The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells.
The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells.
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DOI：
10.1097/cad.0b013e32832ae55f
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发表时间：
2009-07
影响因子：
2.3
通讯作者：
Ireland CM
中科院分区：
文献类型：
--
作者：
LaBarbera DV;Modzelewska K;Glazar AI;Gray PD;Kaur M;Liu T;Grossman D;Harper MK;Kuwada SK;Moghal N;Ireland CM
细胞凋亡对受损细胞的正常发育和清除非常重要。癌细胞逃避凋亡是许多肿瘤类型的关键特征之一。因此，发现促进肿瘤细胞凋亡的药物可能具有巨大的治疗价值。海洋天然产物已显示出作为抗癌药物的巨大潜力，其中一些产品的促凋亡活性正在成为癌症治疗的潜在有用属性。通过对啮齿动物的肿瘤异种移植实验，我们先前发现海洋生物碱NAM A是一种有效的抗肿瘤药物。在这项研究中，我们进一步研究了NAA的作用机制。在培养的肿瘤细胞中，我们发现NAA诱导细胞死亡，伴随着Annexin V染色，线粒体膜电位的破坏，caspase3，8和9的裂解和激活，所有这些都是细胞凋亡的标志。此外，NAA诱导的细胞死亡是caspase依赖的。我们还发现，在NAA抑制肿瘤异种生长的条件下，它诱导caspase3的激活，这表明细胞凋亡是其体内抗肿瘤活性的一部分。细胞凋亡不依赖于细胞外信号调节的激酶1/2，也不需要功能性的P53。我们的研究支持了对嘧啶甲素及其靶点(S)的继续研究，以期开发出更好的癌症临床治疗方法。
Apoptosis is important for normal development and removal of damaged cells. Evasion of apoptosis by cancer cells is one of the key characteristics of many tumor types. Thus, discovering agents that promote apoptosis in tumor cells could have great therapeutic value. Marine natural products have demonstrated great potential as anticancer agents, and the proapoptotic activity of some of these products is emerging as a potentially useful property for cancer treatments. Using a tumor xenograft assay in rodents, we previously found that the marine alkaloid naamidine A is a potent antitumor agent. In this study, we further characterize the mechanism of action of naamidine A. In cultured tumor cells, we find that naamidine A induces cell death, which is accompanied with annexin V staining, disruption of the mitochondrial membrane potential, and cleavage and activation of caspases 3, 8, and 9, all of which are hallmarks of apoptosis. Furthermore, naamidine A-induced cell death is caspase dependent. We also find that under conditions where naamidine A inhibits tumor xenograft growth, it induces activation of caspase 3, suggesting that apoptosis is part of its antitumorigenic activity in vivo. Apoptosis is not dependent on extracellular signal-regulated kinase 1/2, previously characterized molecular targets of naamidine A, nor does it require functional p53. Our studies support the continued study of naamidine A and its target(s) for the potential development of better clinical treatments for cancer.