Narayanan Bhagavathi A, Reddy Bandaru S, Bosland Maarten C, Nargi Dominick, Horton Lori, Randolph Carla, Narayanan Narayanan K
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987, USA.
Clin Cancer Res. 2007 Oct 1;13(19):5965-73. doi: 10.1158/1078-0432.CCR-07-0744.
Nonsteroidal anti-inflammatory drugs mediate anticancer effects by modulating cyclooxygenase-2 (COX-2)-dependent and/or COX-2-independent mechanism(s); however, the toxicity issue is a concern with single agents at higher doses. In this study, we determined the combined effect of celecoxib, a COX-2 inhibitor, along with exisulind (sulindac sulfone/Aptosyn) at low doses in prostate cancer.
We used a sequential regimen of N-methyl-N-nitrosourea + testosterone to induce prostate cancer in Wistar-Unilever rats. Following carcinogen treatment, celecoxib and exisulind individually and their combination at low doses were given in NIH-07 diet for 52 weeks. We determined the incidence of prostatic intraepithelial neoplasia, adenocarcinomas, rate of tumor cell proliferation, and apoptosis. Immunohistochemical and Western blot analysis were done to determine COX-2, epidermal growth factor receptor (EGFR), Akt, androgen receptor, and cyclin D1 expression. Serum prostaglandin E2 and tumor necrosis factor-alpha levels were determined using enzyme immunoassay/ELISA assays.
The rats that received celecoxib in combination with exisulind at low doses showed a significant decrease in prostatic intraepithelial neoplasia and adenocarcinomas as well as an enhanced rate of apoptosis. An overall decrease in COX-2, EGFR, Akt, androgen receptor, and cyclin D1 expression was found associated with tumor growth inhibition. Reduced serum levels of COX-2 protein, prostaglandin E2, and tumor necrosis factor-alpha indicated anti-inflammatory effects. A strong inhibition of total and phosphorylated form of EGFR (Tyr(992) and Tyr(845)) and Akt (Ser(473)) was significant in rats given with these agents in combination.
In this study, we show for the first time that the combination of celecoxib with exisulind at low doses could prevent prostate carcinogenesis by altering key molecular events.
非甾体抗炎药通过调节环氧合酶-2（COX-2）依赖性和/或COX-2非依赖性机制发挥抗癌作用；然而，高剂量单药治疗时的毒性问题令人担忧。在本研究中，我们确定了COX-2抑制剂塞来昔布与低剂量依西美坦（舒林酸砜/Aptosyn）联合应用于前列腺癌的效果。
我们采用N-甲基-N-亚硝基脲+睾酮序贯方案诱导Wistar-联合利华大鼠发生前列腺癌。致癌剂处理后，在NIH-07饮食中单独给予塞来昔布和依西美坦及其低剂量组合，持续52周。我们测定了前列腺上皮内瘤变、腺癌的发生率、肿瘤细胞增殖率和凋亡率。进行免疫组织化学和蛋白质印迹分析以确定COX-2、表皮生长因子受体（EGFR）、Akt、雄激素受体和细胞周期蛋白D1的表达。使用酶免疫测定/酶联免疫吸附测定法测定血清前列腺素E2和肿瘤坏死因子-α水平。
低剂量联合使用塞来昔布和依西美坦的大鼠前列腺上皮内瘤变和腺癌显著减少，凋亡率增加。发现COX-2、EGFR、Akt、雄激素受体和细胞周期蛋白D1表达总体下降与肿瘤生长抑制有关。血清COX-2蛋白、前列腺素E2和肿瘤坏死因子-α水平降低表明具有抗炎作用。联合给予这些药物的大鼠中，EGFR（Tyr(992)和Tyr(845)）和Akt（Ser(473)）的总形式和磷酸化形式受到强烈抑制，这具有显著意义。
在本研究中，我们首次表明低剂量塞来昔布与依西美坦联合应用可通过改变关键分子事件预防前列腺癌发生。
