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Naringenin Enhances the Anti-Tumor Effect of Doxorubicin Through Selectively Inhibiting the Activity of Multidrug Resistance-Associated Proteins but not P-glycoprotein

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Abstract

Purpose

Naringenin has shown paradoxical results to modulate the function of multidrug resistance-associated proteins (MRPs). The aim of this study is to interpret whether naringenin can reverse intrinsic and/or acquired resistance of cancer cells to chemotherapeutic agents.

Methods

The effects of naringenin on the uptake, retention and cytotoxicity of doxorubicin were investigated in A549, MCF-7, HepG2 and MCF-7/DOX cells. Cellular efflux pathways modulated by naringenin were assessed with their specific substrates and inhibitors. The improved antitumor activity of doxorubicin in combination with naringenin was also investigated in vivo.

Results

The IC50 values of doxorubicin in combination with naringenin in A549 and MCF-7 cells were approximately 2-fold lower than that of doxorubicin alone. The increased sensitivity to doxorubicin by naringenin in HepG2 and MCF-7/DOX cells was not observed. Naringenin increased the cellular doxorubicin accumulation through inhibiting doxorubicin efflux in the cells expressing MRPs but not P-gp. In contrast to doxorubicin alone, doxorubicin in combination with naringenin enhanced antitumor activity in vivo with low systemic toxicity.

Conclusion

Naringenin enhances antitumor effect of doxorubicin by selective modulating drug efflux pathways. Naringenin will be a useful adjunct to improve the effectiveness of chemotherapeutic agents in treatment of human cancers.

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Abbreviations

DMSO:

Dimethyl sulfoxide

DOX:

Doxorubicin

FITC:

Fluorescein isothiocyanate

MRPs:

Multidrug resistance-associated proteins

MTT:

Methylthiazoletetrazolium

Nar:

Naringenin

PBS:

Phosphate-buffered saline

P-gp:

P-glycoprotein

PI:

Propidium iodide

Rho123:

Rhodamine 123

Vrp:

Verapamil

5-CFDA:

5-Carboxyfluresceindiacetate

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Acknowledgments

This work was supported by grants from the State Key Development Plan Project (2006CB705706 and 2007CB935801), National Natural Science Foundation of China (90606019, 90713024) and the Chinese Academy of Sciences (KSCX2-YW-R-21 and KJCX2-YW-M02).

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Authors and Affiliations

  1. Protein and Peptide Pharmaceutical Laboratory, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Fa Yun Zhang, Gang Jun Du, Ling Zhang, Chun Ling Zhang & Wei Liang

  2. Department of Pharmacology, Pharmaceutical College of Henan University, Kaifeng, 475001, China

    Gang Jun Du

  3. State Kay Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100083, China

    Wan Liang Lu

  4. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China

    Wei Liang

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  1. Fa Yun Zhang
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Correspondence to Wei Liang.

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Zhang, F.Y., Du, G.J., Zhang, L. et al. Naringenin Enhances the Anti-Tumor Effect of Doxorubicin Through Selectively Inhibiting the Activity of Multidrug Resistance-Associated Proteins but not P-glycoprotein. Pharm Res 26, 914–925 (2009). https://doi.org/10.1007/s11095-008-9793-y

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