Synergistic potential of Ivermectin and doxorubicin in oral squamous cell carcinoma: an in vitro investigation

Doxorubicin (DOX) is widely used in cancer therapy, but its role in oral squamous cell carcinoma (OSCC) is limited by resistance and dose-related toxicities. Ivermectin (IVM), an antiparasitic agent with emerging anticancer properties, may enhance DOX efficacy. This study evaluated the effects of IVM alone and in combination with DOX on OSCC cell lines. In vitro assays, including MTT viability, apoptosis (Annexin V/PI), cell cycle analysis, RT-qPCR of apoptotic, proliferative, and inflammatory markers, and oxidative stress assays, were performed on HN9 and HEp-2 OSCC cell lines, with OEC as control. IVM reduced cancer cell viability in a dose-dependent manner and demonstrated a favorable selectivity profile compared to normal cells. Combination treatment with DOX and IVM significantly enhanced cytotoxicity (CI = 0.368, synergistic), induced S-phase cell cycle arrest, and increased apoptosis through upregulation of BAX, Caspase-3, and P53, alongside downregulation of BCL2. The combination also suppressed Ki-67 and IL-6 expression and markedly increased oxidative stress, indicating mitochondrial dysfunction. IVM exhibits anticancer activity in OSCC cells and synergistically augments the efficacy of DOX. These findings support the potential of DOX + IVM combination therapy as a novel strategy for OSCC, warranting further validation in in vivo and clinical studies.