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Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer

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Abstract

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.

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Acknowledgments

Financial assistance from the Department of Atomic Energy (DAE) and Board of Research in Nuclear Physics (BRNS), Govt. of India (2009/37/45/BRNS) is gratefully acknowledged. We also acknowledge the contributions of Dr. Ravi Kumar Muttineni, Application Specialist, Schrodinger, India for helping us in performing the docking studies.

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Authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Biophysics, Panjab University, Chandigarh, 160014, India

    Chandan Rana, Honit Piplani, Vivek Vaish, Bimla Nehru & S. N. Sanyal

  2. Department of Pharmacology, University of Illinois, Chicago, USA

    Honit Piplani

  3. Centre for Colon Cancer Research, Department of Biological Sciences, University of South Carolina, Columbia, USA

    Vivek Vaish

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  1. Chandan Rana
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  2. Honit Piplani
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  5. S. N. Sanyal
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Correspondence to S. N. Sanyal.

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Rana, C., Piplani, H., Vaish, V. et al. Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer. Mol Cell Biochem 402, 225–241 (2015). https://doi.org/10.1007/s11010-015-2330-5

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