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

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.

Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis

“…It has direct effects on the apoptosis pathway, for example, targeting the pro-apoptotic Bcl-2-related protein or regulating the transcriptional response to apoptotic stimuli via affecting on FoxO3a, NF-κB, and the activity of the p53 family 42–44 . Akt is a potent therapeutic target that may mediate resistance to the apoptotic effects of chemotherapy drugs therapy for a variety of cancers, including colon cancer 45,46 .…”

AF1q Mediates Tumor Progression in Colorectal Cancer by Regulating AKT Signaling

“…AKT is a principal downstream target of the PI3K signaling pathway, and is a pivotal regulator of cell proliferation, apoptosis, invasion, cell cycle control, and EMT [32]; furthermore, AKT activation is associated with poor prognosis in CRC [33,34]. AKT is normally inactive, but can be activated by phosphorylation at Thr308 or Ser473 [35].…”

Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy

“…PIP 3 is able to anchor the Akt protein (also known as protein kinase B, PKB) to the cell membrane, resulting in the activation of Akt via phosphorylation at Thr-308 by phosphoinositide-dependent kinase-1 (PDK1), and at Ser-476 by a PDK1-indepentent mechanism [8]. Akt has been involved in cancer development, in part because it decreases the expression of pro-apoptotic proteins, such as Fas ligand (FasL) and Bim, and activates others that inhibit apoptosis, such as Mouse double minute 2 homolog (Mdm2), B-cell lymphoma 2 (Bcl-2), or X-linked inhibitor of apoptosis proteins (XIAPs) [9,10] …”