Desloratadine Induces TP53-Dependent Apoptosis in MCF-7 Breast Cancer Cells

Breast cancer remains a leading cause of mortality among women despite advances in early detection and targeted therapies, underscoring the need for safer and more effective treatment options. Drug repurposing offers a promising strategy by leveraging existing pharmacological agents with established safety profiles. Desloratadine, a second-generation H1-histamine receptor antagonist widely prescribed for allergic conditions, has attracted interest in oncology because histamine signaling influences proliferation, angiogenesis, and immune responses, yet its anticancer potential remains poorly understood. In this study, we investigated its effects in MCF-7 breast cancer cells, which harbor wild-type <i>TP53</i>. Desloratadine inhibited cell viability in a dose-dependent manner, with an IC₅₀ of 14.2 µg/mL. Mechanistic analyses revealed that growth inhibition was primarily mediated through apoptosis, confirmed by Hoechst 33342 staining, ROS generation, annexin V/PI staining, and caspase-dependent pathways. Gene expression profiling demonstrated upregulation of <i>TP53</i>, <i>FAS</i>, and <i>BAX</i>, alongside reduced <i>PARP-1</i> and <i>NF-κB</i> expression, with no detectable <i>STAT3</i> or <i>BCL2</i> expression. Flow cytometry indicated accumulation of cells in the sub-G₁ phase and G₂/M arrest, consistent with apoptosis induction. Molecular docking further supported these findings, showing that Desloratadine binds with high affinity to p53 (-7.0 kcal/mol), FAS (-6.8 kcal/mol), and NF-κB (-6.5 kcal/mol), forming stabilizing hydrogen bonds and hydrophobic interactions aligned with the observed gene expression changes. To confirm the functional role of <i>TP53</i>, we generated CRISPR-Cas9 knockout MCF-7 cells. Compared with wild-type cells, these knockout cells displayed markedly reduced sensitivity to Desloratadine, with the IC₅₀ shifting from 14.2 µg/mL to 36.4 µg/mL, demonstrating that p53 is a key mediator of the drug's cytotoxic effect. Collectively, these findings identify Desloratadine as a potential repurposed drug candidate for breast cancer therapy, acting at least in part through a p53-dependent apoptotic pathway.