Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin.
Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin.
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DOI：
10.1038/sj.bjc.6602166
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发表时间：
2004-10-04
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Aplidin™（APL）是一种来自海洋的新型抗肿瘤药物，目前正在针对多种癌症进行II期临床试验。由于耐药性可能是APL治疗效果的重要障碍，我们通过将HeLa细胞连续暴露于药物建立了获得性耐药细胞模型。稳定的耐药亚系（HeLa-APL），拥有超过1000倍的相对耐药性APL比亲本细胞，并没有表现出交叉耐药性的一个子集的临床相关的抗肿瘤药物。此外，耐药与P-糖蛋白的过度表达或总体药物蓄积的差异无关。与亲本细胞相比，HeLa-APL细胞的生长速率没有显著差异，细胞周期分布也没有明显改变。Aplidin™诱导JNK和p38 MAPK的快速和持续磷酸化，导致亲本细胞中线粒体凋亡途径的激活，但值得注意的是，在HeLa-APL抗性细胞中，MAPK激活仅以轻微和短暂的方式发生，未能激活上述凋亡机制。这些结果表明，JNK和p38的持续激活是必不可少的触发APL诱导的凋亡程序和HeLa-APL细胞绕过这种凋亡反应，通过防止特定的机制，总理和维持这些信号级联的长期激活。虽然远离人体肿瘤生理学在体内，HeLa-APL细胞代表了一个潜在的有用的工具，在获得的APL的作用模式的见解，在选择非交叉耐药APL结构类似物，以及在调查和开发方法，以防止耐药这种药物。
Aplidin™ (APL) is a new antitumoral drug from marine origin currently in phase II clinical trials against a wide multiplicity of cancers. As resistance may be, as with other drugs, an important obstacle to the APL therapeutic efficacy, we have established an acquired resistance cellular model by continuous exposure of HeLa cells to the drug. The stably resistant subline generated (HeLa-APL), possessing more than 1000-fold relative resistance to APL than parental cells, did not show crossresistance to a subset of clinically relevant antitumoral agents. In addition, resistance was not related to overexpression of P-glycoprotein or differences in overall drug accumulation. Comparing to parental cells, HeLa-APL cells did not present either significant differences in the growth rate or apparent alterations in the cell cycle distribution. Aplidin™ induced rapid and persistent phosphorylation of both JNK and p38 MAPKs, resulting in activation of the mitochondrial apoptotic pathway in parental cells, but, notably, in HeLa-APL-resistant cells MAPKs activation only occurred in a slight and transiently manner, failing to activate the above-mentioned apoptotic machinery. These results suggest that sustained activation of JNK and p38 is essential for triggering the apoptotic programme induced by APL and that HeLa-APL cells bypass this apoptotic response by preventing the specific mechanisms that prime and sustain the long-term activation of these signalling cascades. Although far from human tumour physiology in vivo, HeLa-APL cells represent a potentially useful tool in gaining insights into the mode of action of APL, in selecting non-crossresistant APL structural analogues, as well as in investigating and developing methods to prevent resistance to this drug.
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