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.

癌症化疗经常受到耐药性的阻碍。过去，将抗癌药物与不同作用方式结合起来以避免产生耐药性的想法在过去并未获得预期的成功，因为肿瘤可能同时对多种药物无反应（例如，多药耐药性表型）。但是，肿瘤可能对其他药物特别敏感-这种现象也称为附带敏感性。这似乎是一般的生物学机制，因为它也发生在耐药性大肠杆菌和酿酒酵母中。

在这里，我们及时而全面地概述了抗性癌细胞对天然产物及其衍生物的超敏反应。由于大多数临床建立的抗癌药物是天然产物，或以某种方式或方式衍生自天然产物，因此值得假设天然产物可能会提供有前途的先导化合物，用于开发敏感的辅助抗癌药物。

超敏反应不仅发生在经典的ABC转运蛋白介导的多药耐药性中，而且还发生在许多其他耐药性表型中。抗性的癌症可以是过敏性，从不同的类和起点（天然化合物即有丝分裂纺锤体毒素，DNA拓扑异构酶1种2抑制剂，药用植物中分离不同的植物化学物质，（半）的植物化学物质，抗生素，海洋药物，重组治疗性蛋白质的合成衍生物和其他）。

附带敏感性的分子机制包括：（1）在ABC转运蛋白介导的药物外排过程中，无效的循环增加了ATP水解和活性氧的产生；（2）抑制了ATP的产生；（3）药物靶蛋白的改变（例如，拓扑异构酶和热休克蛋白，Wnt /β-catenin途径的抑制，β-微管蛋白的突变）。

过敏性现象需要通过开发（1）包括侧敏感药物的新型联合治疗方案和（2）在耐药性肿瘤中表现出高度过敏性的新型药物来开发，用于临床肿瘤学。