Yoshida Shigemasa, Honda Akira, Matsuzaki Yasushi, Fukushima Sugano, Tanaka Naomi, Takagiwa Aya, Fujimoto Yoshinori, Miyazaki Hiroshi, Salen Gerald
Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Steroids. 2003 Jan;68(1):73-83. doi: 10.1016/s0039-128x(02)00117-4.
Dehydroepiandrosterone (DHEA) is a naturally occurring steroid synthesized in the adrenal cortex, gonads, brain, and gastrointestinal tract, and it is known to have chemopreventive and anti-proliferative actions on tumors. These effects are considered to be induced by the inhibition of glucose-6-phosphate dehydrogenase (G6PD) and/or HMG-CoA reductase (HMGR) activities. The present study was undertaken to investigate whether endogenous DHEA metabolites, i.e. DHEA-sulfate, 7-oxygenated DHEA derivatives, androsterone, epiandrosterone, and etiocholanolone, have anti-proliferative effects on cancer cells and to clarify which enzyme, G6PD or HMGR, is responsible for growth inhibition. Growth of Hep G2, Caco-2, and HT-29 cells, evaluated by 3-[4,5-dimethylthiazol]-2yl-2,5-diphenyl tetrazolium bromide (MTT) and bromodeoxyuridine incorporation assays, was time- and dose-dependently inhibited by addition of all DHEA-related steroids we tested. In particular, the growth inhibition due to etiocholanolone was considerably greater than that caused by DHEA in all cell lines. The suppression of growth of the incubated steroids was not correlated with the inhibition of G6PD (r=-0.031, n=9, NS) or HMGR (r=0.219, n=9, NS) activities. The addition of deoxyribonucleosides or mevalonolactone to the medium did not overcome the inhibition of growth induced by DHEA or etiocholanolone, while growth suppression by DHEA was partially prevented by the addition of ribonucleosides. These results demonstrate that endogenous DHEA metabolites also have an anti-proliferative action that is not induced by inhibiting G6PD or HMGR activity alone. These non-androgenic DHEA metabolites may serve as chemopreventive or anti-proliferative therapies.
脱氢表雄酮（DHEA）是一种天然存在的类固醇，在肾上腺皮质、性腺、大脑和胃肠道中合成，已知其对肿瘤具有化学预防和抗增殖作用。这些作用被认为是通过抑制葡萄糖-6-磷酸脱氢酶（G6PD）和/或3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）的活性而诱导产生的。本研究旨在调查内源性DHEA代谢产物，即硫酸脱氢表雄酮、7-氧化DHEA衍生物、雄甾酮、表雄甾酮和本胆烷醇酮，是否对癌细胞具有抗增殖作用，并阐明是哪种酶，G6PD还是HMGR，负责生长抑制。通过3-[4,5-二甲基噻唑]-2-基-2,5-二苯基溴化四氮唑（MTT）和溴脱氧尿苷掺入试验评估，添加我们测试的所有与DHEA相关的类固醇后，Hep G2、Caco-2和HT-29细胞的生长受到时间和剂量依赖性抑制。特别是，在所有细胞系中，本胆烷醇酮引起的生长抑制明显大于DHEA引起的生长抑制。所孵育类固醇的生长抑制与G6PD（r=-0.031，n=9，无显著性差异）或HMGR（r=0.219，n=9，无显著性差异）活性的抑制无关。向培养基中添加脱氧核苷或甲羟戊酸内酯并不能克服DHEA或本胆烷醇酮诱导的生长抑制，而添加核糖核苷可部分阻止DHEA对生长的抑制。这些结果表明，内源性DHEA代谢产物也具有抗增殖作用，这种作用不是仅通过抑制G6PD或HMGR活性诱导产生的。这些非雄激素性DHEA代谢产物可作为化学预防或抗增殖疗法。
