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.
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.
Ishikawa
Chie
C
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of Ryukyus, Nishihara, Japan.
Matsuda
Takehiro
T
Okudaira
Taeko
T
Tomita
Mariko
M
Kawakami
Hirochika
H
Tanaka
Yuetsu
Y
Masuda
Masato
M
Ohshiro
Kazuiku
K
Ohta
Takao
T
Mori
Naoki
N
D000368:Aged; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology
D000963:Antimetabolites; C107489:BIRC5 protein, human; D015415:Biomarkers; D004164:Diphosphonates; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C071542:cimadronate; D020169:Caspases; D008798:Mevalonic Acid