P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the
simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different
targets and diverse chemical structures. The exploration of safe and specific inhibitors
of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring
flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors
of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator
in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric
structure of the drug transporter and represented a new generation of inhibitors with
high transporter binding affinity and low toxicity. This review concerned the recent updates
on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms
of their action and their ability to overcome P-gp-mediated MDR in preclinical studies.
It had crucial implications on the discovery of new drug candidates that modulated the efflux
of ABC transporters and also provided some clues for the future development in this promising
Keywords: P-glycoprotein, multidrug resistance, flavonoids, inhibitors, SARs, anticancer.
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