| Establishment of functional telomerase immortalized human hepatocytes and a hepatic stellate cell line for telomere-targeting anticancer drug development. | |
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MedLine Citation:
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PMID: 20456367 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We previously reported that the telomere-targeting drug telomestatin induces apoptosis accompanied by G-tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)-immortalized cells. Because telomere-targeting drugs induce growth arrest in normal cells at higher doses, their development is dependent on the ability to predict toxicity before in vivo use, but no models for this are available. Here, we established two new cell lines, telomerase immortalized human fetal hepatocytes, Hc3716-hTERT, and telomerase immortalized hepatic stellate cells, NPC-hTERT. Examinations showed that Hc3716-hTERT maintained normal mammalian cell morphology, cell growth, albumin expression, and wild-type p53 responsiveness, whereas NPC-hTERT maintained hepatic stellate-like morphology, expression of hepatic stellate markers, alpha-smooth muscle actin, and secretion of type I collagen, an extracellular matrix protein. Given our finding that telomere G-tail length in Hc3716 cells was decreased in senescence and increased by hTERT infection, we next examined the effect of high-dose telomestatin-induced telomere dysfunction and G-tail shortening on cellular functions in Hc3716-hTERT cells. Interestingly, telomestatin decreased expression of cytochrome P450 (CYP) family members CYP3A3/4, CYP3A5, and CYP3A7, mRNA and induced albumin expression at both mRNA and protein levels. These gene expression responses to telomestatin were similar to those of the normal parental cell Hc3716. These established cell lines thus represent the first model for predicting the side-effects of telomere-targeting drugs in normal cells, and should be powerful tools in the development of these drugs. |
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Authors:
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Koji Waki; Kumiko Anno; Taeko Ono; Toshinori Ide; Kazuaki Chayama; Hidetoshi Tahara |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-23 |
Journal Detail:
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Title: Cancer science Volume: 101 ISSN: 1349-7006 ISO Abbreviation: Cancer Sci. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-20 Completed Date: 2010-08-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: England |
Other Details:
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Languages: eng Pagination: 1678-85 Citation Subset: IM |
Affiliation:
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Division of Frontier Medical Science Programs for Biomedical Research, Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology,
toxicity Cell Division Cell Line, Tumor Fetus Gene Amplification Hepatic Stellate Cells / drug effects, enzymology* Hepatocytes / drug effects, enzymology*, virology Humans Oxazoles / pharmacology, toxicity RNA / genetics, isolation & purification RNA, Messenger / genetics Retroviridae / genetics Reverse Transcriptase Polymerase Chain Reaction Telomerase / drug effects, genetics*, metabolism Telomere / drug effects, physiology*, ultrastructure Transduction, Genetic |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Oxazoles; 0/RNA, Messenger; 0/telomestatin; 63231-63-0/RNA; EC 2.7.7.49/TERT protein, human; EC 2.7.7.49/Telomerase |
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