Santamarine Synergizes With Cisplatin via ROS/JNK Axis to Selectively Induce Apoptosis and DNA Damage in Oral Cancer Cells In Vitro.

Santamarine (SAMA), a Michelia compressa-derived sesquiterpene lactone, exhibits ROS‑mediated anticancer activity; however, its potential mechanisms and synergy with cisplatin in oral cancer have not been explored. This study investigated SAMA and cisplatin's combined effects and underlying ROS/MAPK mechanisms of action on oral cancer cells. The combination significantly reduced viability (ATP assay) in oral cancer Ca9‑22 and CAL 27 cells compared with either agent alone, with synergistic indices confirming enhanced antiproliferation. Moreover, this combination markedly suppressed colony formation and cell migration. SAMA/cisplatin induced subG1 accumulation and G2/M arrest, elevated cellular and mitochondrial ROS, and promoted apoptosis, as evidenced by increased annexin V positivity and caspase‑3, -8, and -9 activation, while DNA damage markers γH2AX and 8‑OHdG were also markedly elevated. In contrast, normal oral S‑G cells showed minimal cytotoxic damage and mechanical changes, suggesting selectivity. Mechanistically, JNK inhibition rescued the antiproliferative response and suppressed apoptosis, caspase activation, and DNA damage. Pretreatment with the ROS scavenger NAC attenuated all test effects, confirming ROS dependence. Together, these findings demonstrate that SAMA synergizes with cisplatin to selectively enhance oxidative stress, apoptosis, and DNA damage in oral cancer cells via ROS‑dependent JNK signaling, highlighting its potential as a cisplatin adjunct.