Tsuchiya Hironori, Nagayama Motohiko, Tanaka Toshiyuki, Furusawa Miyuki, Kashimata Masanori, Takeuchi Hiroshi
Department of Dental Pharmacology, Asahi University School of Dentistry, Hozumi, Gifu 501-0296, Japan.
Biofactors. 2002;16(3-4):45-56. doi: 10.1002/biof.5520160301.
Since several anti-cancer drugs interact with cell membrane lipids, the effects of anti-cancer dietary factors on liposomal membranes with different lipid composition were comparatively studied by measuring fluorescence polarization. Fluidity was imparted on both hydrophobic and hydrophilic regions of lipid bilayers by decreasing cholesterol and increasing unsaturated phosphatidylcholine in membranes. At 0.625-10 microM, (-)-epigallocatechin gallate, genistein, apigenin, resveratrol and a reference anti-cancer drug, doxorubicin, rigidified the tumor cell model membranes consisting of 20 mol% cholesterol and 80 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 1.0, but not daidzein. They were more effective on the membrane core than the membrane surface. Quercetin showed a biphasic effect on the hydrophobic regions of membrane lipid bilayers to rigidify above 5 microM and fluidize below 2.5 microM. In contrast, anti-cancer dietary factors and doxorubicin were not or much less effective in rigidifying the normal cell model membranes consisting of 40 mol% cholesterol and 60 mol% phosphatidylcholine with the acyl chain 18:1/16:0 ratio of 0.5. The membrane-rigidifying effects were greater depending on a decrease of the cholesterol/phosphatidylcholine ratio and an increase of the phosphatidylcholine unsaturation degree. Membrane-active dietary factors and doxorubicin inhibited the growth of mouse myeloma cells at 10-100 microM, while the growth inhibition by membrane-inactive daidzein was relatively weak. Anti-cancer dietary factors appear to act on more fluid membranes like tumor cells as well as doxorubicin to induce rigidification, especially in the hydrocarbon core of membrane lipids, which is determined by the composition of cholesterol and unsaturated phospholipids.
由于几种抗癌药物与细胞膜脂质相互作用，通过测量荧光偏振对具有不同脂质组成的脂质体膜上抗癌饮食因子的作用进行了比较研究。通过降低胆固醇含量和增加膜中不饱和磷脂酰胆碱的含量，使脂质双层的疏水和亲水区域都具有流动性。在0.625 - 10微摩尔浓度下，(-)-表没食子儿茶素没食子酸酯、染料木黄酮、芹菜素、白藜芦醇以及一种参考抗癌药物阿霉素，使由20摩尔%胆固醇和80摩尔%磷脂酰胆碱组成、酰基链18:1/16:0比例为1.0的肿瘤细胞模型膜刚性化，但大豆苷元没有这种作用。它们对膜核心的作用比对膜表面更有效。槲皮素对膜脂质双层的疏水区域表现出双相作用，在5微摩尔以上使其刚性化，在2.5微摩尔以下使其流动性增加。相比之下，抗癌饮食因子和阿霉素对由40摩尔%胆固醇和60摩尔%磷脂酰胆碱组成、酰基链18:1/16:0比例为0.5的正常细胞模型膜的刚性化作用不明显或作用小得多。膜刚性化作用随着胆固醇/磷脂酰胆碱比例的降低和磷脂酰胆碱不饱和度的增加而增强。膜活性饮食因子和阿霉素在10 - 100微摩尔浓度下抑制小鼠骨髓瘤细胞的生长，而膜非活性的大豆苷元的生长抑制作用相对较弱。抗癌饮食因子似乎像阿霉素一样作用于像肿瘤细胞这样流动性更强的膜上以诱导刚性化，特别是在膜脂质的烃类核心区域，这由胆固醇和不饱和磷脂的组成决定。
