title: Enhancement of DNA topoisomerase I inhibitor-induced apoptosis by ursodeoxycholic acid.
abstract: 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 NH(2)-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.
authors.affiliation: Division of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ikegami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Maryam
authors.initials: M
authors.lastname: Al Rashid
authors.forename: Susan
authors.initials: S
authors.lastname: Ceryak
authors.forename: Yining
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bernard
authors.initials: B
authors.lastname: Bouscarel
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D014580:Ursodeoxycholic Acid; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D002166:Camptothecin