Singh Rana P, Agarwal Rajesh
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Cancer Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Curr Cancer Drug Targets. 2004 Feb;4(1):1-11. doi: 10.2174/1568009043481605.
Several epigenetic alterations leading to constitutively active mitogenic and cell-survival signaling, and loss of apoptotic response are causally involved in self-sufficiency of prostate cancer (PCA) cells toward uncontrolled growth, and increased secretion of pro-angiogenic factors. Therefore, one targeted approach for PCA prevention, growth control and/or treatment could be inhibition of epigenetic molecular events involved in PCA growth, progression and angiogenesis. In this regard, silibinin/silymarin (silibinin is the major active compound in silymarin) has shown promising efficacy. Our extensive studies with silibinin/silymarin and PCA cells have shown the pleiotropic anticancer effects leading to cell growth inhibition in culture and nude mice. The underlying mechanisms of silibinin/silymarin efficacy against PCA involve alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I and nuclear factor kappa B signaling. Silibinin also synergizes the therapeutic effects of doxorubicin in PCA cells, making it a strong candidate for combination chemotherapy. Silibinin/ silymarin also inhibits the secretion of proangiogenic factors from tumor cells, and causes growth inhibition and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation on Matrigel. More importantly, silibinin inhibits the growth of in vivo advanced human prostate tumor xenograft in nude mice. Recently, due to its non-toxic and mechanism-based strong preventive/therapeutic efficacy, silibinin has entered in phase I clinical trial in prostate cancer patients.
几种表观遗传改变导致有丝分裂原和细胞存活信号持续激活，以及凋亡反应丧失，这些改变与前列腺癌细胞（PCA）自主进行不受控制的生长以及促血管生成因子分泌增加有因果关系。因此，一种针对PCA预防、生长控制和/或治疗的靶向方法可能是抑制参与PCA生长、进展和血管生成的表观遗传分子事件。在这方面，水飞蓟宾/水飞蓟素（水飞蓟宾是水飞蓟素中的主要活性化合物）已显示出有前景的疗效。我们对水飞蓟宾/水飞蓟素和PCA细胞进行的广泛研究表明了其多效抗癌作用，可导致培养的细胞和裸鼠中的细胞生长受到抑制。水飞蓟宾/水飞蓟素对PCA有效作用的潜在机制包括细胞周期进程的改变，以及对有丝分裂原和细胞存活信号的抑制，如表皮生长因子受体、I型胰岛素样生长因子受体和核因子κB信号。水飞蓟宾还能增强阿霉素对PCA细胞的治疗效果，使其成为联合化疗的有力候选药物。水飞蓟宾/水飞蓟素还抑制肿瘤细胞促血管生成因子的分泌，并导致内皮细胞生长抑制和凋亡死亡，同时伴有基质胶上毛细血管管形成的破坏。更重要的是，水飞蓟宾抑制裸鼠体内晚期人前列腺肿瘤异种移植物的生长。最近，由于其无毒且基于机制的强大预防/治疗效果，水飞蓟宾已进入前列腺癌患者的I期临床试验。
