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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
Author(s) -
Ishikawa Chie,
Matsuda Takehiro,
Okudaira Taeko,
Tomita Mariko,
Kawakami Hirochika,
Tanaka Yuetsu,
Masuda Masato,
Ohshiro Kazuiku,
Ohta Takao,
Mori Naoki
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2006.06445.x
Subject(s) - cell culture , cancer research , bisphosphonate , apoptosis , cell growth , mevalonate pathway , cell cycle checkpoint , medicine , cell cycle , endocrinology , immunology , virology , biology , osteoporosis , cancer , biochemistry , genetics , reductase , enzyme
Summary 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.