Field Jessica J, Northcote Peter T, Paterson Ian, Altmann Karl-Heinz, Díaz J Fernando, Miller John H
Centre for Biodiscovery and Schools, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand.
Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington 6140, New Zealand.
Int J Mol Sci. 2017 May 3;18(5):971. doi: 10.3390/ijms18050971.
Zampanolide, first discovered in a sponge extract in 1996 and later identified as a microtubule-stabilizing agent in 2009, is a covalent binding secondary metabolite with potent, low nanomolar activity in mammalian cells. Zampanolide was not susceptible to single amino acid mutations at the taxoid site of β-tubulin in human ovarian cancer 1A9 cells, despite evidence that it selectively binds to the taxoid site. As expected, it did not synergize with other taxoid site microtubule-stabilizing agents (paclitaxel, ixabepilone, discodermolide), but surprisingly also did not synergize in 1A9 cells with laulimalide/peloruside binding site agents either. Efforts to generate a zampanolide-resistant cell line were unsuccessful. Using a standard wound scratch assay in cell culture, it was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551). These properties of covalent binding, the ability to inhibit cell growth in paclitaxel and epothilone resistant cells, and the ability to inhibit cell migration suggest that it would be of interest to investigate zampanolide in preclinical animal models to determine if it is effective in vivo at preventing tumor growth and metastasis.
扎马泊内酯于1996年首次在海绵提取物中被发现，2009年被鉴定为一种微管稳定剂，它是一种共价结合的次生代谢产物，在哺乳动物细胞中具有强大的低纳摩尔活性。尽管有证据表明扎马泊内酯能选择性地结合到紫杉烷位点，但在人卵巢癌1A9细胞中，它对β-微管蛋白紫杉烷位点的单氨基酸突变不敏感。正如预期的那样，它与其他紫杉烷位点微管稳定剂（紫杉醇、伊沙匹隆、盘状海绵醇）没有协同作用，但令人惊讶的是，在1A9细胞中，它与劳利马内酯/佩罗利德结合位点药物也没有协同作用。培育抗扎马泊内酯细胞系的努力未成功。在细胞培养中使用标准的划痕试验，它是人类脐静脉内皮细胞（HUVEC）和成纤维细胞（D551）迁移的有效抑制剂。共价结合的这些特性、抑制紫杉醇和埃坡霉素耐药细胞中细胞生长的能力以及抑制细胞迁移的能力表明，在临床前动物模型中研究扎马泊内酯以确定其在体内预防肿瘤生长和转移是否有效是有意义的。
