Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Pharmacol Res Perspect. 2021 Dec;9(6):e00886. doi: 10.1002/prp2.886.
Breast cancer causes the most cancer fatalities in women worldwide. Approximately one-third of breast cancers metastasize, or spread from primary tumors to other tissues, and have a 70% 5-year mortality rate. Current breast cancer treatments like doxorubicin and paclitaxel become ineffective when breast cancer cells develop multi-drug resistance and overexpress ATP-binding cassette transporters, as the transporters cause a substantial efflux of the chemotherapies. Jadomycins, a group of molecules isolated from Streptomyces venezuelae ISP5230, are shown to be cytotoxic against a variety of cancers, especially breast cancer. Furthermore, jadomycins retain their cytotoxic properties in multi-drug resistant breast cancer cells, as they are not expelled through ATP-binding cassette transporters. Here, we describe the research that supports the potential use of jadomycins as a novel chemotherapy in the treatment of multi-drug resistant, metastatic breast cancer. We present the supportive findings, as well as the mechanisms of action investigated thus far. These include copper-mediated reactive oxygen species generation, aurora B kinase inhibition, and topoisomerase IIα and IIβ inhibition. We also suggest future directions of jadomycin research, which will help to determine if jadomycins can be used as a breast cancer chemotherapy in clinical practice.
乳腺癌是全球导致女性癌症死亡的主要原因。大约三分之一的乳腺癌会转移，即从原发性肿瘤扩散到其他组织，并且有 70%的 5 年死亡率。当乳腺癌细胞产生多药耐药性并过度表达 ATP 结合盒转运蛋白时，当前的乳腺癌治疗方法，如阿霉素和紫杉醇，会变得无效，因为这些转运蛋白会导致化疗药物大量外排。从委内瑞拉链霉菌 ISP5230 中分离得到的一组分子——柔红霉素，被证明对多种癌症具有细胞毒性，尤其是乳腺癌。此外，柔红霉素在多药耐药性乳腺癌细胞中保留其细胞毒性特性，因为它们不会通过 ATP 结合盒转运蛋白排出。在这里，我们描述了支持柔红霉素作为一种新型化疗药物用于治疗多药耐药性、转移性乳腺癌的潜在用途的研究。我们介绍了支持性发现，以及迄今为止研究的作用机制。这些机制包括铜介导的活性氧生成、极光激酶 B 抑制以及拓扑异构酶 IIα 和 IIβ 抑制。我们还提出了柔红霉素研究的未来方向，这将有助于确定柔红霉素是否可以在临床实践中用作乳腺癌化疗药物。
