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Title: | In vivo reversal of P-glycoprotein-mediated drug resistance in a breast cancer xenograft and in leukemia models using a novel, potent, and nontoxic epicatechin EC31 | Authors: | Sun, W Wong, ILK Law, HKW Su, X Chan, TCF Sun, G Yang, X Wang, X Chan, TH Wan, S Chow, LMC |
Issue Date: | Mar-2023 | Source: | International journal of molecular sciences, Mar. 2023, v. 24, no. 5, 4377 | Abstract: | The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 μM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin EC31 was a potent and nontoxic P-gp inhibitor. Its EC50 for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that EC31 restored intracellular drug accumulation by inhibiting P-gp-mediated drug efflux. It did not downregulate the plasma membrane P-gp level nor inhibit P-gp ATPase. It was not a transport substrate of P-gp. A pharmacokinetic study revealed that the intraperitoneal administration of 30 mg/kg of EC31 could achieve a plasma concentration above its in vitro EC50 (94 nM) for more than 18 h. It did not affect the pharmacokinetic profile of coadministered paclitaxel. In the xenograft model of the P-gp-overexpressing LCC6MDR cell line, EC31 reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% (p < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold (p < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of EC31 and doxorubicin significantly prolonged the survival of the mice (p < 0.001 and p < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that EC31 was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers. | Keywords: | EC Epicatechin MDR Modulator Multidrug resistance P-glycoprotein P-gp |
Publisher: | MDPI AG | Journal: | International journal of molecular sciences | ISSN: | 1661-6596 | EISSN: | 1422-0067 | DOI: | 10.3390/ijms24054377 | Rights: | Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). The following publication Sun W, Wong ILK, Law HK-W, Su X, Chan TCF, Sun G, Yang X, Wang X, Chan TH, Wan S, et al. In Vivo Reversal of P-Glycoprotein-Mediated Drug Resistance in a Breast Cancer Xenograft and in Leukemia Models Using a Novel, Potent, and Nontoxic Epicatechin EC31. International Journal of Molecular Sciences. 2023; 24(5):4377 is available at https://doi.org/10.3390/ijms24054377. |
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