Argentatin A and B are naturally occurring triterpenes isolated from Parthenium argentatum A. Gray (guayule) and are recognized for their cytotoxic activity; however, their functional and molecular effects following prolonged exposure remain poorly characterized. The present study evaluated their anti-migratory and anti-angiogenic properties and characterized the associated transcriptomic profiles in cancer cell models following six months of continuous exposure. Both compounds decreased migration in transwell assays and impaired vascular structure formation in HMEC-1 human immortalized endothelial cells. Although argentatin B exhibited greater cytotoxicity under acute conditions, prolonged treatment with argentatin A led to the emergence of heterogeneous drug-tolerant populations. RT-qPCR analysis revealed markedly divergent transcriptional responses during chronic exposure: argentatin A predominantly modulated genes associated with metabolic adaptation, inflammatory signaling and extracellular matrix remodeling, including AKR1B10 and PTGES , whereas, argentatin B preferentially affected genes linked to cell cycle regulation and cellular homeostasis, such as PKMYT1 and PIM1 .Importantly, these transcriptional differences were reflected at protein level, with argentatin A inducing coordinated upregulation of metabolic and stress associated proteins. Collectively these findings demonstrate that although argentatin A and B share key anti-tumor properties, they elicit divergent molecular responses during chronic exposure, suggesting different mechanisms of action and potentially divergent implications for the development of acquired resistance. • Argentatin A and B from guayule inhibit tumor cell migration and endothelial tube formation. • Prolonged exposure to argentatin A promotes adaptative tolerance, whereas argentatin B maintains a cytostatic phenotype. • Chronic Argentatin A treatment induces coordinated metabolic and stress response at transcriptional and protein levels. • Argentatin B induces limited proteomic and transcriptional changes, avoiding activation of metabolic resistance pathways. • Transcriptomic and proteomic analyses reveal distinct long-term modes of action for structurally related argentatins.
Silva‐Nolasco et al. (Thu,) studied this question.