Identification of flavonol derivatives inhibiting MDR1: a strategy to overcome multidrug resistance in cancer

Multidrug resistance is a crucial factor contributing to the failure of cancer treatment. Multidrug resistance protein 1 (MDR1) is the most relevant efflux transporter associated with multidrug resistance. The objective of this study was to identify potent MDR1 inhibitors from flavonols. Fifteen flavonols were identified as inhibitors of MDR1 <i>in vitro</i>, with four compounds exhibiting strong inhibitory activity, having IC₅₀ values below 5 μM. These potent MDR1 inhibitors were found to enhance chemosensitivity to doxorubicin in MDR1-overexpressing cells. The results of the multiple-factor analysis indicated that the 3, 5, and 6-methoxy groups were crucial for enhancing the inhibitory effects on MDR1. Furthermore, the total number of methoxy groups in the flavonol backbone was found to be a significant factor in determining the potency of MDR1 inhibition. These observations provide fundamental insights into the structure-activity relationship between flavonol derivatives and MDR1 inhibition, potentially aiding in overcoming drug resistance in cancer.