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首页> 外文期刊>Journal of Molecular Biochemistry >High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer
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High-throughput cell-based compound screen identifies pinosylvin methyl ether and tanshinone IIA as inhibitors of castration-resistant prostate cancer

机译：基于细胞的高通量化合物筛选确定了松果酚乙烯基甲醚和丹参酮IIA是去势抵抗性前列腺癌的抑制剂

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Current treatment options for castration-resistant prostate cancer (CRPC) are limited. In this study, a high-throughput screen of 4910 drugs and drug-like molecules was performed to identify antiproliferative compounds in androgen ablated prostate cancer cells. The effect of compounds on cell viability was compared in androgen ablated LNCaP prostate cancer cells and in LNCaP cells grown in presence of androgens as well as in two non-malignant prostate epithelial cells (RWPE-1 and EP156T). Validation experiments of cancer specific anti-proliferative compounds indicated pinosylvin methyl ether (PSME) and tanshinone IIA as potent inhibitors of androgen ablated LNCaP cell proliferation. PSME is a stilbene compound with no previously described antineoplastic activity whereas tanshinone IIA is currently used in cardiovascular disorders and proposed as a cancer drug. To gain insights into growth inhibitory mechanisms in CRPC, genome-wide gene expression analysis was performed in PSME- and tanshinone IIA-exposed cells. Both compounds altered the expression of genes involved in cell cycle and steroid and cholesterol biosynthesis in androgen ablated LNCaP cells. Decrease in androgen signalling was confirmed by reduced expression of androgen receptor and prostate specific antigen in PSME- or tanshinone IIA-exposed cells. Taken together, this systematic screen identified a novel anti-proliferative agent, PSME, for CRPC. Moreover, our screen confirmed tanshinone IIA as well as several other compounds as potential prostate cancer growth inhibitors also in androgen ablated prostate cancer cells. These results provide valuable starting points for preclinical and clinical studies for CRPC treatment.
机译：用于去势抵抗性前列腺癌（CRPC）的当前治疗选择是有限的。在这项研究中，对4910种药物和类药物分子进行了高通量筛选，以鉴定雄激素消融的前列腺癌细胞中的抗增殖化合物。比较了雄激素消融的LNCaP前列腺癌细胞和在雄激素存在下生长的LNCaP细胞以及两种非恶性前列腺上皮细胞（RWPE-1和EP156T）中化合物对细胞活力的影响。癌症特异性抗增殖化合物的验证实验表明，松油基乙烯基甲醚（PSME）和丹参酮IIA是雄激素消除LNCaP细胞增殖的有效抑制剂。 PSME是没有先前描述的抗肿瘤活性的二苯乙烯化合物，而丹参酮IIA目前用于心血管疾病，并被提议用作抗癌药物。为了深入了解CRPC中的生长抑制机制，在暴露于PSME和丹参酮IIA的细胞中进行了全基因组基因表达分析。两种化合物均改变了雄激素消融的LNCaP细胞中涉及细胞周期以及类固醇和胆固醇生物合成的基因的表达。在PSME或丹参酮IIA暴露的细胞中，雄激素受体和前列腺特异性抗原的表达降低，从而证实了雄激素信号的减少。综上所述，该系统筛选确定了一种用于CRPC的新型抗增殖剂PSME。此外，我们的筛查结果还证实了丹参酮IIA以及几种其他化合物也可能在雄激素消融的前列腺癌细胞中作为潜在的前列腺癌生长抑制剂。这些结果为CRPC治疗的临床前和临床研究提供了有价值的起点。

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