School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.
Curr Cancer Drug Targets. 2021;21(4):289-305. doi: 10.2174/1568009621666210203111220.
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.
耐药性是癌症化疗治疗失败的主要原因。表观遗传机制的失调被认为会诱导耐药性。据报道，在耐药癌细胞中，许多编码癌症增殖、凋亡、DNA 修复和药物外排的关键介质的基因通过异常的 DNA 甲基化而失调。催化组蛋白翻译后修饰的各种酶的失衡也已知会改变染色质结构并调节多种耐药基因。癌细胞中 miRNA 特征的改变也会导致耐药性。类黄酮是植物、水果、蔬菜和传统草药中广泛存在的一大类天然多酚化合物。类黄酮的促进健康的作用越来越受到研究的关注。类黄酮通过表观遗传机制直接杀死或重新敏化耐药癌细胞对传统抗癌药物的作用。在这篇综述中，我们总结了通过纠正多种耐药机制的异常表观遗传调控来克服耐药性的类黄酮的最新发现。需要更多的研究，包括协同抗癌活性、剂量顺序效应、正常细胞毒性以及动物研究的评估，以确定类黄酮与传统化疗药物联合治疗耐药性癌症的全部潜力。
