The synergistic effect of chimeras consisting of N-terminal smac and modified KLA peptides in inducing apoptosis in breast cancer cell lines.

Abstract

Drug resistance is one of the most important obstacles in effective cancer therapy triggered through various mechanisms. One of these mechanisms is caused by the upregulation of Inhibitor of Apoptosis Proteins (IAPs). IAPs, inhibit apoptosis through direct and/or indirect caspase inhibition, which themselves are antagonized by an endogenous protein called Second Mitochondrial-derived Activator of Caspases, Smac/Diablo, mediated by the presence of a tetrapeptide IAP binding motif at its N-terminus. Accordingly, Smac-based peptides are under intense investigation as anti-cancer drugs and have reached Phase 2 clinical trials, although, Smac based peptides or mimetics alone have not been effective as anti-cancer agents. On the other hand, KLA peptide has shown major toxicity against cancer cells through the induction of apoptosis. Consequently, we designed an anti-cancer chimera by fusing an octa-peptide from the N-terminus of mature Smac protein to a modified proapoptotic KLA peptide (KLAKLCKKLAKLCK) to be called Smac-KLA. This chimera, therefore, possesses both proapoptotic and anti-IAP activities. In addition, we dimerized this chimera via intermolecular disulfide bonds in order to enhance their cellular permeability. Both the Smac-KLA monomeric and dimeric peptides exhibited cytotoxic activity against both MCF-7 and MDA-MB231 breast cancer cell lines at low micromolar concentrations. Importantly, the dimerization of the chimeras enhanced their potency 2-4- fold due to higher cellular uptake.

• Authors: Somayeh Tavakoli, Loghman Firoozpour, Jamshid Davoodi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 655 Pg. 138-144 (05 07 2023) ISSN: 1090-2104 [Electronic] United States
• PMID: 36934589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Caspase 3
• Caspases
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• KLA peptide
• Mitochondrial Proteins
• Peptides
• DIABLO protein, human

Topics

• Female
• Humans
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Breast Neoplasms (drug therapy)
• Caspase 3 (metabolism)
• Caspases (metabolism)
• Inhibitor of Apoptosis Proteins (metabolism)
• Intracellular Signaling Peptides and Proteins (pharmacology)
• MCF-7 Cells
• Mitochondrial Proteins (metabolism)
• Peptides (chemistry)