Tamoxifen Enhances the Chemosensitivity of Bladder Carcinoma Cells

Yeong Shiau Pu*, Teh Sheng Hsieh, Tsong Chang Tsai, Ann Lii Cheng, Chang Yao Hsieh, Ih Jen Su, Ming Kuen Lai

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

35 Scopus citations

Abstract

Purpose: Chemosensitizers, which enhance cellular chemosensitivity and reduce chemoresistance, are expected to substantially improve response rates of systemic chemotherapy for patients with metastatic bladder cancer. Tamoxifen is a nonsteroidal antiestrogen that has been shown to reverse drug resistance in vitro in some cancer models through pathways not related to its antiestrogenic effect. In this study we tried to evaluate its possible effect on chemosensitization of bladder cancer cells. Materials and Methods: In vitro chemosensitivity tests were done with 3 bladder cancer cell lines and 4 cytotoxic agents (methotexate, vinblastine, doxorubicin and cisplatin) in the presence or absence of graded concentrations of tamoxifen. Verapamil was used in parallel experiments to compare the degrees of chemosensitization. The transcript and protein product [P-glycoprotein, (P-gp)] levels of the mdr-1 gene were also examined in the 3 cell lines by reverse-transcription polymerase chain reaction (RT-PCR) and flow cytometric assay, respectively. Results: Tamoxifen at 5 and especially 10 micromolar concentrations, which were minimally toxic to the 3 bladder cancer cell lines used, enhanced the chemosensitivity of bladder cancer cells in most drug combinations in a dose-dependent manner. In some combinations 10 micromolar tamoxifen did better than 5 micromolar in chemosensitization. The effect of chemosensitization was more evident in cells treated with 10 micromolar tamoxifen plus methotrexate and vinblastine in which 12.9 to 95.4-fold and 12.4 to 21.3-fold IC50 reduction was observed, respectively. A less prominent, but still significant, effect could be seen in doxorubicin- and cisplatin-treated cells. Verapamil, although used at concentrations up to 10 micromolar which are higher than systemically tolerable, was not able to enhance chemosensitivity of the 3 bladder cancer cell lines. By flow cytometric analysis of the P-gp level and by RT-PCR assay of the mdr-1 gene transcript level, it was shown that little if any mdr-1 gene expression could be detected in the 3 cell lines. This implies that the mdr-1 gene function may play a minimal role in drug resistance mechanisms of bladder cancer cells and that tamoxifen exerts its chemosensitization effect through pathways other than mdr-1 gene function modulation. Conclusions: Tamoxifen was shown to be a good chemosensitizer in a bladder cancer cell model and may well be tried in combination with systemic chemotherapy for metastatic human bladder cancers in the clinical setting.

Original languageEnglish
Pages (from-to)601-605
Number of pages5
JournalJournal of Urology
Volume154
Issue number2
DOIs
StatePublished - 08 1995
Externally publishedYes

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