Teruyoshi Yokoyama

Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression

The effects of 12 Ca(2+) antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [(3)H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [(3)H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 microM), manidipine (4.65 microM) and benidipine (4.96 microM), followed by bepridil (10.6 microM), barnidipine (12.6 microM), efonidipine (13.0 microM), verapamil (13.2 microM) and nilvadipine (18.0 microM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [(3)H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca(2+) antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA.

Molecular changes to HeLa cells on continuous exposure to cisplatin or paclitaxel.

AbstractObjective: To achieve a reversal of multidrug resistance (MDR) in cancer chemotherapy, it is crucial to clarify the characteristics of MDR cells generated by various types of chemotherapeutic agents and to find novel targets. Methods: Cisplatin- and paclitaxel-resistant HeLa sublines (HeLa/CDDP and HeLa/TXL, respectively) were established by continuous exposure and their cellular changes were examined based on growth inhibition assays, the transport activity of P-glycoprotein/MDR1, and a RT-PCR analysis of MDR-related factors. Results: HeLa/CDDP cells showed cross-resistance to platinum derivatives, whereas HeLa/TXL cells were resistant to a variety of MDR1 substrates. Transport activity of MDR1 was reduced in HeLa/CDDP cells and the expression of MDR1 was significantly accelerated in HeLa/TXL cells, compared with HeLa cells. In addition, the expression levels of MDR-related transporters (MRP1–5 or BCRP), βtubulin which is a target for taxanes, and apoptosis-regulated factors were comparable among the three cell lines. On the other hand, the mRNA levels of γ-glutamyl transferase, but not γ-glutamyl cysteine synthetase, were higher in HeLa/CDDP cells than in HeLa and HeLa/TXL cells. Conclusions: HeLa/CDDP cells showed decreased activity and expression of MDR1 and overexpression of

Membrane Transport and Antitumor Activity of Pirarubicin, and Comparison with Those of Doxorubicin

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Contribution of Specific Transport Systems to Anthracycline Transport in Tumor and Normal Cells

but not

Effects of continuous exposure to digoxin on MDR1 function and expression in Caco-2 cells

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Relationships between the in vitro cytotoxicity and transport characteristics of pirarubicin and doxorubicin in M5076 ovarian sarcoma cells, and comparison with those in Ehrlich ascites carcinoma cells.

whereas the activity of MDR1 in HeLa/TXL cells was significantly enhanced. Thus, the molecular changes to HeLa cells caused by continuous exposure to cisplatin or paclitaxel were in part clarified, and therefore an understanding of the cellular changes induced by chemotherapeutic agents will be necessary to establish a strategy for reversing MDR.