Molecular mechanism of interaction of mitocurcumin-1 with Akt1 and STAT3: an in silico approach.

The bioavailability of curcumin is the limiting factor for its effective use in anti-cancer therapy. Recently, we reported a novel approach to enhance the cellular uptake by conjugating curcumin with triphenyl phosphonium, named mitocurcumin-1. We found that such conjugation significantly increased the uptake of curcumin in various cancer cells and caused cancer cell death by inducing apoptosis by decreasing the phosphorylation of Akt1 (Thr308) and STAT3 (Tyr705). In this study, a molecular mechanistic model deciphering the regulation of phosphorylation of Akt1 and STAT3 by mitocurcumin-1 was investigated and compared with curcumin. The protein structures were obtained from protein data bank data base and protein-ligand interaction studies were performed with mitocurcumin-1 and curcumin. Docking interaction studies of mitocurcumin-1 with Akt1 and STAT3 active sites showed a strong binding affinity of -60.4107 Kcal/mol and -51.1734 Kcal/mol respectively, suggesting mitocurcumin-1 interacted with the residues at the active sites of phosphorylation of these molecules. Further, a Chi rotationary root mean square deviation of 1.468 angstroms and 3.965 angstroms at the active sites in Akt1 and STAT3, respectively indicated that changes in the conformation of protein structure at the active site resulted in the inhibition of phosphorylation of these molecules. To conclude, by using molecular modeling approaches for the first time, we demonstrated the inhibition of Akt1 and STAT3 phosphorylation by mitocurcumin-1.

Structure, function, and epigenetic regulation of BNIP3: a pathophysiological relevance.

BCL-2 [B-cell leukemia/lymphoma 2]/adenovirus E1B 19KD interacting protein 3 (BNIP3) is an atypical BH3 domain only containing member of Bcl2 family of proteins. BNIP3 is known to be involved in various cellular processes depending on the cell type and conditions and also shown to play a role in various disease conditions including myocardial ischemia, autophagy and apoptosis. Though its role in autophagy and its pro-death activity have been reported in various studies, recent findings have shown its contradictory role in the regulation of these cellular processes. The various studies have shown its epigenetic regulation in disease development and progression and also found to be cytoprotective. In this review, we have focused on the structural and functional aspects of BNIP3 in relation to recent advances of its role in autophagy and apoptosis. Also its role of epigenetic regulation of several genes involved in various diseases was also discussed.

Mitochondrial-targeted curcuminoids: a strategy to enhance bioavailability and anticancer efficacy of curcumin.

Although the anti-cancer effects of curcumin has been shown in various cancer cell types, in vitro, pre-clinical and clinical studies showed only a limited efficacy, even at high doses. This is presumably due to low bioavailability in both plasma and tissues, particularly due to poor intracellular accumulation. A variety of methods have been developed to achieve the selective targeting of drugs to cells and mitochondrion. We used a novel approach by conjugation of curcumin to lipophilic triphenylphosphonium (TPP) cation to facilitate delivery of curcumin to mitochondria. TPP is selectively taken up by mitochondria driven by the membrane potential by several hundred folds. In this study, three mitocurcuminoids (mitocurcuminoids-1, 2, and 3) were successfully synthesized by tagging TPP to curcumin at different positions. ESI-MS analysis showed significantly higher uptake of the mitocurcuminoids in mitochondria as compared to curcumin in MCF-7 breast cancer cells. All three mitocurcuminoids exhibited significant cytotoxicity to MCF-7, MDA-MB-231, SKNSH, DU-145, and HeLa cancer cells with minimal effect on normal mammary epithelial cells (MCF-10A). The IC50 was much lower for mitocurcuminoids when compared to curcumin. The mitocurcuminoids induced significant ROS generation, a drop in ΔØm, cell-cycle arrest and apoptosis. They inhibited Akt and STAT3 phosphorylation and increased ERK phosphorylation. Mitocurcuminoids also showed upregulation of pro-apoptotic BNIP3 expression. In conclusion, the results of this study indicated that mitocurcuminoids show substantial promise for further development as a potential agent for the treatment of various cancers.