Dehydroleucodine Induces ROS-Mediated Mitochondrial Apoptosis and G2/M Cell Cycle Arrest in Oral Squamous Cell...

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor clinical outcomes due largely to recurrence and therapy resistance. Dehydroleucodine (DhL) is a sesquiterpene lactone derived from Asteraceae species, which has demonstrated anticancer activity in several tumor models. However, its therapeutic relevance in OSCC has not been established. This study investigated the antitumor effects of DhL and the mechanisms underlying its activity in OSCC using complementary in vitro and in vivo approaches. DhL significantly suppressed cell viability and clonogenic growth in HSC3 and SCC4 cells, with relatively low cytotoxicity toward normal gingival fibroblasts (HGF-1) under the tested conditions. The underlying mechanisms involved apoptotic cell death and G2/M phase arrest, accompanied by reduced cyclin B1 and CDK1 expression. DhL was also shown to promote mitochondrial dysfunction, as indicated by loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, elevated cleaved caspase-3 expression and activity, and increased intracellular reactive oxygen species (ROS) generation. Pretreatment with the antioxidant N-acetylcysteine partially attenuated apoptosis and cell cycle arrest, suggesting that ROS plays a role in both responses. Systemic DhL treatment in an in vivo xenograft model significantly inhibited tumor growth and increased cleaved caspase-3 expression in tumor tissue without a significant loss of body weight. Together, these findings identify DhL as a potent suppressor of OSCC growth, which acts through ROS-associated mitochondrial apoptosis and G2/M arrest, supporting further preclinical evaluation of DhL as a candidate therapeutic agent for OSCC.