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Dionisie CEBOTARI, Evgheni GRUȘAC, Daniel CRISTEA, Delia MINCHEVICI,Nadejda NEGARI, Nadejda RAILEAN, Veronica SARDARI. Biochemical Mechanisms of Acetylsalicylic Acid in Metastatic Chemoprevention: Platelet–Tumor Cell Interactions, the Cyclooxygenase-1/Thromboxane A2 Axis, and the Role of Protein Acetylation: A Review; Proceedings of NanoBioMat 2026(1); 132-157
Biochemical Mechanisms of Acetylsalicylic Acid in Metastatic Chemoprevention: Platelet–Tumor Cell Interactions, the Cyclooxygenase-1/Thromboxane A2 Axis, and the Role of Protein Acetylation: A Review
Dionisie CEBOTARI1*, Evgheni GRUȘAC1, Daniel CRISTEA1, Delia MINCHEVICI1, Nadejda NEGARI3, Nadejda RAILEAN2, Veronica SARDARI1.
1 Department of Biochemistry and Clinical Biochemistry, Nicolae Testemițanu State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
2 Laboratory of Systematics and Molecular Phylogeny, Institute of Zoology, Moldova State University, Chișinău, Republic of Moldova
3 Department of Surgery nr. 5, “Nicolae Testemițanu” State University of Medicine and Pharmacy, Chișinău, Republic of Moldova
*Correspondence: cebotaridionisie@gmail.com
ABSTRACT
Metastasis is the principal cause of cancer-related mortality, and its prevention remains a major clinical challenge. Over the past decades, low-dose acetylsalicylic acid (ASA, aspirin) has emerged as an accessible chemopreventive agent, with randomised controlled trials reporting significant reductions in distant metastasis and cancer mortality, particularly in adenocarcinomas. This narrative review synthesises the biochemical mechanisms underlying this antimetastatic action, centred on the platelet–tumour cell axis. Within the circulation, platelets assemble a protective shield around circulating tumour cells (CTCs) through selectin- and integrin-mediated adhesion and a fibrin meshwork, shielding them from shear stress and natural killer (NK) cell–mediated lysis. A central effector of this process is the cyclooxygenase-1 (COX-1)/thromboxane A2 (TXA2) axis: ASA irreversibly acetylates Ser529 of platelet COX-1, abolishing TXA2 biosynthesis for the platelet lifespan and dismantling the platelet shield. We further examine the platelet-derived growth factors, microparticles and bioactive lipids that remodel the tumour microenvironment, the synergistic TGFβ/Smad and NF-κB signalling that drives an epithelial–mesenchymal-like transition, and the concentration-dependent, COX-independent ("off-platelet") effects unlikely to contribute at therapeutic doses. Finally, we discuss the clinical evidence, the bleeding-risk trade-off, emerging predictive biomarkers, and drug-delivery and nanotechnology-based strategies for optimising aspirin. Collectively, these data position low-dose ASA as a mechanistically grounded, platelet-targeted tool for metastatic chemoprevention.
Keywords: acetylsalicylic acid; aspirin; metastasis; chemoprevention; platelets; cyclooxygenase-1; thromboxane A2; circulating tumour cells; drug delivery.