Enhancement of DNA topoisomerase I inhibitor-induced apoptosis by ursodeoxycholic acid
Enhancement of DNA topoisomerase I inhibitor-induced apoptosis by ursodeoxycholic acid
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DOI：
10.1158/1535-7163.mct-05-0107
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发表时间：
2006-01-01
影响因子：
5.7
通讯作者：
Bouscarel, B
中科院分区：
文献类型：
--
作者：
Ikegami, T;Matsuzaki, Y;Bouscarel, B
某些疏水胆汁酸，包括脱氧胆酸和鹅脱氧胆酸，不仅对肝脏而且对肠道都有毒性作用。此外，熊去氧胆酸（UDCA）。对肝脏细胞凋亡有保护作用，对肠道有保护和毒性作用。本研究的目的是阐明UDCA对肠道HT-29细胞毒性作用的机制。在这里，我们发现UDCA增强了磷脂酰丝氨酸外化和SN-38诱导的核体间DNA断裂，SN-38是DNA拓扑异构酶I抑制剂CPT-11最有效的代谢物。此外，在UDCA存在的情况下，SN-38诱导的线粒体膜电位丧失和线粒体膜通透性转变增强，导致通过集落形成实验确定的致死率增加。udca诱导的细胞凋亡增加既不是由于SN-38细胞内积累的改变，也不是由于SN-38细胞周期阻滞。当SN-38刺激后UDCA存在时，凋亡增加的效果最好，UDCA不依赖于caspase-8，但依赖于caspase-9和caspase-3的激活。此外，UDCA增强了sn -38诱导的c-Jun nh2末端激酶的激活。综上所述，在加入拓扑异构酶I抑制剂后，UDCA增加了SN-38的凋亡作用，同时降低了SN-38的坏死作用，在靶向细胞死亡和促进伤口愈合方面具有潜在的临床意义。然而，在抗肿瘤化疗中使用这种胆汁酸作为增强剂还需要进一步的临床评估。
Certain hydrophobic bile acids, including deoxycholic acid and chenodeoxycholic acid, exert toxic effects not only in the liver but also in the intestine. Moreover, ursodeoxycholic acid (UDCA), which. has protective actions against apoptosis in the liver, may have both protective and toxic effects in the intestine. The goal of the present study was to clarify the mechanisms responsible for the toxic effect of UDCA in intestinal HT-29 cells. Here, we show that UDCA potentiated both phosphatidylserine externalization and internucleosomal DNA fragmentation induced by SN-38, the most potent metabolite of the DNA topoisomerase I inhibitor, CPT-11. Furthermore, the loss of mitochondrial membrane potential as well as mitochondrial membrane permeability transition induced by SN-38 was enhanced in the presence of UDCA, resulting in an increased lethality determined by colony-forming assay. This UDCA-induced increased apoptosis was not due to alteration of either intracellular accumulation of SN-38 or cell cycle arrest by SN-38. The increased apoptosis was best observed when UDCA was present after SN-38 stimulation and was independent of caspase-8 but dependent on caspase-9 and caspase-3 activation. Furthermore, UDCA enhanced SN-38-induced c-Jun NH2-terminal kinase activation. In conclusion, UDCA increases the apoptotic effects while decreasing the necrotic effects of SN-38 when added after the topoisomerase I inhibitor, showing potential clinical relevance as far as targeted cell death and improved wound healing are concerned. However, the use of this bile acid as an enhancer in antitumor chemotherapy should be further evaluated clinically.