Biomarkers of response to low-dose aspirin in familial adenomatous polyposis patients

Lanas, Á. (Universidad de Zaragoza) ; Tacconelli, S. ; Contursi, A. ; Piazuelo, E. (Universidad de Zaragoza) ; Bruno, A. ; Ronci, M. ; Marcone, S. ; Dovizio, M. ; Sopeña, F. (Universidad de Zaragoza) ; Falcone, L. ; Milillo, C. ; Mucci, M. ; Ballerini, P. ; Patrignani, P.

Resumen: Background: The results of Aspirin prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP) are controversial. Methods: We conducted a biomarker-based clinical study in eight FAP patients treated with enteric-coated low-dose Aspirin (100 mg daily for three months) to explore whether the drug targets mainly platelet cyclooxygenase (COX)-1 or affects extraplatelet cellular sources expressing COX-isozymes and/or off-target effects in colorectal adenomas. Results: In FAP patients, low-dose Aspirin-acetylated platelet COX-1 at Serine529 (>70%) was associated with an almost complete inhibition of platelet thromboxane (TX) B2 generation ex vivo (serum TXB2). However, enhanced residual urinary 11-dehydro-TXB2 and urinary PGEM, primary metabolites of TXA2 and prostaglandin (PG)E2, respectively, were detected in association with incomplete acetylation of COX-1 in normal colorectal biopsies and adenomas. Proteomics of adenomas showed that Aspirin significantly modulated only eight proteins. The upregulation of vimentin and downregulation of HBB (hemoglobin subunit beta) distinguished two groups with high vs. low residual 11-dehydro-TXB2 levels, possibly identifying the nonresponders and responders to Aspirin. Conclusions: Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA2 and PGE2 biosynthesis were found, plausibly for a marginal inhibitory effect on prostanoid biosynthesis in the colorectum. Novel chemotherapeutic strategies in FAP can involve blocking the effects of TXA2 and PGE2 signaling with receptor antagonists.

Idioma: Inglés

DOI: 10.3390/cancers15092457

Año: 2023

Publicado en: Cancers 15, 9 (2023), 2457 [21 pp.]
ISSN: 2072-6694

Factor impacto JCR: 4.5 (2023)

Categ. JCR: ONCOLOGY rank: 78 / 322 = 0.242 (2023) - Q1 - T1

Factor impacto CITESCORE: 8.0 - Oncology (Q1) - Cancer Research (Q2)

Factor impacto SCIMAGO: 1.391 - Oncology (Q1) - Cancer Research (Q2)

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS/PI14-01218
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI17-01109

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)