Comparative Evaluation of the Antitumor Effect of Rosmarinic Acid and Nordihydroguaiaretic Acid in Osteosarcoma Cells

Abstract Osteosarcoma is the most common type of bone cancer and is known for its high likelihood of metastasis. Rosmarinic acid (RA) and nordihydroguaiaretic acid (NDGA) are plant polyphenols that offer promising health benefits. From a molecular structure point of view, RA and NDGA are quite similar, but one difference stands out: hydrophobicity. Based on this feature, this work aimed to compare RA and NDGA in a panel of antioxidant assays and as cytotoxic and antiproliferative agents, inhibitors of cell migration, and inducers of intracellular reactive oxygen species (ROS) production in murine osteosarcoma cells (UMR-106) and preosteoblastic cells (MC3T3-E1). Our comparative study establishes that NDGA exerts markedly stronger cytotoxic, antiproliferative, and antimigratory effects than RA in osteosarcoma UMR-106 cells, associated with greater intracellular oxidative activity and disruption of redox homeostasis. While RA retains significant antioxidant activity and minimal cytotoxicity toward differentiated MC3T3-E1 osteoblastic cells, its comparatively low cytotoxicity in the present model suggests a more limited therapeutic effect than NDGA under the conditions tested. NDGA emerges as a potent experimental candidate for further investigation in osteosarcoma, although its translational potential remains limited by concerns regarding systemic toxicity and the need for validation in human osteosarcoma models. Future studies should aim to optimize NDGA delivery and selectivity, elucidate the molecular pathways involved, and explore synergistic combinations with standard therapies. Ultimately, the divergent activities of RA and NDGA underscore the importance of structural and physicochemical determinants in dictating the therapeutic potential of plant polyphenols against osteosarcoma.