Prostate, 2010, 70(11):1211–1221.

Phenoxodiol inhibits growth of metastatic prostate cancer cells

Marina Venero, Luis A. Espinoza, et al

Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia, USA; Marshall Edwards Inc.,140 Wicks Road, North Ryde 2113, New South Wales, Australia

BACKGROUND: Phenoxodiol, a synthetic analog of Genistein, is being assessed in several clinical studies against a range of cancer types and was shown to have a good efficacy and safety profile. In this study we tested the effects of Phenoxodiol against prostate cancer cell lines.

METHODS: Cell-cycle analysis, plasmatic membrane damage, clonogenic assay, comet assay, and Western blot methodologies were employed to assess the effects of Phenoxodiol on prostate cancer cell lines. An in vivo model confirmed the potential therapeutic efficacy of Phenoxodiol when administered orally to tumor bearing mice.

RESULTS: Phenoxodiol treatment promoted a marked inhibition of proliferation and loss of colony formation in LNCaP cells in a dose- and time-dependent manner. Similar effects were also observed in the metastatic prostate cell lines PC3 and DU145. Activation of poly(ADP ribose) polymerase 1 (PARP-1) clearly indicates the induction of DNA damage by Phenoxodiol. Oral administration of Phenoxodiol induced a considerable growth inhibition of malignant tumors generated by inoculation of LNCaP cells into Balb/c nu/nu athymic mice.

CONCLUSIONS: These data demonstrated that Phenoxodiol promotes apoptosis, as determined by PARP-1 degradation, via mitochondrial depolarization and G1/S cell-cycle arrest thereby confirming that it is active against androgen-dependent and independent prostate cancer cells. Although a precise target for Phenoxodiol has not been identified, these data contribute to our understanding of the mechanism by which this drug promotes cell death in prostate cancer cells, and warrants the continued clinical development of Phenoxodiol as a therapeutic for the treatment of metastatic prostate cancer.

美国《前列腺癌》，2010年8月

脱氢雌马酚抑制转移性前列腺癌细胞的生长

玛丽娜 威娜柔，路易斯 A 埃斯皮诺萨等

美国乔治敦大学医学中心生物化学和分子以及细胞生物学系; 澳大利亚马绍尔爱德华兹

背景︰ 脱氢雌马酚，是一种金雀异黄素的合成类似物，在针对一系列癌症类型的几项临床研究被评价，并且被证明有良好的疗效和安全性。在本研究中我们测试了脱氢雌马酚对前列腺癌细胞的作用。

方法︰ 细胞周期分析、 等离子膜损伤、 克隆形成试验，彗星和印迹方法被用来评估雌马酚对前列腺癌细胞的影响。当对荷瘤小鼠口服给药时一种体内模型确认了雌马酚潜在的疗效。

结果︰雌马酚疗法以剂量和时间依赖的方式在LNCaP 细胞中促进了显著的抑制增殖作用和菌群成形的损失。在转移性前列腺细胞 PC3 和 DU145 中也观察到了类似的作用。聚合酶 (PARP-1) 的激活清楚地表明雌马酚诱导的 DNA 损伤。给Balb/c裸鼠接种LNCaP 细胞后将雌马酚口服给药可以对恶性肿瘤的生长产生相当大的抑制作用。

结论︰ 这些数据证明 雌马酚通过线粒体去极化和 G1/S 细胞周期阻滞可以促进细胞凋亡，就像PARP-1决定的那样，从而证实了它可以积极对抗依赖雄激素和独立的前列腺癌细胞。虽然尚未确定雌马酚精确的靶标，这些数据有助于我们理解它的作用机制。这种药物在前列腺癌细胞中可以促进细胞死亡，并且对雌马酚治疗转移性前列腺癌的临床实验需要继续发展。