Soma M R, Corsini A, Paoletti R
Institute of Pharmacological Sciences, University of Milan, Italy.
Toxicol Lett. 1992 Dec;64-65 Spec No:1-15. doi: 10.1016/0378-4274(92)90167-i.
Cholesterol in animals is a major structural component of cell membranes. It may therefore play a functional role in the modulation of cell osmolarity, the process of pinocytosis and the activities of membrane-associated proteins such as ionic pumps, immune responses, etc. A major relationship exists between the cell-growth processes and the cholesterol biosynthetic pathway. The cholesterol needed for new membranes may be derived either from endogenous synthesis or from exogenous sources, principally plasma low-density-lipoproteins (LDL) which enter the cells by receptor-mediated endocytosis. Both these pathways are enhanced in rapidly growing cells. Conversely, if synthesis is inhibited and no exogenous cholesterol is available, cell growth is blocked. The 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase (the rate-limiting reaction in cholesterol biosynthesis) is the enzyme which catalyzes the conversion of HMGCoA to mevalonic acid. It has been suggested that mevalonate may play an important role in cell proliferation. All cells need at least two products synthesized from mevalonate in order to proliferate, and the only one yet identified is cholesterol. Other melavonate-derived potential candidates as cell-cycle and cell-survival products include the dolichols ubiquinone side chains, isopentenyladenosine derivatives, etc. Furthermore, it has recently been shown that membrane association appears to be an important function in mevalonate-derive modifications of several important proteins such as cellular membrane G proteins, those coded for by oncogenes (ras proteins) and lamins (nuclear proteins). In recent years the development of cholesterol-synthesis-inhibiting drugs, for lowering plasma cholesterol levels has mainly been centred on the control of HMGCoA reductase activity (vastatins). However, because mevalonic acid is the precursor of numerous metabolites, any reduction of such activity may potentiate pleiotropic effects. Vastatins are now, therefore, receiving increased attention as potential pharmacological tools for the control of abnormal cell growth in pathological situations, i.e. tumours and vascular smooth muscle cell proliferation under atherogenic conditions. In our laboratories, we have demonstrated that simvastatin can prevent arterial myocyte proliferation both in vivo and in vitro. Simvastatin can also inhibit in vitro the rate of human glioma cell growth, since it shows a strong synergistic inhibitory effect on cell proliferation when used in association with anticancer agents such as Carmustine or beta-interferon. Both simvastatin-induced cell growth inhibition and the synergy observed with these drugs can be completely reversed by incubating cells with mevalonate. This shows that the effect of simvastatin of cell proliferation is due to its specific inhibitory activity on intracellular mevalonate synthesis.
动物体内的胆固醇是细胞膜的主要结构成分。因此，它可能在调节细胞渗透压、胞饮作用过程以及膜相关蛋白（如离子泵、免疫反应等）的活性中发挥功能性作用。细胞生长过程与胆固醇生物合成途径之间存在着主要关系。新细胞膜所需的胆固醇可能来自内源性合成或外源性来源，主要是血浆低密度脂蛋白（LDL），它通过受体介导的内吞作用进入细胞。这两条途径在快速生长的细胞中都会增强。相反，如果合成受到抑制且没有外源性胆固醇可用，细胞生长就会受阻。3-羟基-3-甲基戊二酰辅酶A（HMGCoA）还原酶（胆固醇生物合成中的限速反应）是催化HMGCoA转化为甲羟戊酸的酶。有人提出甲羟戊酸可能在细胞增殖中起重要作用。所有细胞为了增殖至少需要两种由甲羟戊酸合成的产物，目前唯一已确定的是胆固醇。其他由甲羟戊酸衍生的作为细胞周期和细胞存活产物的潜在候选物包括多萜醇、泛醌侧链、异戊烯基腺苷衍生物等。此外，最近已表明膜结合似乎是甲羟戊酸对几种重要蛋白质（如细胞膜G蛋白、癌基因编码的蛋白（ras蛋白）和核纤层蛋白（核蛋白））进行修饰的重要功能。近年来，用于降低血浆胆固醇水平的胆固醇合成抑制药物的开发主要集中在控制HMGCoA还原酶活性（他汀类药物）。然而，由于甲羟戊酸是众多代谢产物的前体，这种活性的任何降低都可能增强多效性作用。因此，他汀类药物作为控制病理情况下异常细胞生长（即肿瘤和动脉粥样硬化条件下的血管平滑肌细胞增殖）的潜在药理学工具正受到越来越多的关注。在我们的实验室中，我们已经证明辛伐他汀在体内和体外都能阻止动脉肌细胞增殖。辛伐他汀还能在体外抑制人胶质瘤细胞的生长速度，因为当它与卡莫司汀或β-干扰素等抗癌药物联合使用时，对细胞增殖表现出强烈的协同抑制作用。用甲羟戊酸孵育细胞可以完全逆转辛伐他汀诱导的细胞生长抑制以及与这些药物观察到的协同作用。这表明辛伐他汀对细胞增殖的作用是由于其对细胞内甲羟戊酸合成的特异性抑制活性。
