Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter

被引:23
作者
Wu, Chung-Pu [1 ,2 ,3 ,5 ]
Hsiao, Sung-Han [1 ]
Murakami, Megumi [7 ]
Lu, Yu-Jen [5 ]
Li, Yan-Qing [2 ]
Huang, Yang-Hui [3 ,5 ]
Hung, Tai-Ho [4 ,6 ]
Ambudkar, Suresh V. [7 ]
Wu, Yu-Shan [8 ]
机构
[1] Chang Gung Univ, Coll Med, Grad Inst Biomed Sci, Tao Yuan 333, Taiwan
[2] Chang Gung Univ, Coll Med, Dept Physiol & Pharmacol, Tao Yuan 333, Taiwan
[3] Chang Gung Univ, Coll Med, Mol Med Res Ctr, Tao Yuan 333, Taiwan
[4] Chang Gung Univ, Coll Med, Dept Chinese Med, Tao Yuan 333, Taiwan
[5] Chang Gung Mem Hosp, Dept Neurosurg, Tao Yuan 333, Taiwan
[6] Taipei Chang Gung Mem Hosp, Dept Obstet & Gynecol, Taipei 105, Taiwan
[7] NCI, Lab Cell Biol, CCR, NIH, Bethesda, MD 20850 USA
[8] Tunghai Univ, Dept Chem, Taichung 407, Taiwan
基金
美国国家卫生研究院;
关键词
multidrug resistance; ABCG2; alpha-mangostin; modulator; HUMAN P-GLYCOPROTEIN; LEUKEMIA-CELL-LINES; BREAST-CANCER CELLS; GARCINIA-MANGOSTANA; DRUG TRANSPORTER; HISTONE DEACETYLASE; KINASE INHIBITORS; MYELOID-LEUKEMIA; FUMITREMORGIN-C; ATP HYDROLYSIS;
D O I
10.1021/acs.molpharmaceut.7b00334
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The ATP-binding cassette (ABC) drug transporter ABCG2 can actively efflux a wide variety of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular accumulation of these drugs. Therefore, the overexpression of ABCG2 often contributes to the development of multidrug resistance-(MDR) in cancer cells, which is one of the major obstacles to successful cancer chemotherapy. Moreover, ABCG2 is highly expressed in various tissues including the intestine and blood-brain barrier (BBB), limiting the absorption and bioavailability of many therapeutic agents. For decades, the task of developing a highly effective synthetic inhibitor of ABCG2 has been hindered mostly by the intrinsic toxicity, the lack of specificity, and complex pharmacokinetics. Alternatively, considering the wide range of diversity and relatively nontoxic nature of natural products, developing potential modulators of ABCG2 from natural sources is particularly valuable. aMangostin is a natural xanthone derived from the pericarps of mangosteen (Gareinia mangostana L.) with various pharmacological purposes, including suppressing angiogenesis and inducing cancer cell, growth arrest. In this study, we demonstrated that at nontoxic concentrations, a-mangostin effectively and selectively inhibits ABCG2-mediated drug transport and reverses MDR in ABCG2-overexpressing MDR cancer cells. Direct interactions between a-mangostin and the ABCG2 drug binding site(s) were confirmed by stimulation of ATPase activity and by inhibition of photolabeling of the substrate-binding site(s) of ABCG2 with [I-125]iodoarylazidoprazosin. In summary, our findings show that-alpha-mangostin has great potential to be further developed into a promising modulator of ABCG2 for reversing MDR and for its use in combination therapy for patients with MDR tumors.
引用
收藏
页码:2805 / 2814
页数:10
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