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Gibberellin derivative GA-13315 sensitizes multidrug-resistant cancer cells by antagonizing ABCB1 while agonizes ABCC1

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Abstract

Purpose

GA-13315 is a gibberellin derivative that reveals antitumor and antineoplastic effects both in vitro and in vivo. In the present study, the chemosensitizing effects of GA-13315 in multidrug-resistant cell lines were examined and the underlying mechanisms were investigated.

Methods

Cytotoxicity and chemosensitizing effects of GA-13315 were determined by MTT assay. Function of ABC transporter was analyzed by measuring intracellular drug accumulation of doxorubicin and rhodamine 123 and by determining the ATPase activity of ABC transporter. Expression levels of apoptosis regulators were analyzed using real-time quantitative PCR and Western blot.

Results

GA-13315 selectively killed MCF-7/adr cells that overexpress P-glycoprotein (ABCB1) over the parent MCF-7 cells. In combination with conventional chemotherapeutic agents, GA-13315 at sub-toxic concentrations reversed the multidrug resistance mediated by ABCB1 but exacerbated the resistance conferred by multidrug resistance-associated protein 1 (ABCC1). GA-13315 increased intracellular accumulation of doxorubicin and rhodamine 123 in MCF-7/adr cells and in ABCB1-transfected HEK293 cells but facilitated drug flush-out from cells that overexpress ABCC1. GA-13315 inhibited the ATPase activity of ABCB1 while stimulated that of ABCC1. Moreover, the downregulated expression of Bax in MCF-7/adr cells was restored by GA-13315 markedly.

Conclusion

These data suggest that GA-13315 sensitizes multidrug-resistant cells at least partially by impeding the efflux function of ABCB1. The upregulation of Bax by GA-13315 may also contribute to the sensitizing action. The opposite effects of GA-13315 on different ATP-binding cassette transporters and their implications in overcoming drug resistance require further investigation.

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Abbreviations

MDR:

Multidrug resistance

ABC:

(ATP)-binding cassette

P-gp:

Permeability glycoprotein

MRP1:

Multidrug resistance-associated protein 1

BCRP:

Breast cancer resistance protein

DOX:

Doxorubicin

PTX:

Paclitaxel

NVT:

Mitoxantrone

VRP:

Verapamil

Rho123:

Rhodamine 123

MTT:

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

PMSF:

Phenylmethylsulfonyl fluoride

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Acknowledgments

This work was supported by grant from the National Natural Science Foundation of China (No. 81160405 to Chen Qing).

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Authors and Affiliations

  1. School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Chun Rong West Street No. 1168, Chenggong, Kunming, 650500, China

    Jiao Mo, Min Kang, Jun-Xian Ye & Chen Qing

  2. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Cui Hu West Road No. 2, Kunming, 650091, China

    Jing-Bo Chen & Hong-bin Zhang

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  1. Jiao Mo
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Correspondence to Hong-bin Zhang or Chen Qing.

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Mo, J., Kang, M., Ye, JX. et al. Gibberellin derivative GA-13315 sensitizes multidrug-resistant cancer cells by antagonizing ABCB1 while agonizes ABCC1. Cancer Chemother Pharmacol 78, 51–61 (2016). https://doi.org/10.1007/s00280-016-3051-5

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