SBP-0636457, a Novel Smac Mimetic, Cooperates with Doxorubicin to Induce Necroptosis in Breast Cancer Cells during Apoptosis Blockage

Breast cancer (BC) is a common health concern worldwide. Doxorubicin (Dox) is a widely used chemotherapeutic agent to treat various cancers, including BC. However, drug resistance and severe side effects often hinder the clinical application of Dox. Combination therapy is an effective potent strategy to increase chemosensitivity and reduce the adverse effects. Smac is a proapoptotic protein that interacts with inhibitors of apoptosis proteins (IAPs) and thereby promotes cell death. Smac mimetic compounds can mimic its function and can be used to kill cancer cells. In this study, Dox and SBP-0636457, a novel Smac mimetic, were found to have cooperative effects in inducing BC cell death. Dox and SBP-0636457 cotreatment induced necroptosis instead of apoptosis in BC cells. Receptor-interacting serine/threonine-protein kinase 1 or mixed-lineage kinase domain-like silencing could attenuate cell death caused by Dox/SBP-0636457 in BC cells. In addition, this combined treatment caused synergistic induction of TNFα, and TNFα/TNFR signalling is essential for cell death induced by Dox/SBP-0636457 in BC cells. Moreover, both canonical and noncanonical nuclear factor kappa B pathways were found to contribute to TNFα upregulation induced by Dox/SBP-0636457. Therefore, the findings suggest that SBP-0636457 combined with Dox is an alternative strategy for treating BC.