Document Detail

Bisphosphonate incadronate inhibits growth of human T-cell leukaemia virus type I-infected T-cell lines and primary adult T-cell leukaemia cells by interfering with the mevalonate pathway.
MedLine Citation:
PMID:  17233845     Owner:  NLM     Status:  MEDLINE    
Anti-resorptive bisphosphonates are used for the treatment of hypercalcaemia and bone complications associated with malignancies and osteoporosis, but also have been shown to have anti-tumour effects in various cancers. Adult T-cell leukaemia (ATL) is a fatal T-cell malignancy caused by infection with human T-cell leukaemia virus type I (HTLV-I), and remains incurable. ATL is associated with osteolytic bone lesions and hypercalcaemia, both of which are major factors in the morbidity of ATL. Thus, the search for anti-ATL agents that have both anti-tumour and anti-resorptive activity is warranted. The bisphosphonate agent, incadronate, prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells, but not of non-infected T-cell lines or normal peripheral blood mononuclear cells. Incadronate induced S-phase cell cycle arrest and apoptosis in HTLV-I-infected T-cell lines, and treatment of these cells with substrates of the mevalonate pathway blocked the incadronate-mediated growth suppression. Incadronate also prevented the prenylation of Rap1A protein. These results demonstrated that incadronate-induced growth suppression occurs by interfering with the mevalonate pathway. Importantly, treatment with incadronate reduced tumour formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into severe combined immunodeficient mice. These findings suggest that incadronate could be potentially useful for the treatment of ATL.
Chie Ishikawa; Takehiro Matsuda; Taeko Okudaira; Mariko Tomita; Hirochika Kawakami; Yuetsu Tanaka; Masato Masuda; Kazuiku Ohshiro; Takao Ohta; Naoki Mori
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of haematology     Volume:  136     ISSN:  0007-1048     ISO Abbreviation:  Br. J. Haematol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-19     Completed Date:  2007-03-29     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0372544     Medline TA:  Br J Haematol     Country:  England    
Other Details:
Languages:  eng     Pagination:  424-32     Citation Subset:  IM    
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of Ryukyus, Nishihara, Japan.
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MeSH Terms
Antimetabolites / pharmacology,  therapeutic use*
Apoptosis / drug effects
Biological Markers / analysis
Blotting, Western / methods
Caspases / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Diphosphonates / pharmacology,  therapeutic use*
Human T-lymphotropic virus 1*
Jurkat Cells
Leukemia, T-Cell / drug therapy*,  metabolism
Leukemia-Lymphoma, Adult T-Cell / drug therapy,  metabolism
Mevalonic Acid / metabolism*
Mice, SCID
Microtubule-Associated Proteins / analysis,  metabolism
Middle Aged
Neoplasm Proteins / analysis,  metabolism
Neoplasm Transplantation
Signal Transduction / drug effects
T-Lymphocytes / metabolism*,  virology
Reg. No./Substance:
0/Antimetabolites; 0/BIRC5 protein, human; 0/Biological Markers; 0/Diphosphonates; 0/Microtubule-Associated Proteins; 0/Neoplasm Proteins; 138330-18-4/cimadronate; 150-97-0/Mevalonic Acid; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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