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Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance

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Abstract

Multidrug resistance (MDR) is one of the main obstacles in tumor chemotherapy. A promising approach to solving this problem is to utilize a nontoxic and potent modulator able to reverse MDR, which in combination with anticancer drugs increases the anticancer effect. Experiments were carried out to examine the potential of tetrandrine (Tet) as a MDR-reversing agent. Survival of cells incubated with Tet at 2.5 μmol/l for 72 h was over 90%. Tet at 2.5 μmol/l almost completely reversed resistance to vincristine (VCR) in KBv200 cells. Tet at a concentration as low as 0.625 μmol/l produced a 7.6-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive KB cells in vitro. In the KBv200 cell xenograft model in nude mice, neither Tet nor VCR inhibited tumor growth. However, VCR and Tet combined inhibited tumor growth by 45.7%, 61.2% and 55.7% in three independent experimental settings. In the KB cell xenograft model in nude mice, Tet did not inhibit tumor growth, but VCR and the combination of VCR and Tet inhibited tumor growth by 40.6% and 41.6%, respectively. Mechanism studies showed that Tet inhibited [3H]azidopine photoaffinity labeling of P-gp and increased accumulation of VCR in MDR KBv200 cells in a concentration-dependent manner. The results suggest that Tet is a potent MDR-reversing agent in vitro and in vivo. Its mechanism of action is via directly binding to P-gp and increasing intracellular VCR accumulation.

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Abbreviations

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

MDR:

Multidrug resistance

MTT:

3-(4,5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

P-gp:

P-glycoprotein

SDS:

Sodium dodecyl sulfate

Tet:

Tetrandrine

VCR:

Vincristine

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Acknowledgements

We would like to thank Prof. Y.S. Liu (Chinese Academy of Medical Sciences, Beijing) for providing the KB and KBv200 cell lines, Dr. X.P. Pan (Kuming Institute of Botany, Chinese Academy of Sciences) for providing the tetrandrine. This work was supported in part by a Key Science and Technology Project Research Grant of Guangdong Province (no. 990B82), a grant from the Natural Science Foundation of Guangdong Province (no. 9800104) and an Excellent Youth Grant from the Ministry of Health (no. 9905), P. R. China.

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Authors and Affiliations

  1. Cancer Center, Sun Yat-Sen University, 510060, Guangzhou, China

    Liwu Fu, Yongju Liang, Yan Ding, Liming Chen, Yanli Ye, Xiaoping Yang & Qichao Pan

  2. Huangpu Hospital, Sun Yat-Sen University, 510080, Guangzhou, China

    Liwen Deng

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  1. Liwu Fu
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Correspondence to Liwu Fu.

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Fu, L., Liang, Y., Deng, L. et al. Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Chemother Pharmacol 53, 349–356 (2004). https://doi.org/10.1007/s00280-003-0742-5

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