Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport

被引:3
|
作者
Wu, Chung-Pu [1 ,2 ,3 ]
Murakami, Megumi [4 ]
Li, Yen-Ching [1 ]
Huang, Yang-Hui [1 ]
Chang, Yu-Tzu [1 ]
Hung, Tai-Ho [3 ,5 ,6 ]
Wu, Yu-Shan [7 ]
Ambudkar, Suresh V. [4 ]
机构
[1] Chang Gung Univ, Grad Inst Biomed Sci, Coll Med, Taoyuan 33302, Taiwan
[2] Chang Gung Univ, Coll Med, Dept Physiol & Pharmacol, Taoyuan 33302, Taiwan
[3] Taipei Chang Gung Mem Hosp, Dept Obstet & Gynecol, Taipei 10507, Taiwan
[4] NCI, Lab Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[5] Chang Gung Univ, Coll Med, Dept Med, Taoyuan 33302, Taiwan
[6] Keelung Chang Gung Mem Hosp, Dept Obstet & Gynecol, Keelung 20401, Taiwan
[7] Tunghai Univ, Dept Chem, Taichung 40704, Taiwan
关键词
ATP-binding cassette transporter; multidrug resistance; natural products; ABCG2; imperatorin; FUNCTIONAL-CHARACTERIZATION; KINASE INHIBITORS; NATURAL-PRODUCTS; GENE-EXPRESSION; IN-VITRO; ABCG2; PROTEIN; OVEREXPRESSION; APOPTOSIS; INDUCTION;
D O I
10.3390/ph16111595
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The high expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the emergence of multidrug resistance (MDR) in individuals afflicted with either solid tumors or blood cancers. MDR poses a major impediment in the realm of clinical cancer chemotherapy. Recently, substantial endeavors have been dedicated to identifying bioactive compounds isolated from nature capable of counteracting ABCG2-mediated MDR in cancer cells. Imperatorin, a natural coumarin derivative renowned for its diverse pharmacological properties, has not previously been explored for its impact on cancer drug resistance. This study investigates the chemosensitizing potential of imperatorin in ABCG2-overexpressing cancer cells. Experimental results reveal that at sub-toxic concentrations, imperatorin significantly antagonizes the activity of ABCG2 and reverses ABCG2-mediated MDR in a concentration-dependent manner. Furthermore, biochemical data and in silico analysis of imperatorin docking to the inward-open conformation of human ABCG2 indicate that imperatorin directly interacts with multiple residues situated within the transmembrane substrate-binding pocket of ABCG2. Taken together, these results furnish substantiation that imperatorin holds promise for further evaluation as a potent inhibitor of ABCG2, warranting exploration in combination drug therapy to enhance the effectiveness of therapeutic agents for patients afflicted with tumors that exhibit high levels of ABCG2.
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页数:20
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