Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Department of Chemistry, St. John's College of Liberal Arts and Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Cells. 2021 Feb 21;10(2):458. doi: 10.3390/cells10020458.
Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of 'biaryl' polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.
多药耐药性（MDR）是癌症治疗中的主要临床挑战之一，降低了传统抗癌化疗药物的疗效。在已知的耐药机制中，通过 ATP 结合盒（ABC）转运蛋白的药物外排，即 P-糖蛋白（P-gp），已被确定为 MDR 的主要机制。ABC 转运蛋白的主要功能是调节各种组织中膜屏障内外源小分子的运输。P-gp 和类似的外排泵与 MDR 相关，因为它们在许多癌症类型中过度表达。克服这种多药耐药模式的一种深入研究方法是开发小分子来调节 P-gp 活性。这种策略提高了对否则无效的抗癌药物的癌细胞敏感性。尽管迄今为止已经确定了多代 P-gp 抑制剂，但报道的化合物表现出低临床疗效和不良反应。最近，天然多酚已成为解决与 P-gp 相关的 MDR 的一类有前途的化合物。本综述重点介绍了结构独特的“联苯”多酚类化合物中选定成员的化学结构和抗癌活性。讨论集中在鞣花酸、鞣花酸衍生物和五味子素的抗癌特性上。这里强调了它们固有的抗癌活性及其使 MDR 细胞系对常规抗癌药物敏感的能力的研究报告。此外，还简要讨论了这些天然产物可能引入药物化学研究的轴向手性（即，阻转异构现象）。
