Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, FL, 34949, USA.
Chembiochem. 2020 Aug 17;21(16):2356-2366. doi: 10.1002/cbic.202000180. Epub 2020 May 12.
Chemical investigation of a benthic marine cyanobacterium yielded the anticancer agent dolastatin 15, originally isolated from a mollusk. Dolastatin 15 is a microtubule-destabilizing agent with analogues undergoing clinical evaluation. Profiling against a panel of isogenic HCT116 colorectal cancer cells showed remarkable differential cytotoxicity against the parental cells over isogenic cells lacking HIF or other key players in the pathway, including oncogenic KRAS and VEGF. Dolastatin 15 displayed an antivascularization effect in human endothelial cells and in zebrafish vhl mutants with activated Hif, thus signifying its clinical potential as a treatment for solid tumors with an angiogenic component. Global transcriptome analysis with RNA sequencing suggested that dolastatin 15 could affect other major cancer pathways that might not directly involve tubulin or HIF. The identification of the true producer of a clinically relevant agent is important for sustainable supply, as is understanding the biosynthesis, and future genetic manipulation of the biosynthetic gene cluster for analogue production.
从一种底栖海洋蓝藻中提取出了抗癌药物 dolastatin 15，该药物最初是从软体动物中分离出来的。Dolastatin 15 是一种微管去稳定剂，其类似物正在进行临床评估。对一组同源 HCT116 结直肠癌细胞进行分析显示，与缺乏 HIF 或该通路其他关键因子（包括致癌 KRAS 和 VEGF）的同源细胞相比，该药物对亲本细胞具有显著的差异细胞毒性。Dolastatin 15 在人内皮细胞和激活 Hif 的斑马鱼 vhl 突变体中显示出抗血管生成作用，因此表明其作为具有血管生成成分的实体瘤治疗方法的临床潜力。通过 RNA 测序进行的全转录组分析表明，Dolastatin 15 可能会影响其他主要的癌症途径，这些途径可能不直接涉及微管或 HIF。确定一种临床相关药物的真正生产者对于可持续供应很重要，同时还需要了解生物合成，以及用于类似物生产的生物合成基因簇的未来遗传操作。
