Tumor-specificity and type of cell death induced by vitamin K2 derivatives and prenylalcohols.
Tumor-specificity and type of cell death induced by vitamin K2 derivatives and prenylalcohols.
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发表时间：
2008
影响因子：
2
通讯作者：
H. Sakagami;K. Hashimoto;Fumika Suzuki;M. Ishihara;H. Kikuchi;T. Katayama;K. Satoh
中科院分区：
文献类型：
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作者：
H. Sakagami;K. Hashimoto;Fumika Suzuki;M. Ishihara;H. Kikuchi;T. Katayama;K. Satoh
研究了14种维生素K2（甲基萘醌(MK)-n, n = 1-14）和10种侧链异戊烯基数目不同(n)的戊烯醇衍生物（n = 1-10）对9种人肿瘤细胞系和3种人正常口腔细胞的细胞毒性。在维生素K2衍生物中，MK-2 （n = 2）的细胞毒性最强，其次是MK-1 （n = 1）和MK-3 （n = 3）。MK-1、MK-2和MK-3的肿瘤特异性指数最高（TS分别为> 2.0、2.0和> 1.7）。各戊基醇中，香叶香醇（GG） （n = 4）的细胞毒性最高，其次是法尼醇（n = 3）和香叶香醇（GF） （n = 3）。GG的肿瘤特异性最高（TS= 1.8），其次是法尼醇（TS= > 1.4）， GF （TS= > < 1.3）。然而，MK-2和GG的肿瘤特异性远低于常规化疗药物。MK-2对人类早幼粒细胞白血病HL-60和鳞状细胞癌HSC-4细胞系的核小体间DNA断裂均无诱导作用，而白血病细胞系对MK-2和GG最敏感，胶质母细胞瘤细胞系对MK-2和GG最耐药。GG在HL-60细胞中诱导边缘核体间DNA断裂，但在HSC-4细胞中没有。MK-2和GG都没有诱导自噬体的形成，也没有明显改变细胞内三种多胺的浓度。电子自旋共振（ESR）光谱显示，只有MK-1 （n = 1）以及细胞毒性较低的GGF （n = 7）和GFF （n = 8）产生自由基，表明细胞毒性与自由基产生之间缺乏联系。目前的研究表明，维生素K2衍生物中1,4-萘醌结构（包括α， β -不饱和酮）的存在赋予它们诱导非凋亡性细胞死亡的能力。
Fourteen vitamin K2 (menaquinone (MK)-n, n = 1-14) and ten prenylalcohol derivatives (n = 1-10) with different numbers (n) of isoprenyl groups in the side chains were investigated for their cytotoxicity against nine human tumor cell lines and three human normal oral cells. Among the vitamin K2 derivatives, MK-2 (n = 2) showed the greatest cytotoxicity, followed by MK-1 (n = 1) and MK-3 (n = 3). MK-1, MK-2 and MK-3 showed the highest tumor-specific index (TS= > 2.0, 2.0 and > 1.7, respectively). Among the prenylalcohols, geranylgeraniol (GG) (n = 4) showed the highest cytotoxicity, followed by farnesol (n = 3) and geranylfarnesol (GF) (n = 3). GG showed the highest tumor-specificity (TS = 1.8), followed by farnesol (TS = > 1.4), GF (TS= > < 1.3). However, the tumor-specificity of MK-2 and GG was much lower than that of conventional chemotherapeutic agents. The human leukemic cell lines were the most sensitive, whereas the human glioblastoma cell lines were the most resistant to MK-2 and GG. MK-2 did not induce internucleosomal DNA fragmentation in either the human promyelocytic leukemia HL-60 or the human squamous cell carcinoma HSC-4 cell lines. GG induced marginal internucleosomal DNA fragmentation in the HL-60 cells, but not in the HSC-4 cells. Both MK-2 and GG did not induce the formation of autophagosomes, nor did they clearly change the intracellular concentration of three polyamines. Electron spin resonance (ESR) spectroscopy showed that only MK-1 (n = 1), as well as GGF (n = 7) and GFF (n = 8) which had lower cytotoxicity, produced radicals, suggesting the lack of connection between cytotoxicity and radical production. The present study demonstrates that the presence of 1,4-naphtoquinone structure (including alpha,beta-unsaturated ketones) in vitamin K2 derivatives confers on them the ability to induce non-apoptotic cell death.