Department of Biophysics, Panjab University, Chandigarh 160014, India.
Biomed Pharmacother. 2012 Mar;66(2):116-30. doi: 10.1016/j.biopha.2011.11.019. Epub 2012 Feb 17.
Non-steroidal anti-inflammatory drugs (NSAIDs) have become promising agents for the chemoprevention of colorectal cancer presumably by inducing apoptosis. However, the role of NSAIDs in the regulation of NHE-1, intracellular calcium Ca(2+) homeostasis and Calpain 9 signaling pathway seems unclear. Male Sprague-Dawley rats were used as model for experimental colorectal cancer. Effects of pro-carcinogen (DMH) and NSAIDs were studied via morphological examination of tumors, histopathological changes, Ca(2+) homeostasis, production of reactive oxygen species (ROS), changes in mitochondrial membrane potential (MMP or ΔΨ(M)) and expression profile of target genes and proteins both at transcription and translation levels respectively. Size and number of tumors were found less in NSAIDs co-administered groups as compared to the DMH alone. Higher expression of NHE-1 was observed in DMH group whereas Calpain 9 was up-regulated in NSAIDs co-administered groups. Ca(2+) levels and reactive oxygen species were observed elevated in NSAIDs co-administered groups. ΔΨ(M) was found higher in DMH alone group along with the increased expression of the anti-apoptotic and mitochondrial membrane guard protein, Bcl-2. Expression levels of various pro-apoptotic proteins were observed higher in case of NSAIDs co-administered groups. Down-regulation of NHE-1, along with an increased Ca(2+) and induction of intrinsic pathway of apoptosis via activated Calpain 9 could be a putative mechanism pursued by Sulindac and Celecoxib for the chemoprevention of colorectal cancer.
非甾体抗炎药（NSAIDs）通过诱导细胞凋亡，已成为结直肠癌化学预防有希望的药物。然而，NSAIDs 在调节 NHE-1、细胞内钙离子([Ca(2+)]i)稳态和 Calpain 9 信号通路中的作用似乎并不清楚。雄性 Sprague-Dawley 大鼠被用作实验性结直肠癌的模型。通过肿瘤形态学检查、组织病理学变化、[Ca(2+)]i 稳态、活性氧（ROS）产生、线粒体膜电位（MMP 或 ΔΨ（M））变化以及目标基因和蛋白质的转录和翻译水平的表达谱，研究了促癌原（DMH）和 NSAIDs 的作用。与单独 DMH 相比，联合 NSAIDs 组的肿瘤大小和数量较少。DMH 组中 NHE-1 的表达较高，而 NSAIDs 联合组中 Calpain 9 的表达上调。联合 NSAIDs 组中观察到 [Ca(2+)]i 水平和活性氧升高。单独 DMH 组的 ΔΨ（M）较高，同时抗凋亡和线粒体膜保护蛋白 Bcl-2 的表达增加。联合 NSAIDs 组中各种促凋亡蛋白的表达水平较高。NHE-1 的下调，以及通过激活的 Calpain 9 诱导的 [Ca(2+)]i 增加和内在凋亡途径的诱导，可能是非甾体抗炎药用于结直肠癌化学预防的一种潜在机制。
