Chemoprevention of hepatocellular carcinoma by dehydroepiandrosterone and its derivatives

脱氢表雄酮(DHEA)是年轻人体内含量最丰富的肾上腺雄激素。DHEA在预防人类癌变中的生理作用仍存在争议，但大量报道表明，DHEA的药理剂量对啮齿动物肿瘤具有化学预防和抗增殖作用。本研究旨在为脱氢表雄酮的临床应用提供基础数据和方法。主要研究结果如下：1.建立了一种灵敏可靠的高分辨GC-MS稳定同位素稀释法测定脱氢表雄酮相关类固醇的方法。该方法可以同时测定人血清中DHEA及其衍生物的含量。此外，为了评价脱氢表雄酮对胆固醇代谢的影响，建立了高灵敏的LC-MS/MS方法来定量胆固醇和胆汁酸生物合成途径中的几个关键中间体。2.脱氢表雄酮…的作用对肝癌细胞系的增殖有较多的研究。我们论证了DHEA的四种抗增殖机制：1)通过抑制葡萄糖-6-磷酸脱氢酶的活性来耗尽NADPH和核糖-5-磷酸；2)通过抑制HMG-CoA还原酶的活性来抑制胆固醇的生物合成途径；3)干扰细胞的增殖信号通路(MAPK级联)；以及4)通过抑制PI3K/Akt信号通路来诱导细胞凋亡。高胆固醇血症是肝细胞癌患者重要的副肿瘤综合征之一，DHEA通过抑制胆固醇生物合成途径抑制肝细胞癌的增殖。因此，我们利用荷瘤大鼠模型研究了高胆固醇血症与肝癌相关的分子机制。因此，携带肝癌的大鼠的高胆固醇血症是由于核受体LXRpha的激活导致肿瘤胆固醇外流增加所致。固醇调节元件结合蛋白(SREBP)处理系统的过度表达通过维持作为这种核受体配体的组织中高水平的氧固醇来促进LXRpha的激活。较少

Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgenic steroid in young adult humans. The physiological functions of DHEA in preventing human carcinogenesis are still controversial, but a lot of reports have shown that pharmacological doses of DHEA show chemopreventive and anti-proliferative effects on tumors in rodents. The present study was undertaken to obtain basic data and methods for the clinical use of DHEA in the future. The following results were obtained.1.Sensitive and reliable method for the quantification of DHEA-related steroids by a stable isotope-dilution technique using high-resolution GC-MS was developed. The method made it possible to determine simultaneously DHEA and DHEA derivative levels in human serum. In addition, to evaluate the effects of DHEA on cholesterol metabolism, highly sensitive LC-MS/MS methods for the quantification of several key intermediates in the cholesterol and bile acid biosynthetic pathways were developed.2.The effects of DHEA … More on the proliferation of hepatic cancer cell lines were studied. We demonstrated the following four mechanisms of the anti-proliferation by DHEA : 1) depletion of NADPH and ribose-5-phosphate due to the inhibition of glucose-6-phosphate dehydrogenase activity, 2) suppression of cholesterol biosynthetic pathway by inhibition of HMG-CoA reductase activity, 3) interference with a cell proliferation signaling pathway (MAPK cascade), and 4)induction of apoptosis through the inhibition of the PI3K/Akt signaling pathway.3. Hypercholesterolemia is one of the important paraneoplastic syndromes in patients with hepatocellular carcinoma and DHEA inhibits the proliferation of hepatocellular carcinoma by inhibiting cholesterol biosynthetic pathway. Therefore, we investigated the molecular mechanisms of hypercholesterolemia associated with hepatoma by using a hepatoma-bearing rat model. As a result, hypercholesterolemia in the hepatoma-bearing rats was caused by the increased cholesterol efflux from tumors due to the activation of a nuclear receptor, LXRalpha. Over-expression of the sterol regulatory element-binding protein (SREBP) processing system contributes to the activation of LXRalpha by maintaining high tissue levels of oxysterols that are ligands for this nuclear receptor. Less