Oncotarget

Research Papers:

Bufalin reverses ABCB1-mediated drug resistance in colorectal cancer

Ze-Ting Yuan, Xiao-Jing Shi, Yu-Xia Yuan, Yan-Yan Qiu, Yu Zou, Cheng Liu, Hui Yu, Xue He, Ke Xu and Pei-Hao Yin _

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Oncotarget. 2017; 8:48012-48026. https://doi.org/10.18632/oncotarget.18225

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Abstract

Ze-Ting Yuan1,*, Xiao-Jing Shi1,*, Yu-Xia Yuan1,*, Yan-Yan Qiu1, Yu Zou1, Cheng Liu1, Hui Yu1, Xue He1, Ke Xu1 and Pei-Hao Yin1,2

1Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China

2Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China

*These authors have contributed equally to this work

Correspondence to:

Pei-Hao Yin, email: yinpeihao1975@hotmail.com

Ke Xu, email: cola519@163.com

Keywords: bufalin, colorectal cancer, multidrug resistance, ABC transporters, ABCB1

Received: October 25, 2016    Accepted: April 29, 2017    Published: May 26, 2017

ABSTRACT

Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan’su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer.


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