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Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance.


ABSTRACT: Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20?cells, and sensitized NCI-H460/MX20?cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.

SUBMITTER: Cai CY 

PROVIDER: S-EPMC6718313 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance.

Cai Chao-Yun CY   Zhai Hong H   Lei Zi-Ning ZN   Tan Cai-Ping CP   Chen Bao-Li BL   Du Zhao-Yi ZY   Wang Jing-Quan JQ   Zhang Yun-Kai YK   Wang Yi-Jun YJ   Gupta Pranav P   Wang Bo B   Chen Zhe-Sheng ZS  

European journal of medicinal chemistry 20190624


Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized  ...[more]

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