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.

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 EC over 10 μM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin was a potent and nontoxic P-gp inhibitor. Its EC for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that 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 could achieve a plasma concentration above its in vitro EC (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, reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% ( < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold ( < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of and doxorubicin significantly prolonged the survival of the mice ( < 0.001 and < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers.