Uncaria alkaloids reverse ABCB1-mediated cancer multidrug resistance

Huang,Bao-Yuan; Zeng,Yu; Li,Ying-Jie; Huang,Xiao-Jun; Hu,Nan; Yao,Nan; Chen,Min-Feng; Yang,Zai-Gang; Chen,Zhe-Sheng; Zhang,Dong-Mei; Zeng,Chang-Qing

doi:10.3892/ijo.2017.4005

Uncaria alkaloids reverse ABCB1-mediated cancer multidrug resistance

Authors:
- Bao-Yuan Huang
- Yu Zeng
- Ying-Jie Li
- Xiao-Jun Huang
- Nan Hu
- Nan Yao
- Min-Feng Chen
- Zai-Gang Yang
- Zhe-Sheng Chen
- Dong-Mei Zhang
- Chang-Qing Zeng
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Affiliations: National Administration of Traditional Chinese Medicine Key Laboratory of Chinese Medicine Digital Quality Evaluation Technology, College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Institute of Uncaria, Jianhe Science and Technology Bureau, Jianhe, Guizhou 556400, P.R. China
Published online on: May 17, 2017 https://doi.org/10.3892/ijo.2017.4005
Pages: 257-268

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Abstract

The overexpression of ATP-binding cassette (ABC) transporters is the main cause of cancer multidrug resistance (MDR), which leads to chemotherapy failure. Uncaria alkaloids are the major active components isolated from uncaria, which is a common Chinese herbal medicine. In this study, the MDR-reversal activities of uncaria alkaloids, including rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine (Icory), hirsutine and hirsuteine, were screened; they all exhibited potent reversal efficacy when combined with doxorubicin. Among them, Icory significantly sensitized ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to vincristine, doxorubicin and paclitaxel, but not to the non-ABCB1 substrate cisplatin. Noteworthy, Icory selectively reversed ABCB1-overexpressing MDR cancer cells but not ABCC1- or ABCG2-mediated MDR. Further mechanistic study revealed that Icory increased the intracellular accumulation of doxorubicin in ABCB1-overexpressing cells by blocking the efflux function of ABCB1. Instead of inhibiting ABCB1 expression and localization, Icory acts as a substrate of the ABCB1 transporter by competitively binding to substrate binding sites. Collectively, these results indicated that Icory reversed ABCB1-mediated MDR by suppressing its efflux function, and it would be beneficial to increase the efficacy of these types of uncaria alkaloids and develop them to be selective ABCB1-mediated MDR-reversal agents.

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