Restoring apoptosis in breast cancer via peptide mediated disruption of survivin IAP interaction.

Apoptosis is a form of programmed cell death mediated by caspases and regulated through both intrinsic and extrinsic pathways. Many cancers evade apoptosis, resulting in uncontrolled cell survival and tumor progression. Inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP1, cIAP2, ML-IAP (also known as Livin), Survivin, NAIP, ILP-2, and BRUCE (also known as Apollon), play crucial roles in suppressing apoptosis and promoting cancer cell survival. Survivin, which is overexpressed in various malignancies, inhibits caspase activity, protects XIAP from proteasomal degradation, and suppresses the intrinsic apoptotic pathway by inhibiting caspase-9 activity. In this study, we investigated the protective role of Survivin on other IAPs, particularly NAIP and cIAP1, using bioinformatics approaches such as homology modeling, molecular docking, and molecular dynamics simulations. Experimental validation in MCF-7 breast cancer cells demonstrated that a novel anticancer peptide, P3, disrupts the interaction between Survivin and IAPs. At 25 µM, P3 significantly enhanced caspase-8 and -9 (initiator) and caspases-3 and -7 (executioner) activities, activating pathways. These effects were confirmed by flow cytometry and DAPI/PI staining, showing increased apoptosis without necrosis. Our findings indicate P3 as a promising peptide-based therapy to overcome apoptosis resistance in breast cancer by targeting Survivin-IAP complexes, providing a foundation for novel anticancer strategies.