Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Prostate. 2014 Jun;74(8):839-51. doi: 10.1002/pros.22801. Epub 2014 Mar 9.
Resveratrol (RSV) and resveratrol analogs have a potential use in prostate cancer chemoprevention due to effects on for example, cell growth, apoptosis, angiogenesis, and metastasis. However, inhibition of CYP17A1, a key enzyme in the androgen biosynthesis and a target for prostate cancer therapy, has not been explored as a possible mechanism behind the effects on prostate cancer.
Human adrenocortical carcinoma cells, H295R, were treated with RSV, piceatannol (PIC), 3,5,4'-triacetylresveratrol (RSVTA), 3,5-diacetylresveratrol (RSVDA), and 3,5,4'-trimethylresveratrol (RSVTM) for 24 hr at concentrations of 1, 5, 10, 25, and 50 µM. Steroid secretion, enzyme activities, and gene expression of key steps in steroidogenesis were investigated.
Secretion of dihydroepiandrosterone (DHEA), testosterone, and cortisol were drastically decreased by all test compounds at concentrations that did not affect cell viability. Progesterone and aldosterone secretion were increased. This steroid secretion pattern can be explained by the demonstrated inhibition of CYP17A1 enzyme activity. The most efficient CYP17A1 inhibitors were the synthetic analogs RSVTA, RSVDA, and RSVTM. Inhibition by RSVTM was more selective on the 17,20-lyase activity than hydroxylase activity of CYP17A1. Treatment of cells with all compounds, except RSVTM, caused increased estradiol levels, which could be explained by the demonstrated inhibition of estrogen sulfate conjugation, catalyzed by SULT1E1.
Our results on CYP17A1 inhibition of RSV and RSV analogs suggest a novel mechanism for chemoprevention of prostate cancer by resveratrol and the analogs. Especially RSVTM, which has a preferential inhibition on the 17,20-lyase activity of CYP17A1, may be a promising candidate for prostate cancer chemoprevention.
白藜芦醇（RSV）和白藜芦醇类似物由于对细胞生长、凋亡、血管生成和转移等方面的影响，具有在前列腺癌化学预防中的潜在用途。然而，抑制细胞色素 P45017A1（CYP17A1）——雄激素生物合成的关键酶和前列腺癌治疗的靶点——尚未被探索为其对前列腺癌影响的可能机制。
用 RSV、白皮杉醇（PIC）、3,5,4'-三乙酰白藜芦醇（RSVTA）、3,5-二乙酰白藜芦醇（RSVDA）和 3,5,4'-三甲氧基白藜芦醇（RSVTM）在浓度为 1、5、10、25 和 50µM 下处理人肾上腺皮质癌细胞 H295R24 小时。研究了类固醇分泌、类固醇生物合成关键步骤的酶活性和基因表达。
所有测试化合物在不影响细胞活力的浓度下，都大大降低了脱氢表雄酮（DHEA）、睾酮和皮质醇的分泌。孕激素和醛固酮的分泌增加。这种类固醇分泌模式可以用 CYP17A1 酶活性的抑制来解释。最有效的 CYP17A1 抑制剂是合成类似物 RSVTA、RSVDA 和 RSVTM。RSVTM 对 CYP17A1 的 17,20-裂解酶活性的抑制比羟化酶活性更具选择性。除 RSVTM 外，用所有化合物处理细胞都会导致雌二醇水平升高，这可以用雌激素硫酸酯化的抑制来解释，这种抑制由 SULT1E1 催化。
我们关于 RSV 和 RSV 类似物对 CYP17A1 抑制的研究结果表明，白藜芦醇和类似物对前列腺癌的化学预防具有新的机制。特别是 RSVTM，它对 CYP17A1 的 17,20-裂解酶活性具有优先抑制作用，可能是前列腺癌化学预防的有希望的候选药物。
