Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine.
Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine.
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DOI：
10.1038/sj.bjc.6600265
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发表时间：
2002-05-06
影响因子：
8.8
通讯作者：
D'Incalci, M
中科院分区：
文献类型：
--
作者：
Erba, E;Bassano, L;Di Liberti, G;Muradore, I;Chiorino, G;Ubezio, P;Vignati, S;Codegoni, A;Desiderio, M A;Faircloth, G;Jimeno, J;D'Incalci, M
阿普利定，脱氢二氢白念珠菌素B，是从地中海衣状白念珠菌中分离得到的一种海洋脱脂肽，目前正处于II期临床试验中。在人类Molt-4白血病细胞中，阿普利定被发现在纳摩尔浓度下具有细胞毒性，并诱导G1期和G2期阻滞。药物诱导的细胞周期紊乱和随后的细胞死亡似乎与大分子合成(蛋白质、核糖核酸、脱氧核糖核酸)无关，因为这些影响发生在大分子合成没有明显影响的浓度(例如10 NM)。10 NM阿普利定作用1 h可抑制鸟氨酸脱羧酶活性，随后腐胺水平显著下降。这一发现的相关性值得怀疑，因为添加腐胺并没有显著降低阿普利定的细胞周期扰动或细胞毒性。阿普利定引起的细胞周期紊乱也不是由于对细胞周期蛋白依赖性激酶的影响。虽然阿普利定的作用机制尚不清楚，但细胞周期时相紊乱和快速诱导Molt-4细胞凋亡似乎是由于与已知抗癌药物不同的机制所致。《英国癌症杂志》(2002)86,1510-1517。DOI：10.1038/sj/bjc/6600265 www.bjancer.com2002英国癌症研究中心
Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4 leukaemia cells Aplidine was found to be cytotoxic at nanomolar concentrations and to induce both a G1 arrest and a G2 blockade. The drug-induced cell cycle perturbations and subsequent cell death do not appear to be related to macromolecular synthesis (protein, RNA, DNA) since the effects occur at concentrations (e.g. 10 nM) in which macromolecule synthesis was not markedly affected. Ten nM Aplidine for 1 h inhibited ornithine decarboxylase activity, with a subsequently strong decrease in putrescine levels. This finding has questionable relevance since addition of putrescine did not significantly reduce the cell cycle perturbations or the cytotoxicity of Aplidine. The cell cycle perturbations caused by Aplidine were also not due to an effect on the cyclin-dependent kinases. Although the mechanism of action of Aplidine is still unclear, the cell cycle phase perturbations and the rapid induction of apoptosis in Molt-4 cells appear to be due to a mechanism different from that of known anticancer drugs. British Journal of Cancer (2002) 86, 1510–1517. DOI: 10.1038/sj/bjc/6600265 www.bjcancer.com © 2002 Cancer Research UK