Rana Chandan, Piplani Honit, Vaish Vivek, Nehru Bimla, Sanyal S N
Department of Biophysics, Panjab University, Chandigarh, 160014, India.
Mol Cell Biochem. 2015 Apr;402(1-2):225-41. doi: 10.1007/s11010-015-2330-5. Epub 2015 Feb 3.
Phosphatidylinositol 3-kinase (PI3-K)/PTEN/Akt signaling is over activated in various tumors including colon cancer. Activation of this pathway regulates multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth that underlie the biology of a cancer cell. In the present study, the chemopreventive effects have been observed of Diclofenac, a preferential COX-2 inhibitory non-steroidal anti-inflammatory drugs, and Curcumin, a natural anti-inflammatory agent, in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats. The tumor-promoting role of PI3-K/Akt/PTEN signal transduction pathway and its association with anti-apoptotic family of proteins are also observed. Both Diclofenac and Curcumin downregulated the PI3-K and Akt expression while promoting the apoptotic mechanism. Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members (Bad and Bax) while decreasing the anti-apoptotic Bcl-2 protein. An up-regulation of cysteine protease family apoptosis executioner, such as caspase-3 and -9, is seen. Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding, as also evident by negative glide score of Bcl-2. These drugs stimulated apoptosis by increasing reactive oxygen species (ROS) generation and simultaneously decreasing the mitochondrial membrane potential (ΔΨ M). Diclofenac and Curcumin showed anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway, inducing apoptosis, increasing ROS generation, and decreasing ΔΨ M. The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together, rather than individually.
磷脂酰肌醇3激酶（PI3-K）/PTEN/Akt信号通路在包括结肠癌在内的多种肿瘤中过度激活。该信号通路的激活调节多种生物学过程，如凋亡、代谢、细胞增殖和细胞生长，这些都是癌细胞生物学特性的基础。在本研究中，观察到双氯芬酸（一种选择性COX-2抑制性非甾体抗炎药）和姜黄素（一种天然抗炎剂）在大鼠中由二盐酸1,2-二甲基肼诱导的结直肠癌发生早期的化学预防作用。还观察到PI3-K/Akt/PTEN信号转导通路的促肿瘤作用及其与抗凋亡蛋白家族的关联。双氯芬酸和姜黄素均下调PI3-K和Akt表达，同时促进凋亡机制。给予双氯芬酸和姜黄素显著增加促凋亡Bcl-2家族成员（Bad和Bax）的表达，同时降低抗凋亡Bcl-2蛋白。可见半胱氨酸蛋白酶家族凋亡执行者如caspase-3和-9的上调。双氯芬酸和姜黄素通过多个氢键在活性位点直接相互作用抑制Bcl-2蛋白，Bcl-2的负滑行评分也证明了这一点。这些药物通过增加活性氧（ROS）生成并同时降低线粒体膜电位（ΔΨM）来刺激凋亡。双氯芬酸和姜黄素通过下调PI3-K/Akt/PTEN通路、诱导凋亡、增加ROS生成和降低ΔΨM显示出抗肿瘤作用。当双氯芬酸和姜黄素联合给药而非单独给药时，发现抗肿瘤和凋亡作用增强。
