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¹ Division of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Japan and ² Departments of Medicine, ³ Pharmacology and Physiology, and ⁴ Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, District of Columbia

Requests for reprints: Bernard Bouscarel, George Washington University Medical Center, 2300 Eye Street, Northwest Ross Hall, Room 523, Washington, DC 20037. Phone: 202-994-2114; Fax: 202-994-3435. E-mail: bbouscarel{at}mfa.gwu.edu

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. [Mol Cancer Ther 2006;5(1):68–79]

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Note: Presented in part at the Annual Meeting of the American Gastroenterological Association in May 2001 and Annual Meeting of the AACR in July 2003.

Received 4/ 6/05; revised 10/14/05; accepted 10/28/05.