Drug resistance is the major reason accounting for the treatment failure in cancer chemotherapy.
Dysregulation of the epigenetic machineries is known to induce chemoresistance. It
was reported that numerous genes encoding the key mediators in cancer proliferation, apoptosis,
DNA repair, and drug efflux are dysregulated in resistant cancer cells by aberrant DNA methylation.
The imbalance of various enzymes catalyzing histone post-translational modifications is also
known to alter chromatin configuration and regulate multiple drug resistance genes. Alteration in
miRNA signature in cancer cells also gives rise to chemoresistance. Flavonoids are a large group
of naturally occurring polyphenolic compounds ubiquitously found in plants, fruits, vegetables and
traditional herbs. There has been increasing research interest in the health-promoting effects of
flavonoids. Flavonoids were shown to directly kill or re-sensitize resistant cancer cells to conventional
anticancer drugs by epigenetic mechanisms. In this review, we summarize the current findings
of the circumvention of drug resistance by flavonoids through correcting the aberrant epigenetic
regulation of multiple resistance mechanisms. More investigations including the evaluation of synergistic
anticancer activity, dosing sequence effect, toxicity in normal cells, and animal studies, are
warranted to establish the full potential of the combination of flavonoids with conventional chemotherapeutic
drugs in the treatment of cancer with drug resistance.