Review of the Apoptosis Pathways in Pancreatic Cancer and the Anti-apoptotic Effects of the Novel Sea Cucumber Compound, Frondoside A
Review of the Apoptosis Pathways in Pancreatic Cancer and the Anti-apoptotic Effects of the Novel Sea Cucumber Compound, Frondoside A
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DOI：
10.1196/annals.1414.025
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Adrian, T. E.
中科院分区：
文献类型：
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作者：
Li, X.;Roginsky, A. B.;Adrian, T. E.
胰腺癌细胞对常规化疗剂的生长抑制和肿瘤诱导作用具有抗性。在肿瘤发生过程中存在多种遗传和表观遗传事件，使癌细胞能够避免正常生长限制和凋亡。对所涉及的机制的研究已经导致了多种策略，这些策略鼓励细胞死亡和凋亡发生。所涉及的途径进行了总结，连同一些最近开发的策略，以促进这种癌症中的细胞死亡，并特别关注的frondoside A，一种新的三萜类糖苷从大西洋海参，黄瓜frondosa分离。通过H-3-胸苷掺入和细胞计数测定，Frondoside A以浓度和时间依赖性方式抑制AsPC-1人胰腺癌细胞的增殖。与细胞生长的抑制相一致，frondoside A诱导了与凋亡一致的显著形态学变化。碘化丙啶DNA染色显示，在福氏叶苷A诱导下，凋亡细胞亚G0/G1期细胞数增多。通过Annexin V结合和TUNEL检测证实了Frondoside A诱导的细胞凋亡。此外，蛋白质印迹法显示Bcl-2和Mcl-1的表达减少，Bax的表达增加，半胱天冬酶3、7和9的活化，以及细胞周期蛋白依赖性激酶抑制剂p21的表达增加。这些发现表明，frondoside A通过线粒体途径和激活caspase级联反应诱导人胰腺癌细胞凋亡。最后，一个非常低浓度的frondoside A（10 μ g/kg/天）抑制生长的AsPC-1异种移植在无胸腺小鼠。总之，胰腺癌迫切需要新的化疗药物，因为目前可用的治疗方案的反应性差。Frondoside A对人胰腺癌细胞具有较强的生长抑制作用，其增殖抑制伴随着明显的凋亡。Frondoside A可能对这种毁灭性疾病的治疗或化学预防有价值。
Pancreatic cancer cells are resistant to the growth-inhibitory and apoptosis-inducing effects of conventional chemotherapeutic agents. There are multiple genetic and epigenetic events during the process of carcinogenesis that enable the cancer cells to avoid normal growth constraints and apoptosis. Investigation of the mechanisms involved has led to multiple strategies that encourage cell death and apoptosis to occur. The pathways involved are summarized in this review, together with some recently developed strategies to promote cell death in this cancer and with a particular focus on the frondoside A, a novel triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A inhibited proliferation of AsPC-1 human pancreatic cancer cells in a concentration- and time-dependent manner, as measured by H-3-thymidine incorporation and cell counting. In concert with inhibition of cell growth, frondoside A induced significant morphological changes consistent with apoptosis. Propidium iodide DNA staining showed an increase of sub-G0/G1 cell population of apoptotic cells induced by frondoside A. Frondoside A-induced apoptosis was confirmed by annexin V binding and TUNEL assay. Furthermore, western blotting showed a decrease in expression of Bcl-2 and Mcl-1, an increase in Bax expression, activation of caspases 3, 7, and 9, and an increase in the expression of the cyclin-dependent kinase inhibitor, p21. These findings show that frondoside A induced apoptosis in human pancreatic cancer cells through the mitochondrial pathway and activation of the caspase cascade. Finally, a very low concentration of frondoside A (10 mu g/kg/day) inhibited growth of AsPC-1 xenografts in athymic mice. In conclusion, new chemotherapeutic agents are desperately needed for pancreatic cancer because of the poor responsiveness to currently available treatment options. Frondoside A has potent growth inhibitory effects on human pancreatic cancer cells, and the inhibition of proliferation is accompanied by marked apoptosis. Frondoside A may be valuable for the treatment or chemoprevention of this devastating disease.