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Cytotoxicity of arsenic trioxide to transitional carcinoma cells
Yeong-Shiau Pu1, Tzyh-Chyuan Hour, Jun Chen
1Department of Urology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China.
Objectives:
To explore the therapeutic efficacy of arsenic trioxide (As2O3) in human transitional cell carcinomas, we investigated the potential use of the compound as a chemotherapeutic agent and the possible cross-resistance with cisplatin in this malignancy.
Methods:
Three bladder transitional carcinoma cell lines, NTUB1, NTUB1/P (cisplatin-resistant), and NTUB1/As (As2O3-resistant), were used. The chemosensitivity of the three cell lines to cisplatin and As2O3 was determined by the microculture tetrazolium assay. The modulatory effect of buthionine sulfoximine (BSO) on As2O3 cytotoxicity was studied by combining the two agents simultaneously or sequentially and evaluated using the median-effect analysis. Cellular glutathione contents were determined using a biochemical method.
Results:
There was evident cross-resistance between cisplatin and As2O3 in the cell model used. BSO significantly enhanced As2O3 cytotoxicity in the three cell lines, indicating synergism in combination. In the presence of 3 microM BSO, the sensitivity of NTUB1, NTUB1/P, and NTUB1/As to As2O3 was increased 3, 7.4, and 8.4-fold, respectively. Among the three different combination schedules, greater cytotoxic effects were obtained by concurrent exposure to both agents. A significant dose-response relationship was found between the BSO concentrations and glutathione contents in NTUB1 (P = 0.007) and NTUB1/As (P = 0.05) but not NTUB1/P (P = 0.1) cells.
Conclusions:
As2O3 in the presence of BSO may be an active agent against transitional cell carcinoma. Our results have clinical implications and warrant further investigation.
Insights
Arsenic trioxide (As2O3) shows potential against transitional cell carcinoma, especially when combined with buthionine sulfoximine (BSO). This combination overcomes cisplatin resistance and enhances As2O3
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Transitional cell carcinoma (TCC) presents therapeutic challenges.
- Cisplatin resistance is a significant clinical issue in TCC treatment.
- Arsenic trioxide (As2O3) is being explored as a novel chemotherapeutic agent.
Purpose of the Study:
- To evaluate the therapeutic efficacy of arsenic trioxide (As2O3) in human TCC.
- To investigate potential cross-resistance between As2O3 and cisplatin.
- To assess the modulatory effect of buthionine sulfoximine (BSO) on As2O3 cytotoxicity.
Main Methods:
- Utilized three human bladder TCC cell lines: NTUB1, NTUB1/P (cisplatin-resistant), and NTUB1/As (As2O3-resistant).
- Assessed chemosensitivity to As2O3 and cisplatin using the microculture tetrazolium assay.
- Studied the effect of BSO on As2O3 cytotoxicity through median-effect analysis and measured cellular glutathione levels.
Main Results:
- Observed cross-resistance between cisplatin and As2O3 in the TCC cell model.
- Buthionine sulfoximine (BSO) significantly enhanced As2O3 cytotoxicity, demonstrating synergism.
- BSO increased As2O3 sensitivity by 3 to 8.4-fold across cell lines; concurrent exposure yielded greater effects.
- A dose-response relationship was noted between BSO concentration and glutathione levels in sensitive cell lines.
Conclusions:
- Arsenic trioxide (As2O3), in combination with BSO, shows promise as an active agent against transitional cell carcinoma.
- The findings suggest potential clinical applications for this combination therapy.
- Further investigation is warranted to explore the clinical implications of As2O3 and BSO in TCC treatment.