Coumarin Derivatives as Anticancer Agents: Mechanistic Landscape with an Emphasis on Breast Cancer

Nov 13, 2025Molecules (Basel, Switzerland)

Coumarin Compounds as Cancer Fighters, Focusing on How They Work Against Breast Cancer

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Coumarin derivatives may serve as versatile small-molecule anticancer agents with potential across various tumor types.

Evidence suggests coumarins induce apoptosis through mechanisms such as caspase activation and the balance of pro- and anti-apoptotic proteins.
Modulation of the PI3K/Akt/mTOR pathway is associated with the anticancer activity of coumarin-based compounds.
Inhibition of angiogenesis via VEGFR-2 and interference with estrogen biosynthesis are highlighted as key mechanisms.
Selected coumarin chemotypes show varying potency and selectivity across different cancer models like breast (MCF-7 and MDA-MB-231), lung (A549), prostate (PC-3), and colorectal lines.
Translational gaps are noted, including challenges in selectivity for non-malignant cells and incomplete pharmacokinetic and safety profiles.
Priorities for preclinical optimization include the selection of biology-aligned targets and the integration of pharmacokinetic and toxicity assessments.

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Coumarin derivatives constitute a versatile small-molecule chemotype with broad anticancer potential. This narrative review synthesizes recent in vitro and in vivo evidence on coumarin-based scaffolds, emphasizing breast cancer and covering lung, prostate, and colorectal models. We summarize major mechanisms of action-including induction of apoptosis (caspase activation and BAX/BCL-2 balance), modulation of PI3K/Akt/mTOR signaling, inhibition of angiogenesis (VEGFR-2), interference with estrogen biosynthesis (aromatase/ER axis), chaperone targeting (Hsp90), and attenuation of multidrug resistance (efflux pumps/autophagy)-and highlight representative chemotypes (e.g., benzimidazole, triazole, furocoumarins, topoisomerase- and CDK-oriented hybrids). Where available, we contrast potency and selectivity across models (e.g., MCF-7 vs. MDA-MB-231; A549; PC-3; colon lines) and discuss structure-activity trends linking substituent patterns (heteroaryl linkers, judicious halogenation, polar handles) to pathway engagement. We also delineate translational gaps limiting clinical progress-selectivity versus non-malignant cells, incomplete pharmacokinetic and safety characterization, and limited validation beyond xenografts. Finally, we outline priorities for preclinical optimization: biology-aligned target selection with biomarkers, resistance-aware combinations (e.g., PI3K/mTOR ± autophagy modulation; MDR mitigation), and early integration of ADME/tox and PK/PD to confirm on-target exposure. Collectively, the evidence supports coumarins as adaptable, multi-target anticancer leads, particularly promising in hormone-dependent breast cancer while remaining relevant to other tumor types.

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Coumarin Derivatives as Anticancer Agents: Mechanistic Landscape with an Emphasis on Breast Cancer

Abstract

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