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Reversal of multidrug resistance of cancer through inhibition of P-glycoprotein by 5-bromotetrandrine

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Abstract

Purpose

The present study aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet), a bromized derivative of tetrandrine (Tet), in vitro and in vivo.

Methods

Drug sensitivity was determined using the MTT assay. The in vivo effect of Tet was investigated using nude mice grafted with sensitive and resistant KB human epidermoid cancer cells. Doxorubicin (Dox) accumulation was analyzed by fluorospectrophotometry and the protein and mRNA levels of P-glycoprotein (P-gp) were determined by immunocytochemistry and RT-PCR, respectively.

Results

BrTet at 0.25, 0.5 and 1 μM reversed Dox resistance in MDR human breast cancer MCF-7/Dox cells dose-dependently and its potency was greater than that of Tet at the same concentrations. BrTet reversed vincristine (VCR), Dox and paclitaxel resistance in MDR human oral epidermoid carcinoma KBv200 cells as well as innate VCR and Dox resistance in human hepatocellular carcinoma Bel7402 cells. However, BrTet showed no effect on the IC50 values of the above-mentioned anticancer drugs in sensitive MCF-7 and KB cells. No reversal effect of BrTet on the cytotoxicity of 5-fluorouracil and cisplatin, non-P-gp substrates, was observed. In nude mice bearing KBv200 xenografts on the left flank and KB xenografts on the right flank, i.p. injection of 5 mg/kg and 10 mg/kg BrTet significantly enhanced the antitumor activity of Dox against KBv200 xenografts with inhibitory rates of 33.0% and 39.2%, while Dox alone inhibited the growth of KBv200 xenografts by only 11.6%. No enhancement by BrTet was seen in KB xenografts. Moreover, BrTet at 5 mg/kg reversed paclitaxel resistance in KBv200 xenografts. Fluorospectrophotometric assay showed that BrTet significantly increased the intracellular accumulation of Dox in MCF-7/Dox cells in a dose-dependent manner. BrTet also inhibited the overexpression of P-gp in MCF-7/Dox cells, but had no effect on mdr1 expression.

Conclusions

BrTet showed significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase in intracellular accumulation of anticancer drugs. BrTet may be a promising MDR modulator for eventual assessment in the clinic.

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Abbreviations

BrTet :

Bromotetrandrine

Dox :

Doxorubicin

EDTA :

Ethylenediamine tetraacetic acid

5-FU :

5-Fluorouracil

GADPH :

Glyceraldehyde-3-phosphate dehydrogenase

MDR :

Multidrug resistance

MTT :

Dimethyl thiazolyl-2,5-diphenyltetrazolium bromide

PBS :

Phosphate-buffered saline

P-gp :

P-glycoprotein

Tet :

Tetrandrine

VCR :

Vincristine

VPM :

Verapamil

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Acknowledgement

Partial financial support for this research was provided from the National Natural Science Foundation of China (no. 37171101).

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Author notes

  1. Jing Jin

    Present address: Department of Pharmacology, University of Cambridge, Cambridge, UK

Authors and Affiliations

  1. Department of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, Chengdu, People’s Republic of China

    Feng-Peng Wang

  2. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

    Huailing Wei

  3. Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, People’s Republic of China

    Gengtao Liu

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  1. Jing Jin
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Correspondence to Gengtao Liu.

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Jin, J., Wang, FP., Wei, H. et al. Reversal of multidrug resistance of cancer through inhibition of P-glycoprotein by 5-bromotetrandrine. Cancer Chemother Pharmacol 55, 179–188 (2005). https://doi.org/10.1007/s00280-004-0868-0

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  • DOI: https://doi.org/10.1007/s00280-004-0868-0

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