Selective cytotoxicity of Gomortega keule essential oil through a ROS-mediated pro-apoptotic mechanism

Alejandro Madrid^1,2*Valentina Silva¹Alessandra Russo³Alejandra Catalina Moller⁴Elizabeth Sánchez⁵Joan Villena García⁶Carlos Jara⁷Iván Montenegro^2,8*

• ¹Laboratorio de Productos Naturales y Síntesis Orgánica (LPNSO), Facultad de Ciencias Naturales y Exactas, Universidad de Playa Ancha, Avda. Leopoldo Carvallo 270, Valparaíso, Chile, Valparaiso, Chile
• ²Millennium Nucleus Bioproducts, Genomics and Environmental Microbiology (BioGEM), Avenida España 1680, 2390123 Valparaíso, Chile, Valparaiso, Chile
• ³Department of Drug and Health Sciences, University of Catania, Catania, Italy
• ⁴Escuela de Tecnología Médica, Facultad de Medicina, Universidad de Valparaíso, Chile, Viña del Mar, Chile
• ⁵Centro de Biotecnología, Dr. Daniel AlKalay Lowitt, Universidad Técnica Federico Santa María, Valparaiso, Chile
• ⁶Center of Interdisciplinary Biomedical and Engineering Research for Health (MEDING), Escuela de Medicina, Facultad de Medicina, Universidad de Valparaíso, Viña del Mar, Chile
• ⁷Center of Interdisciplinary Biomedical and Engineering Research for Health (MEDING), Escuela de Kinesiología, Facultad de Medicina, Universidad de Valparaíso, Viña del Mar, Chile
• ⁸Centro de Investigaciones Biomédicas, Escuela de Medicina, Universidad de Valparaíso, Viña del Mar, Chile

Cancer is a leading cause of mortality worldwide, prioritizing the search for new therapies with improved toxicity profiles. Natural products, such as essential oils (EOs), are a valuable source of potential chemotherapeutic agents. Gomortega keule, a Chilean endemic tree, has traditional uses, but its cytotoxic potential remains unexplored. This study investigated the chemical composition and cytotoxic activity of G. keule leaf EO. The chemical analysis revealed a unique profile rich in diterpenes (>50%), mainly phyllocladene (28.08%) and kaur-16-ene (19.74%), suggesting a distinct chemotype. The EO demonstrated potent cytotoxic activity against breast (MCF-7), prostate (PC-3), and colon (HT-29) cancer cell lines, with IC50 values of 3.97, 2.43, and 9.76 µg/mL, respectively. Remarkably, the EO exhibited exceptional selectivity, proving significantly more toxic to cancer cells than to non-tumorigenic cells. Specifically, it achieved a Selectivity Index (SI) of 24.01 for breast cancer cells compared to normal MCF-10A cells. Crucially, this selectivity profile significantly outperformed standard chemotherapeutic agents (daunorubicin and 5-fluorouracil), which displayed high toxicity towards healthy cells in this model. The mechanism of action involves the selective induction of reactive oxygen species (ROS), leading to mitochondrial membrane depolarization (ΔΨm) and caspase activation, culminating in apoptotic cell death. These findings highlight G. keule EO as a promising source for developing selective cytotoxic agents.