Selective sensitivity of betel nut-related oral squamous cell carcinoma to evodiamine through cell cycle arrest, growth inhibition and apoptosis induction.

Head and neck cancer, particularly oral squamous cell carcinoma (OSCC), remains a major global health burden, with especially high incidence and mortality in Taiwan due to the widespread habit of betel quid chewing. Betel nut mediated OSCC (BN-OSCC) is characterized by aggressive clinical behavior, including increased risks of recurrence, metastasis, and poor survival outcomes, and exhibits limited responsiveness to conventional chemoradiotherapy. Therefore, the development of novel therapeutic agents and radiosensitizers is urgently needed. Evodiamine (EVO), a bioactive quinolone alkaloid isolated from Evodia rutaecarpa, has demonstrated broad anti-tumor activities across multiple cancer types, including inhibition of proliferation, suppression of metastasis, and induction of apoptosis. Although previous studies have reported the anti-OSCC effects of EVO through modulation of pathways such as Akt, EPRS1, and RAGE, its specific impact on BN-OSCC remains unclear. In this study, we investigated the anti-cancer effects of EVO in BN-OSCC and non-BN-OSCC cell lines. Our results demonstrate that EVO significantly inhibits cell viability and proliferation in a dose-dependent manner in BN-OSCC rather than non-BN-OSCC cells. Importantly, EVO induces apoptosis through activation of the caspase-dependent pathway, as evidenced by increased cleavage of caspase-3, caspase-9, and PARP. Furthermore, EVO treatment leads to mitochondrial dysfunction and enhances pro-apoptotic signaling, suggesting involvement of the intrinsic apoptotic pathway. Collectively, these findings indicate that EVO exerts potent anti-tumor effects in BN-OSCC cells by triggering caspase-dependent apoptosis. This study provides novel insights into the therapeutic potential of EVO and supports its development as a promising candidate for the treatment of betel nut mediated oral cancer.