Maeda Masayo, Murakami Manabu, Takegami Tsutomu, Ota Takahide
Department of Chemistry, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
Toxicol Appl Pharmacol. 2008 Jun 1;229(2):232-8. doi: 10.1016/j.taap.2008.01.008. Epub 2008 Jan 26.
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.
拉帕醇[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。研究了拉帕醇对小鼠B16BL6黑色素瘤细胞实验性转移的影响。在静脉注射肿瘤细胞前6小时单次口服高毒剂量的拉帕醇(80-100毫克/千克)可显著促进转移。在T细胞缺陷小鼠和NK细胞受抑制的小鼠中也观察到了这种转移促进作用。用拉帕醇对B16BL6细胞进行体外处理仅轻微促进转移，这表明拉帕醇主要通过影响T细胞和NK细胞以外的宿主因素来促进转移。在静脉注射肿瘤细胞前6小时单次口服最常用的维生素K拮抗剂华法林，也可显著促进B16BL6细胞的转移。预先给予维生素K3几乎完全抑制了拉帕醇和华法林对转移的促进作用，这表明拉帕醇对转移的促进作用源于维生素K拮抗作用。口服拉帕醇或华法林6小时后，蛋白C水平最大程度降低，而凝血酶原时间未延长。这些观察结果表明，高毒剂量的拉帕醇通过抑制维生素K依赖途径诱导高凝状态来促进转移。另一方面，连续口服低无毒剂量的拉帕醇(5-20毫克/千克)通过未知机制微弱但显著地抑制转移，这表明拉帕醇可能用作抗转移剂。
