Singh Rana P, Agarwal Rajesh
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262, USA.
Mol Carcinog. 2006 Jun;45(6):436-42. doi: 10.1002/mc.20223.
Prostate cancer (PCA) is the most invasive malignancy and second leading cause of cancer deaths in American males. One approach to reduce PCA incidence, growth and metastasis is prevention and intervention targeted towards mitogenic and survival signaling and cell-cycle regulation. This approach is based on the rationale that overexpression of receptor tyrosine kinases (RTKs) and/or non-receptor tyrosine kinases leads to persistent autocrine stimulation of malignant cells for deregulated cell-cycle progression and uncontrolled growth. PCA progression has also been associated with transition from a paracrine to an autocrine relationship between receptors and growth ligands as this malignancy progresses to an advanced androgen-independent aggressive stage. Together, these studies suggest that targeting RTK-mediated signaling pathways along with cell-cycle regulators could be a practical and translational approach for PCA prevention and intervention. Here, we provide evidence that a naturally occurring nontoxic flavanoid, silibinin, targets the epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R) and NF-kappaB (nuclear factor-kappa B) pathways in PCA. Furthermore, it modulates cell-cycle regulators, including cyclin-dependent kinases (CDKs), Cip/Kip and cyclins for its anticancer efficacy against PCA. Silibinin inhibits growth of PCA cells from human, mouse, and rat origins, and also suppresses human prostate tumor xenograft growth in nude mice. Silibinin also inhibits PCA growth in the transgenic adenocarcinoma of mouse prostate (TRAMP) mouse model. Now, silibinin has been entered into phase I/II clinical trials in human PCA patients where preliminary observations were suggestive of its further study in a larger base of the patient population.
前列腺癌（PCA）是美国男性中最具侵袭性的恶性肿瘤，也是癌症死亡的第二大主要原因。降低PCA发病率、生长和转移的一种方法是针对有丝分裂原和生存信号以及细胞周期调控进行预防和干预。这种方法基于这样的理论基础，即受体酪氨酸激酶（RTK）和/或非受体酪氨酸激酶的过表达会导致恶性细胞持续的自分泌刺激，从而导致细胞周期进展失调和生长失控。随着这种恶性肿瘤发展到晚期雄激素非依赖性侵袭性阶段，PCA的进展还与受体和生长配体之间从旁分泌关系向自分泌关系的转变有关。这些研究共同表明，靶向RTK介导的信号通路以及细胞周期调节因子可能是一种用于PCA预防和干预的实用且可转化的方法。在此，我们提供证据表明，一种天然存在的无毒类黄酮水飞蓟宾可靶向PCA中的表皮生长因子受体（EGFR）、胰岛素样生长因子-1受体（IGF-1R）和核因子κB（NF-κB）通路。此外，它还调节细胞周期调节因子，包括细胞周期蛋白依赖性激酶（CDK）、Cip/Kip和细胞周期蛋白，以发挥其对PCA的抗癌功效。水飞蓟宾可抑制源自人、小鼠和大鼠的PCA细胞的生长，还可抑制裸鼠体内人前列腺肿瘤异种移植的生长。水飞蓟宾也可抑制小鼠前列腺转基因腺癌（TRAMP）小鼠模型中的PCA生长。目前，水飞蓟宾已进入人类PCA患者的I/II期临床试验，初步观察结果表明其值得在更大规模的患者群体中进一步研究。
