FEXOFENADINE in cancer models exhibits significant concentration-dependent cytotoxic effects by disrupting mitochondrial homeostasis and pro-survival pathways.
Fexofenadine Induces ROS-Mediated Apoptosis and Mitochondrial Dysfunction
Repurposing established therapeutics with known safety profiles offers an accelerated strategy for identifying novel oncologic interventions. Fexofenadine, a widely used second-generation H1 antihistamine, was evaluated for its biological activity in human cervical carcinoma (HeLa) and lung adenocarcinoma (A549) cell lines, as well as non-tumorigenic bronchial epithelial cells (BEAS-2B).
Exposing malignant cells to fexofenadine resulted in a concentration-dependent reduction in cell viability, yielding IC50 values of approximately 211 µM for HeLa cells and 293 µM for A549 cells, compared to 391 µM in non-tumorigenic BEAS-2B cells. Flow cytometric analysis confirmed robust induction of apoptosis, supported by elevated caspase-3/7 activity, Annexin V positivity, and functional inactivation of anti-apoptotic Bcl-2 via phosphorylation.
Ultrastructural examination via transmission electron microscopy revealed pronounced mitochondrial swelling, loss of cristae, and dilation of rough endoplasmic reticulum cisternae. These morphological alterations coincided with intracellular reactive oxygen species (ROS) accumulation and mitochondrial membrane depolarization. Pretreatment with the antioxidant N-acetyl-L-cysteine significantly attenuated ROS production and partially suppressed apoptotic cell death, establishing redox imbalance as a critical driver of fexofenadine-mediated cytotoxicity.
Fexofenadine Attenuates Pro-Survival Pathways in Preclinical Cancer Models
Beyond mitochondrial disruption, fexofenadine suppressed key intracellular signaling cascades regulating cell survival and proliferation. Flow cytometric profiling demonstrated a significant reduction in the activation of the PI3K/AKT and MAPK/ERK pathways. This signaling attenuation coincided with double-strand DNA damage, as evidenced by increased phosphorylation of ATM and histone H2A.X.
Furthermore, fexofenadine induced G0/G1 cell cycle arrest, markedly lowered the mitotic index, and inhibited long-term clonogenic growth in both cancer cell lines. In scratch assays, fexofenadine delayed wound closure, demonstrating reduced cell migration.
The cellular stress response also involved autophagy modulation, characterized by a biphasic response in LC3-II levels. Lower concentrations promoted autophagosome formation, whereas higher concentrations shifted cells toward apoptotic execution. Co-treatment with chloroquine, an autophagy inhibitor, markedly enhanced apoptosis, indicating that autophagic responses play a cytoprotective role during initial fexofenadine exposure. Crucially, non-tumorigenic BEAS-2B cells displayed markedly lower sensitivity, supporting a degree of selective toxicity toward malignant phenotypes.
Reference
Trybus E et al. Fexofenadine Induces ROS-Dependent Mitochondrial Dysfunction and Suppresses PI3K/AKT and MAPK Signaling in Cervical and Lung Cancer Cells. Cancers. 2026;18(13):2156.
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