Jasplakinolide在体外可抑制肌动蛋白细胞骨架，从而抑制前列腺癌细胞的生长。,Journal of the National Cancer Institute

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Jasplakinolide在体外可抑制肌动蛋白细胞骨架，从而抑制前列腺癌细胞的生长。
Journal of the National Cancer Institute ( IF 9.9 ) Pub Date : 1995-01-04 , DOI: 10.1093/jnci/87.1.46
A M Senderowicz ₁ , G Kaur , E Sainz , C Laing , W D Inman , J Rodríguez , P Crews , L Malspeis , M R Grever , E A Sausville

Affiliation

背景技术据报道，Jasplakinolide是由印度洋-太平洋海绵（Jaspis johnstoni）生产的环二肽，可抑制乳腺癌细胞的生长。目的研究了jasplakinolide对三种人类永生化前列腺癌细胞系（PC-3，LNCaP和TSU-Pr1）增殖的影响。详细研究了jasplakinolide对PC-3细胞系的生长抑制作用，以阐明其作用机理。方法使用细胞计数研究生长抑制。基于蛋白质的微孔板测定法用于评估引起持续性生长抑制所需的暴露时间，并研究茉莉酮醇内酯类似物的作用。通过掺入放射性标记的前体来评估代谢变化。使用若丹明鬼笔环肽（RP）和抗细胞骨架成分的抗体，通过荧光显微镜研究了茉莉素醇对细胞骨架的影响。通过从固定细胞中提取结合的荧光物质并在荧光分光光度计中测量荧光量来量化RP结合的变化。结果暴露于jasplakinolide 48小时可有效抑制PC-3，LNCaP和TSU-Pr1细胞的生长。jasplakinolide导致50％生长抑制的剂量对于PC-3细胞为65 nM，对于LNCaP细胞为41 nM，对于TSU-Pr1细胞为170 nM。在PC-3细胞中，暴露于160 nM 48小时会导致总的生长抑制作用，即使去除药物后这种作用仍持续数天。几种jasplakinolide类似物也抑制PC-3细胞的生长，尽管大环内酯环的刚度改变的类似物无效。暴露于jasplakinolide后，在PC-3细胞中未观察到DNA，RNA或蛋白质合成或细胞内三磷酸腺苷水平的早期变化。jasplakinolide对生长的抑制作用伴随着惊人的形态变化。几倍的曝光导致多核细胞。对PC-3细胞中这些变化的进一步研究显示，肌动蛋白细胞骨架发生了戏剧性的早期破坏，RP结合的统计学上显着降低。jasplakinolide的剂量，暴露时间和结构类似物抑制生长的模式与肌动蛋白分布中的变化相对应。结论Jasplakinolide代表一种新型海洋天然产物，对人前列腺癌细胞系具有强大的体外抗增殖活性，并且似乎靶向肌动蛋白的细胞骨架。含义Jasplakinolide是进一步临床前开发的潜在候选药物，并且是一类新型治疗剂的先导结构，可以破坏哺乳动物细胞中的肌动蛋白细胞骨架。

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Jasplakinolide's inhibition of the growth of prostate carcinoma cells in vitro with disruption of the actin cytoskeleton.

BACKGROUND Jasplakinolide, a cyclodepsipeptide produced by an Indo-Pacific sponge, Jaspis johnstoni, has been reported to inhibit the growth of breast cancer cells. PURPOSE The effects of jasplakinolide on the proliferation of three human immortalized prostate carcinoma cell lines (PC-3, LNCaP, and TSU-Pr1) were studied. The growth-inhibitory effect of jasplakinolide on the PC-3 cell line was studied in detail to elucidate its mechanism of action. METHODS Cell counts were used to study growth inhibition. A protein-based microplate assay was used to assess the time of exposure needed to cause persistent growth inhibition and to study the effects of jasplakinolide analogues. Metabolic changes were assessed by following the incorporation of radiolabeled precursors. The effects of jasplakinolide on the cytoskeleton were studied by fluorescent microscopy, using rhodamine phalloidin (RP) and antibodies to cytoskeletal components. Changes in RP binding were quantified by extracting bound fluorescent material from fixed cells and measuring the amount of fluorescence in a spectrofluorometer. RESULTS The growth of PC-3, LNCaP, and TSU-Pr1 cells was potently inhibited by exposure to jasplakinolide for 48 hours; doses of jasplakinolide that led to 50% growth inhibition were 65 nM for PC-3 cells, 41 nM for LNCaP cells, and 170 nM for TSU-Pr1 cells. In PC-3 cells, exposure to 160 nM for 48 hours led to total growth inhibition, which persisted for several days even after drug removal. Several jasplakinolide analogues also inhibited the growth of PC-3 cells, although analogues in which the rigidity of the macrolide ring was altered were ineffective. No early changes in the synthesis of DNA, RNA, or protein or in intracellular adenosine triphosphate levels were seen in the PC-3 cells after exposure to jasplakinolide. Growth inhibition by jasplakinolide was accompanied by striking morphologic changes. Exposure for several doublings led to multinucleated cells. Further investigation of these changes in the PC-3 cells revealed a dramatic and early disruption of the actin cytoskeleton and a statistically significant decrease in RP binding. The doses of jasplakinolide, the time of exposure, and the pattern of growth inhibition by structural analogues corresponded with the changes seen in actin distribution. CONCLUSIONS Jasplakinolide represents a novel marine natural product with potent in vitro antiproliferative activity against human prostate carcinoma cell lines, and it appears to target the actin cytoskeleton. IMPLICATIONS Jasplakinolide is a potential candidate for further preclinical development and a lead structure for a novel class of therapeutic agents that can disrupt the actin cytoskeleton in mammalian cells.

更新日期：2019-11-01

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