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
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
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DOI：
10.1111/j.1365-2141.2006.06445.x
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发表时间：
2007-02-01
影响因子：
6.5
通讯作者：
Mori, Naoki
中科院分区：
文献类型：
--
作者：
Ishikawa, Chie;Matsuda, Takehiro;Mori, Naoki
抗吸收双磷酸盐被用于治疗高钙血症以及与恶性肿瘤和骨质疏松症相关的骨并发症，但也被证明在各种癌症中具有抗肿瘤作用。成人T细胞白血病(ATL)是由人类T细胞白血病病毒I型(HTLV-I)感染引起的一种致死性T细胞恶性肿瘤，至今仍无法治愈。ATL与溶骨性骨损害和高钙血症有关，这两个因素都是ATL发病的主要因素。因此，寻找同时具有抗肿瘤和抗吸收活性的抗ATL药物是必要的。双膦酸类药物因卡膦酸盐可抑制HTLV-I感染的T细胞系和原代ATL细胞的生长，但不能抑制未感染的T细胞系或正常外周血单核细胞的生长。英卡膦酸盐诱导HTLV-I感染的T细胞发生S期细胞周期停滞和凋亡，甲氧戊酸途径底物处理这些细胞可阻断因卡膦酸钠介导的生长抑制作用。Incadronate还可阻止Rap1a蛋白的前烯基化。这些结果表明，因卡磷酸钠诱导的生长抑制是通过干扰甲羟戊酸途径而发生的。重要的是，当感染HTLV-I的T细胞被接种到严重联合免疫缺陷小鼠的皮下时，英卡膦酸盐治疗减少了这些细胞的肿瘤形成。这些发现表明，因卡膦酸盐可能对ATL的治疗有潜在的帮助。
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.