Adhami Vaqar Mustafa, Aziz Moammir Hasan, Reagan-Shaw Shannon R, Nihal Minakshi, Mukhtar Hasan, Ahmad Nihal
Department of Dermatology, University of Wisconsin Medical Science Center, 1300 University Avenue, Madison, WI 53706, USA.
Mol Cancer Ther. 2004 Aug;3(8):933-40.
Prostate cancer is the second leading cause of cancer-related deaths in males in the United States. This warrants the development of novel mechanism-based strategies for the prevention and/or treatment of prostate cancer. Several studies have shown that plant-derived alkaloids possess remarkable anticancer effects. Sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis, has been shown to possess antimicrobial, anti-inflammatory, and antioxidant properties. Previously, we have shown that sanguinarine possesses strong antiproliferative and proapoptotic properties against human epidermoid carcinoma A431 cells and immortalized human HaCaT keratinocytes. Here, employing androgen-responsive human prostate carcinoma LNCaP cells and androgen-unresponsive human prostate carcinoma DU145 cells, we studied the antiproliferative properties of sanguinarine against prostate cancer. Sanguinarine (0.1-2 micromol/L) treatment of LNCaP and DU145 cells for 24 hours resulted in dose-dependent (1) inhibition of cell growth [as evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay], (2) arrest of cells in G0-G1 phase of the cell cycle (as assessed by DNA cell cycle analysis), and (3) induction of apoptosis (as evaluated by DNA ladder formation and flow cytometry). To define the mechanism of antiproliferative effects of sanguinarine against prostate cancer, we studied the effect of sanguinarine on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Immunoblot analysis showed that sanguinarine treatment of both LNCaP and DU145 cells resulted in significant (1) induction of cyclin kinase inhibitors p21/WAF1 and p27/KIP1; (2) down-regulation of cyclin E, D1, and D2; and (3) down-regulation of cyclin-dependent kinase 2, 4, and 6. A highlight of this study was the fact that sanguinarine induced growth inhibitory and antiproliferative effects in human prostate carcinoma cells irrespective of their androgen status. To our knowledge, this is the first study showing the involvement of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery during cell cycle arrest and apoptosis of prostate cancer cells by sanguinarine. These results suggest that sanguinarine may be developed as an agent for the management of prostate cancer.
前列腺癌是美国男性癌症相关死亡的第二大主要原因。这就需要开发基于新机制的前列腺癌预防和/或治疗策略。多项研究表明，植物源性生物碱具有显著的抗癌作用。血根碱是一种从血根草植物加拿大血根草中提取的生物碱，已被证明具有抗菌、抗炎和抗氧化特性。此前，我们已表明血根碱对人表皮样癌A431细胞和永生化人HaCaT角质形成细胞具有强大的抗增殖和促凋亡特性。在此，我们使用雄激素反应性人前列腺癌LNCaP细胞和雄激素非反应性人前列腺癌DU145细胞，研究了血根碱对前列腺癌的抗增殖特性。用0.1 - 2微摩尔/升血根碱处理LNCaP和DU145细胞24小时，导致剂量依赖性的：(1)细胞生长抑制[通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐试验评估]；(2)细胞周期停滞于G0 - G1期(通过DNA细胞周期分析评估)；(3)凋亡诱导(通过DNA梯状条带形成和流式细胞术评估)。为了确定血根碱对前列腺癌抗增殖作用的机制，我们研究了血根碱对已知调节细胞周期和凋亡机制的关键分子事件的影响。免疫印迹分析表明，用血液根碱处理LNCaP和DU145细胞均导致显著的：(1)细胞周期蛋白激酶抑制剂p21/WAF1和p27/KIP1的诱导；(2)细胞周期蛋白E、D1和D2的下调；(3)细胞周期蛋白依赖性激酶2、4和6的下调。这项研究的一个亮点是，无论雄激素状态如何，血根碱均可在人前列腺癌细胞中诱导生长抑制和抗增殖作用。据我们所知，这是第一项表明血根碱在前列腺癌细胞的细胞周期停滞和凋亡过程中涉及细胞周期蛋白激酶抑制剂 - 细胞周期蛋白 - 细胞周期蛋白依赖性激酶机制的研究。这些结果表明，血根碱可能被开发为一种治疗前列腺癌的药物。
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