Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia, USA.
Prostate. 2010 Aug;70(11):1211-21. doi: 10.1002/pros.21156.
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.
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.
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.
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.
苯并恶唑二醇是染料木黄酮的一种合成类似物，目前正在针对多种癌症类型进行多项临床研究，其疗效和安全性良好。在这项研究中，我们检测了苯并恶唑二醇对前列腺癌细胞系的作用。
采用细胞周期分析、质膜损伤、集落形成试验、彗星试验和 Western blot 方法评估苯并恶唑二醇对前列腺癌细胞系的作用。体内模型证实了苯并恶唑二醇经口服给药对荷瘤小鼠的潜在治疗效果。
苯并恶唑二醇处理以剂量和时间依赖的方式显著抑制 LNCaP 细胞的增殖和集落形成。在转移性前列腺癌细胞系 PC3 和 DU145 中也观察到类似的作用。多聚（ADP 核糖）聚合酶 1（PARP-1）的激活清楚地表明苯并恶唑二醇诱导了 DNA 损伤。苯并恶唑二醇的口服给药显著抑制了 LNCaP 细胞接种到 Balb/c nu/nu 裸鼠中产生的恶性肿瘤的生长。
这些数据表明，苯并恶唑二醇通过线粒体去极化和 G1/S 细胞周期阻滞诱导 PARP-1 降解，从而促进细胞凋亡，证实其对雄激素依赖性和非依赖性前列腺癌细胞均具有活性。虽然尚未确定苯并恶唑二醇的确切靶标，但这些数据有助于我们理解该药物促进前列腺癌细胞死亡的机制，并证明苯并恶唑二醇作为治疗转移性前列腺癌的治疗药物具有持续的临床开发价值。
