Kaseb Ahmed O, Chinnakannu Kannagi, Chen Di, Sivanandam Arun, Tejwani Sheela, Menon Mani, Dou Q Ping, Reddy G Prem-Veer
Department of Hematology/Oncology, Henry Ford Hospital, MI 458202, USA.
Cancer Res. 2007 Aug 15;67(16):7782-8. doi: 10.1158/0008-5472.CAN-07-1483.
Relapse of prostate cancer after androgen ablation therapy is hormone-refractory, with continued tumor growth being dependent on the androgen receptor (AR). E2F-1, a regulator of cell proliferation and viability, reportedly plays a role in the development of hormone-refractory prostate cancer. Thymoquinone is a component of Nigella sativa, an herb used for thousands of years for culinary and medicinal purposes in Asian and Middle Eastern countries and has been reported to have an antineoplastic effect both in vitro and in vivo. We observed that thymoquinone inhibited DNA synthesis, proliferation, and viability of cancerous (LNCaP, C4-B, DU145, and PC-3) but not noncancerous (BPH-1) prostate epithelial cells by down-regulating AR and E2F-1. In LNCaP cells, this was associated with a dramatic increase in p21(Cip1), p27(Kip1), and Bax. Thymoquinone blunted progression of synchronized LNCaP cells from G1 to S phase, with a concomitant decrease in AR and E2F-1 as well as the E2F-1-regulated proteins necessary for cell cycle progression. In a xenograft prostate tumor model, thymoquinone inhibited growth of C4-2B-derived tumors in nude mice. This in vivo suppression of tumor growth, as with C4-2B cell growth in culture, was associated with a dramatic decrease in AR, E2F-1, and cyclin A as determined by Western blot of tissue extracts. Tissue immunohistochemical staining confirmed a marked reduction in E2F-1 and showed induction of apoptosis on terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay. These findings show that thymoquinone suppresses the expression of AR and E2F-1 necessary for proliferation and viability of androgen-sensitive as well as androgen-independent prostate cancer cells both in vitro and in vivo and, moreover, produced no noticeable side effects in mice. We conclude that thymoquinone, a naturally occurring herbal product, may prove to be effective in treating hormone-sensitive as well as hormone-refractory prostate cancer. Furthermore, because of its selective effect on cancer cells, we believe that thymoquinone can also be used safely to help prevent the development of prostate cancer.
雄激素剥夺治疗后前列腺癌的复发具有激素抵抗性，肿瘤的持续生长依赖于雄激素受体（AR）。据报道，细胞增殖和活力的调节因子E2F-1在激素抵抗性前列腺癌的发展中起作用。百里醌是黑种草的一种成分，这种草药在亚洲和中东国家已有数千年用于烹饪和药用的历史，据报道其在体外和体内均具有抗肿瘤作用。我们观察到，百里醌通过下调AR和E2F-1来抑制癌性（LNCaP、C4-B、DU145和PC-3）而非非癌性（BPH-1）前列腺上皮细胞的DNA合成、增殖和活力。在LNCaP细胞中，这与p21（Cip1）、p27（Kip1）和Bax的显著增加有关。百里醌使同步化的LNCaP细胞从G1期到S期的进程受阻，同时AR和E2F-1以及细胞周期进程所需的E2F-1调节蛋白减少。在异种移植前列腺肿瘤模型中，百里醌抑制了裸鼠体内C4-2B衍生肿瘤的生长。与培养中的C4-2B细胞生长一样，这种体内肿瘤生长抑制与组织提取物的蛋白质免疫印迹法测定的AR、E2F-1和细胞周期蛋白A的显著减少有关。组织免疫组化染色证实E2F-1明显减少，并在末端脱氧核苷酸转移酶介导的dUTP缺口末端标记试验中显示出凋亡诱导。这些发现表明，百里醌在体外和体内均抑制雄激素敏感以及雄激素非依赖性前列腺癌细胞增殖和活力所需的AR和E2F-1的表达，而且在小鼠中未产生明显的副作用。我们得出结论，天然草药产品百里醌可能被证明对治疗激素敏感性以及激素抵抗性前列腺癌有效。此外，由于其对癌细胞的选择性作用，我们认为百里醌也可安全用于帮助预防前列腺癌的发生。
