Department of Biophysics, Panjab University, Chandigarh, India.
Eur J Cancer Prev. 2013 May;22(3):215-28. doi: 10.1097/CEJ.0b013e3283584932.
The molecular mechanisms by which colon cancer cells regulate the expression of various proinflammatory and anti-inflammatory cytokines and transcription factors resulting in tumor progression have not been well clarified. The present study thus explores the effect of cancer cell-derived cytokines and transcription factors on the chemoprevention of a rat model of early colon carcinogenesis. Elevated expression of proinflammatory cytokines [interleukin-1β (IL-1β), IL-2, interferon γ, and tumor necrosis factor-α] and the transcription factors [Janus kinase 3 (Jak3) and signal transducer and activator of transcription 3 (Stat3)] was found in the 1,2-dimethylhydrazine dihydrochloride (DMH) group; however, this elevated expression was reversed by the individual and combination treatment with piroxicam, a traditional nonsteroidal anti-inflammatory drug [inhibiting both cyclooxygenase-1 (COX-1) and COX-2] and c-phycocyanin, a cyanobacterium-derived biliprotein from Spirulina platensis (selective COX-2 inhibitor). In the DMH group, low expression of IL-4, an anti-inflammatory cytokine, was further observed with respect to the other groups. Expression of inducible nitric oxide synthase and nitric oxide/citrulline levels was also analyzed and was found to be elevated with DMH treatment. Increased apoptotic index and stimulated levels of Bcl-2-associated death promoter (Bad), a proapoptotic protein, were observed in piroxicam-treated and c-phycocyanin-treated rats. In-silico molecular docking of piroxicam as a ligand with several regulatory proteins was performed, indicating that, except inducible nitric oxide synthase, it effectively binds with COX-1, COX-2, Jak3, and Stat3. Piroxicam and c-phycocyanin perhaps showed chemopreventive properties by inhibiting proinflammatory cytokines and Jak3/Stat3 signaling while promoting apoptosis. In addition, a combination regimen was found to be more beneficial than monotherapy.
结肠癌细胞调控各种促炎和抗炎细胞因子和转录因子表达的分子机制尚未得到充分阐明。因此，本研究探讨了癌细胞来源的细胞因子和转录因子对大鼠早期结肠癌发生化学预防的影响。在 1,2-二甲基肼二盐酸盐（DMH）组中发现促炎细胞因子[白细胞介素-1β（IL-1β）、IL-2、干扰素γ和肿瘤坏死因子-α]和转录因子[Janus 激酶 3（Jak3）和信号转导和转录激活因子 3（Stat3）]表达升高；然而，这种升高的表达被吡罗昔康（一种传统的非甾体抗炎药[抑制环氧化酶-1（COX-1）和 COX-2]和螺旋藻衍生的蓝藻蛋白 c-藻蓝蛋白单独和联合治疗所逆转）。在 DMH 组中，与其他组相比，抗炎细胞因子 IL-4 的表达进一步降低。还分析了诱导型一氧化氮合酶和一氧化氮/瓜氨酸水平的表达，发现 DMH 处理后其表达升高。在吡罗昔康和 c-藻蓝蛋白处理的大鼠中观察到凋亡指数增加和促凋亡蛋白 Bcl-2 相关死亡促进剂（Bad）水平升高。进行了吡罗昔康作为配体与几种调节蛋白的计算机分子对接，表明除诱导型一氧化氮合酶外，它还能有效结合 COX-1、COX-2、Jak3 和 Stat3。吡罗昔康和 c-藻蓝蛋白可能通过抑制促炎细胞因子和 Jak3/Stat3 信号通路同时促进细胞凋亡而表现出化学预防特性。此外，联合治疗方案比单一疗法更有益。
