Bioprospecting of Brazilian Restinga Plants Reveals a Myrciaria floribunda Fraction with Apoptotic Activity Against Oral Carcinoma Cells

Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the head and neck region, and current chemotherapeutic regimens, based largely on platinum compounds, are limited by low selectivity and severe adverse effects. Aiming to identify selective cytotoxic agents from the Brazilian Atlantic Forest, we screened seventeen ethanolic extracts derived from ten plant species collected in Restinga ecosystems (Myrciaria floribunda, Myrcia amazonica, Myrsine parvifolia, Myrcia ovata, Pilocarpus spicatus, Eugenia sulcata, Eugenia pruniformis, Ocotea indecora, Ocotea notata, and Ocotea pulchella) against the OSCC cell line SCC-9 and primary human gingival fibroblasts. Among the active extracts, those from M. floribunda leaves and stem were the most potent and selective, with IC50 values of 78.7 and 56.9 µg/mL and selectivity indices of 7.14 and 6.80, respectively. Liquid–liquid partitioning of the stem extract yielded an ethyl acetate fraction (MfEA) that was further evaluated against a panel of eight tumor cell lines and against primary fibroblasts, displaying IC50 values ranging from 9.4 to 92.7 µg/mL and selectivity indices between 6.1 and 60.5. Chemical profiling of MfEA by UPLC-DAD-QTOF-ESI-HRMS/MS tentatively annotated gallic and ellagic acids, hydrolyzable tannins, and pentacyclic triterpenoids, several of which have individually been reported to exhibit antitumor activity. In SCC-9 cells, MfEA induced morphological hallmarks of apoptosis, activated effector caspases-3/7, increased the sub-G0/G1 population, and promoted phosphatidylserine externalization, without a detectable increase in H2O2 levels. MfEA exhibited negligible hemolytic activity (<3%) and, in C57BL/6 mice, an estimated intraperitoneal LD50 close to 200 mg/kg, with full tolerability at 100 mg/kg. Together, these findings identify the ethyl acetate fraction from Myrciaria floribunda as a promising lead from the Brazilian Restinga for further anticancer drug development.