Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.
Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.
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DOI：
10.3892/ijo.31.2.323
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发表时间：
2007-08
影响因子：
5.2
通讯作者：
Mutsumi Ogawa;S. Nakai;Akihiro Deguchi;T. Nonomura;T. Masaki;N. Uchida;H. Yoshiji;S. Kuriyama
中科院分区：
文献类型：
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作者：
Mutsumi Ogawa;S. Nakai;Akihiro Deguchi;T. Nonomura;T. Masaki;N. Uchida;H. Yoshiji;S. Kuriyama
尽管大量研究表明维生素K对多种肿瘤细胞系具有抗肿瘤活性，但证明维生素K体内抗肿瘤作用的报道很少，对结直肠癌（CRC）的抗肿瘤作用仍有待研究。因此，在体外和体内检查了维生素K对CRC的抗肿瘤作用。维生素K2、K3和K5以剂量依赖方式抑制结肠26细胞的增殖，而维生素K1则无此作用。在流式细胞仪上，维生素K2、K3和K5诱导细胞凋亡是通过细胞周期的亚G1期的群体来提出的。Hoechst 33342染色和双色流式细胞术检测，使用荧光素异硫氰酸酯结合的膜联蛋白V和碘化丙啶证实，维生素K2，K3和K5诱导结肠26细胞凋亡死亡。维生素K2、K3和K5显著上调结肠26细胞中caspase-3的酶活性。泛半胱天冬酶抑制剂，苄氧基羰基-Val-Ala-Asp-氟甲基酮，基本上防止维生素K介导的细胞凋亡。使用皮下建立的结肠26肿瘤的同基因小鼠的体内研究表明，静脉内施用维生素K2、K3和K5显著抑制肿瘤生长。维生素K处理组中凋亡肿瘤细胞的数量显著大于对照组。这些结果表明，维生素K2，K3和K5在体外和体内通过诱导肿瘤细胞的半胱天冬酶依赖性凋亡而对CRC产生有效的抗肿瘤作用，这表明这些K族维生素可能是治疗CRC患者的有希望的药物。
Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.