caa a22 4500 606233946 CHVBK 20210128101234.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s11010-015-2330-5 doi (NATIONALLICENCE)springer-10.1007/s11010-015-2330-5 Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer [Elektronische Daten] [Chandan Rana, Honit Piplani, Vivek Vaish, Bimla Nehru, S. Sanyal] 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. Springer Science+Business Media New York, 2015 Apoptosis nationallicence Bcl-2 nationallicence Colon cancer nationallicence Curcumin nationallicence Diclofenac nationallicence PI3-K nationallicence Rana Chandan Department of Biophysics, Panjab University, 160014, Chandigarh, India aut Piplani Honit Department of Biophysics, Panjab University, 160014, Chandigarh, India aut Vaish Vivek Department of Biophysics, Panjab University, 160014, Chandigarh, India aut Nehru Bimla Department of Biophysics, Panjab University, 160014, Chandigarh, India aut Sanyal S. Department of Biophysics, Panjab University, 160014, Chandigarh, India aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 402/1-2(2015-04-01), 225-241 0300-8177 402:1-2<225 2015 402 11010 https://doi.org/10.1007/s11010-015-2330-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2330-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Rana Chandan Department of Biophysics, Panjab University, 160014, Chandigarh, India aut NATIONALLICENCE 700 1- Piplani Honit Department of Biophysics, Panjab University, 160014, Chandigarh, India aut NATIONALLICENCE 700 1- Vaish Vivek Department of Biophysics, Panjab University, 160014, Chandigarh, India aut NATIONALLICENCE 700 1- Nehru Bimla Department of Biophysics, Panjab University, 160014, Chandigarh, India aut NATIONALLICENCE 700 1- Sanyal S. Department of Biophysics, Panjab University, 160014, Chandigarh, India aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 402/1-2(2015-04-01), 225-241 0300-8177 402:1-2<225 2015 402 11010