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Takano, M. et al.

Mikihisa Takano, Yoshifumi Otani, Minori Tanda, Masashi Kawami, Junya Nagai, Ryoko Yumoto,

Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2.

Paclitaxel-resistant HepG2 (PR-HepG2) cells were established by long-term exposure of HepG2 cells to paclitaxel and expression and function of efflux (P-glycoprotein, MRP2) and influx (OATP1B3) transporters for paclitaxel were examined to understand the mechanisms underlying the resistance. mRNA expression of P-glycoprotein (P-gp) increased in PR-HepG2 more than in HepG2 cells, while that of MRP2 did not change. Interestingly, mRNA expression of OATP1B3 drastically decreased in PR-HepG2 cells. [(3)H]Paclitaxel uptake was less in PR-HepG2 than in HepG2 cells and the uptake in both cells increased by metabolic inhibition. The uptake of [(3)H]paclitaxel and rhodamine 123 increased by verapamil, a P-gp inhibitor. Probenecid, an MRP inhibitor, did not affect [(3)H]paclitaxel uptake in both cells. Sulfobromophthalein, an OATP1B3 inhibitor, inhibited [(3)H]paclitaxel uptake in HepG2 but not in PR-HepG2 cells. Cytotoxicity studies showed that the resistance of PR-HepG2 cells to paclitaxel was reversed by verapamil. PR-HepG2 cells showed cross-resistance to doxorubicin, a P-gp substrate, but not to cisplatin. These results indicate that enhanced expression and function of P-gp may be a predominant mechanism of paclitaxel resistance in PR-HepG2 cells and the reduced influx via OATP1B3 may also serve to lower intracellular paclitaxel concentration in cooperation with P-gp-mediated efflux.[1]

References

Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. Takano, M., Otani, Y., Tanda, M., Kawami, M., Nagai, J., Yumoto, R. Drug Metab. Pharmacokinet. (2009) [Pubmed]

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