Saleem Mohammad, Kweon Mee-Hyang, Yun Jung-Mi, Adhami Vaqar Mustafa, Khan Naghma, Syed Deeba N, Mukhtar Hasan
Department of Dermatology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Cancer Res. 2005 Dec 1;65(23):11203-13. doi: 10.1158/0008-5472.CAN-05-1965.
In prostate cancer, a fine balance between cell proliferation and apoptotic death is lost, resulting in increased cellular mass and tumor progression. One approach to redress this imbalance and control this malignancy is its preventive intervention through the use of dietary natural agents. Here, we investigated the growth-inhibitory effect and associated mechanisms of Lupeol, a triterpene present in fruits and vegetables, in androgen-sensitive human prostate cancer cells. Lupeol treatment resulted in significant inhibition of cell viability in a dose-dependent manner and caused apoptotic death of prostate cancer cells. Lupeol was found to induce the cleavage of poly(ADP-ribose) polymerase protein and degradation of acinus protein with a significant increase in the expression of FADD protein. Among all death receptor targets examined, Lupeol specifically caused a significant increase in the expression of Fas receptor. The small interfering RNA-mediated silencing of the Fas gene and inhibition of caspase-6, caspase-8, and caspase-9 by their specific inhibitors confirmed that Lupeol specifically activates the Fas receptor-mediated apoptotic pathway in androgen-sensitive prostate cancer cells. The treatment of cells with a combination of anti-Fas monoclonal antibody and Lupeol resulted in higher cell death compared with the additive effect of the two compounds alone, suggesting a synergistic effect. Lupeol treatment resulted in a significant inhibition in growth of tumors with concomitant reduction in prostate-specific antigen secretion in athymic nude mice implanted with CWR22Rnu1 cells. Because early clinical prostate cancer growth is an androgen-dependent response, the results of the present study suggest that Lupeol may have a potential to be an effective agent against prostate cancer.
在前列腺癌中，细胞增殖与凋亡死亡之间的精细平衡被打破，导致细胞数量增加和肿瘤进展。纠正这种失衡并控制这种恶性肿瘤的一种方法是通过使用膳食天然物质进行预防性干预。在此，我们研究了水果和蔬菜中存在的三萜类化合物羽扇豆醇对雄激素敏感的人前列腺癌细胞的生长抑制作用及其相关机制。羽扇豆醇处理以剂量依赖的方式显著抑制细胞活力，并导致前列腺癌细胞凋亡死亡。发现羽扇豆醇可诱导聚（ADP-核糖）聚合酶蛋白的裂解和腺泡蛋白的降解，同时FADD蛋白的表达显著增加。在所有检测的死亡受体靶点中，羽扇豆醇特异性地导致Fas受体的表达显著增加。Fas基因的小干扰RNA介导的沉默以及其特异性抑制剂对caspase-6、caspase-8和caspase-9的抑制作用证实，羽扇豆醇在雄激素敏感的前列腺癌细胞中特异性激活Fas受体介导的凋亡途径。与单独使用两种化合物的相加作用相比，用抗Fas单克隆抗体和羽扇豆醇联合处理细胞导致更高的细胞死亡，表明存在协同作用。羽扇豆醇处理显著抑制了接种CWR22Rnu1细胞的无胸腺裸鼠肿瘤的生长，同时前列腺特异性抗原分泌减少。由于早期临床前列腺癌的生长是雄激素依赖性反应，本研究结果表明羽扇豆醇可能有潜力成为一种有效的抗前列腺癌药物。
