Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Biotechnol Adv. 2020 Jan-Feb;38:107342. doi: 10.1016/j.biotechadv.2019.01.009. Epub 2019 Jan 29.
Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs - a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae. Here, we give a timely and comprehensive overview on hypersensitivity in resistant cancer cells towards natural products and their derivatives. Since the majority of clinically established anticancer drugs are natural products or are in one way or another derived from them, it is worth hypothesizing that natural products may deliver promising lead compounds for the development of collateral sensitive anticancer drugs. Hypersensitivity occurs not only in classical ABC transporter-mediated multidrug resistance, but also in many other resistance phenotypes. Resistant cancers can be hypersensitive to natural compounds from diverse classes and origins (i.e. mitotic spindle poisons, DNA topoisomerase 1 and 2 inhibitors, diverse phytochemicals isolated from medicinal plants, (semi)synthetic derivatives of phytochemicals, antibiotics, marine drugs, recombinant therapeutic proteins and others). Molecular mechanisms of collateral sensitivity include (1) increased ATP hydrolysis and reactive oxygen species production by futile cycling during ABC transporter-mediated drug efflux, (2) inhibition of ATP production, and (3) alterations of drug target proteins (e.g. increased expression of topoisomerases and heat shock proteins, inhibition of Wnt/β-catenin pathway, mutations in β-tubulin). The phenomenon of hypersensitivity needs to be exploited for clinical oncology by the development of (1) novel combination protocols that include collateral sensitive drugs and (2) novel drugs that specifically exhibit high degrees of hypersensitivity in resistant tumors.
癌症化疗常常受到耐药性的阻碍。将具有不同作用机制的抗癌药物联合使用以避免耐药性发展的概念在过去并没有取得预期的成功，因为肿瘤可能同时对许多药物（例如多药耐药表型）不敏感。然而，肿瘤可能对其他药物特别敏感——这种现象也称为旁系敏感性。这似乎是一种普遍的生物学机制，因为它也发生在耐药性大肠杆菌和酿酒酵母中。在这里，我们及时全面地综述了耐药癌细胞对天然产物及其衍生物的超敏现象。由于大多数临床应用的抗癌药物是天然产物，或以某种方式衍生自它们，因此可以假设天然产物可能为开发具有旁系敏感性的抗癌药物提供有前途的先导化合物。超敏反应不仅发生在经典的 ABC 转运蛋白介导的多药耐药中，也发生在许多其他耐药表型中。耐药性癌症对来自不同类别和来源的天然化合物可能具有超敏性（即有丝分裂纺锤体毒物、DNA 拓扑异构酶 1 和 2 抑制剂、从药用植物中分离出的各种植物化学物质、植物化学物质的（半）合成衍生物、抗生素、海洋药物、重组治疗蛋白等）。旁系敏感性的分子机制包括（1）通过 ABC 转运蛋白介导的药物外排过程中的无效循环增加 ATP 水解和活性氧的产生，（2）抑制 ATP 产生，以及（3）改变药物靶蛋白（例如拓扑异构酶和热休克蛋白表达增加、Wnt/β-catenin 通路抑制、β-微管蛋白突变）。通过开发（1）包含旁系敏感药物的新组合方案和（2）在耐药肿瘤中特异性表现出高度超敏性的新型药物，需要将超敏现象用于临床肿瘤学。
