Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol
Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol
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DOI：
10.1016/j.taap.2008.01.008
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发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Ota, Takahide
中科院分区：
文献类型：
--
作者：
Maeda, Masayo;Murakami, Manabu;Ota, Takahide
拉帕胆碱[2-羟基-3-（3-甲基-2-丁烯基）-1，4-萘醌]是一种具有抗肿瘤活性的维生素K拮抗剂。研究拉帕胆碱对小鼠B16 BL 6黑色素瘤细胞实验转移的影响。单次口服高毒性剂量的拉帕胆碱（80-100 mg/kg）6小时前静脉注射的肿瘤细胞显着促进转移。在T细胞缺陷小鼠和NK抑制小鼠中也观察到这种转移促进作用。在体外用拉帕胆碱处理B16 BL 6细胞仅轻微地促进转移，表明拉帕胆碱主要通过影响T细胞和NK细胞以外的宿主因子来促进转移。在静脉注射肿瘤细胞前6 h口服华法林（最常用的维生素K拮抗剂）也显著促进B16 BL 6细胞的转移。拉帕胆碱和华法林的转移促进几乎完全抑制了维生素K3的预给药，这表明拉帕胆碱的转移促进来自维生素K拮抗作用。口服拉帕胆碱或华法林后6小时，蛋白C水平最大程度降低，凝血酶原时间无延长。这些观察结果表明，高毒性剂量的拉帕胆碱通过诱导高凝状态促进转移，这是维生素K依赖性途径抑制的结果。另一方面，连续口服低无毒剂量的拉帕胆碱（5-20 mg/kg）通过未知机制微弱但显著地抑制转移，表明拉帕胆碱可能用作抗转移剂。(C)2008年爱思唯尔公司All rights reserved.
Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonly used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent. (C) 2008 Elsevier Inc. All rights reserved.