species, decreased mitochondrial membrane potential, and caspase-3 activation.
Conclusions:
- As(2)O(3) in combination with BSO demonstrates potential as an active agent against both chemonaive and cisplatin-resistant transitional carcinomas.
- As(2)O(3)-induced cytotoxicity appears to operate via the conventional apoptotic pathway.
- Findings suggest clinical implications and warrant further investigation.