Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients
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 e...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/9/2457 |
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| author | Angel Lanas Stefania Tacconelli Annalisa Contursi Elena Piazuelo Annalisa Bruno Maurizio Ronci Simone Marcone Melania Dovizio Federico Sopeña Lorenza Falcone Cristina Milillo Matteo Mucci Patrizia Ballerini Paola Patrignani |
| author_facet | Angel Lanas Stefania Tacconelli Annalisa Contursi Elena Piazuelo Annalisa Bruno Maurizio Ronci Simone Marcone Melania Dovizio Federico Sopeña Lorenza Falcone Cristina Milillo Matteo Mucci Patrizia Ballerini Paola Patrignani |
| author_sort | Angel Lanas |
| collection | DOAJ |
| description | 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) B<sub>2</sub> generation ex vivo (serum TXB<sub>2</sub>). However, enhanced residual urinary 11-dehydro-TXB<sub>2</sub> and urinary PGEM, primary metabolites of TXA<sub>2</sub> and prostaglandin (PG)E<sub>2</sub>, 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-TXB<sub>2</sub> levels, possibly identifying the nonresponders and responders to Aspirin. Conclusions: Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA<sub>2</sub> and PGE<sub>2</sub> 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 TXA<sub>2</sub> and PGE<sub>2</sub> signaling with receptor antagonists. |
| first_indexed | 2024-03-11T04:23:14Z |
| format | Article |
| id | doaj.art-64be45d9795d48b9af1b8f5da4b36df0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T04:23:14Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
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| series | Cancers |
| spelling | doaj.art-64be45d9795d48b9af1b8f5da4b36df02023-11-17T22:39:59ZengMDPI AGCancers2072-66942023-04-01159245710.3390/cancers15092457Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis PatientsAngel Lanas0Stefania Tacconelli1Annalisa Contursi2Elena Piazuelo3Annalisa Bruno4Maurizio Ronci5Simone Marcone6Melania Dovizio7Federico Sopeña8Lorenza Falcone9Cristina Milillo10Matteo Mucci11Patrizia Ballerini12Paola Patrignani13University Hospital LB, Aragon Health Research Institute (IISAragon), CIBERehd, University of Zaragoza, 50009 Zaragoza, SpainCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyInstituto Aragonés de Ciencias de la Salud (IACS), 50009 Zaragoza, SpainCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyDepartment of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University, 66100 Chieti, ItalyTrinity Translational Medicine Institute, Trinity College Dublin, D02 PN40 Dublin, IrelandCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyUniversity Hospital LB, Aragon Health Research Institute (IISAragon), CIBERehd, University of Zaragoza, 50009 Zaragoza, SpainCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyCenter for Advanced Studies and Technology (CAST), “G. d’Annunzio” University, 66100 Chieti, ItalyBackground: 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) B<sub>2</sub> generation ex vivo (serum TXB<sub>2</sub>). However, enhanced residual urinary 11-dehydro-TXB<sub>2</sub> and urinary PGEM, primary metabolites of TXA<sub>2</sub> and prostaglandin (PG)E<sub>2</sub>, 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-TXB<sub>2</sub> levels, possibly identifying the nonresponders and responders to Aspirin. Conclusions: Although low-dose Aspirin appropriately inhibited the platelet, persistently high systemic TXA<sub>2</sub> and PGE<sub>2</sub> 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 TXA<sub>2</sub> and PGE<sub>2</sub> signaling with receptor antagonists.https://www.mdpi.com/2072-6694/15/9/2457plateletscolorectal adenomascyclooxygenasesCOX acetylationthromboxaneprostaglandin E<sub>2</sub> |
| spellingShingle | Angel Lanas Stefania Tacconelli Annalisa Contursi Elena Piazuelo Annalisa Bruno Maurizio Ronci Simone Marcone Melania Dovizio Federico Sopeña Lorenza Falcone Cristina Milillo Matteo Mucci Patrizia Ballerini Paola Patrignani Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients Cancers platelets colorectal adenomas cyclooxygenases COX acetylation thromboxane prostaglandin E<sub>2</sub> |
| title | Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients |
| title_full | Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients |
| title_fullStr | Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients |
| title_full_unstemmed | Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients |
| title_short | Biomarkers of Response to Low-Dose Aspirin in Familial Adenomatous Polyposis Patients |
| title_sort | biomarkers of response to low dose aspirin in familial adenomatous polyposis patients |
| topic | platelets colorectal adenomas cyclooxygenases COX acetylation thromboxane prostaglandin E<sub>2</sub> |
| url | https://www.mdpi.com/2072-6694/15/9/2457 |
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