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Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action

ABSTRACT: In a preliminary study in healthy subjects, the investigators determined the pharmacokinetic and pharmacodynamic of enteric-coated acetylsalicylic acid (ASA) (Adiro 100 mg, Bayer), and the variability (coefficient of variation), accuracy and precision of a novel biomarker of ASA action, i.e., quantification of the extent of COX-1 acetylation at serine-529, using a stable isotope dilution liquid chromatography multiple reaction monitoring/mass spectrometry (LC-MS) technique. Now, the investigators will perform a clinical study in individuals undergoing Colorectal cancer (CRC) to validate the hypothesis that that low-dose ASA given once daily is acting primarily by selectively acetylating platelet COX-1 and suppressing its activity throughout the 24-hour dosing interval. In contrast, it is expected that the inhibitory effect on extra-platelet sources of COX-1 will be short-lasting, if any, affecting only partially COX-1, and this effect will be completely reversed at 24 hours after dosing. This is an important point which will strengthen the platelet hypothesis underpinning the apparent adequacy of a 24-hour dosing interval of ASA administration for the anticancer effect detected in cardiovascular trials. These patients will be stratified into individuals with adenomas/carcinomas (20 to 30%) and patients without clinically detected adenomas/carcinomas (about 70 to 80%).

DISEASE(S): We Will Perform This Clinical Study To Address The Hypothesis That Low-dose Aspirin Given Once Daily Is Acting Primarily By Selectively Acetylating Platelet Cox-1 And Suppressing Its Activity Throughout The 24-hour Dosing Interval.,Con Este Estudio Queremos Validar La Hipótesis De Que La Toma Diaria De Aas A Dosis Bajas Actúa Primariamente Mediante La Acetilación Selectiva De La Cox-1 Plaquetaria Y La Supresión De Su Actividad Durante El Intervalo De Dosis De 24 Horas.,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2165599 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Results: MiRNA expression profiling of 1281 human miRNAs revealed relevant expression of 221 miRNAs consistently expressed in all samples at all time points. Correlation of platelet miRNA ranks was highly significant with data from other studies. Global distribution of miRNA expression was relatively similar in all subjects. No miRNA exhibited a significant effect of time at level 0.05. This finding was supported by exploratory analysis of predicted time effects from the mixed effects models. Furthermore, no significant effect of ASA could be found. Concerning the functional implication of the 20 most abundantly expressed miRNAs, we found 6 functional themes: nuclear import, cell cycle, transmembrane receptor protein serine/threonine kinase signaling pathway, regulation of kinase activity, pathways in cancer, and leukocyte differentiation. Conclusion: Our study shows that the platelet miRNA profile is remarkably stable in healthy subjects and is not affected by single-dose ASA treatment. For this reason, single-point analysis of platelet miRNA profile is reasonable when inter-individual differences are studied. The functional annotation network points toward additional extra-platelet effects of platelet miRNAs. We assessed the platelet miRNA profile blood in 5 volunteers at five time points over a time course of 10 days; 24 h prior to the last blood sampling, all subjects took 500 mg acetylsalicylic acid (ASA) once. Platelet miRNA was isolated from platelet-rich plasma which was leucocyte-depleted by negative bead separation. Then miRNA array analysis was performed on the isolated platelet miRNA. Temporal patterns and the effect of ASA were explored by a linear mixed effects model for each miRNA. For the 20 most abundantly expressed platelet miRNAs, a target gene search was performed by using miRWalk for validated and predicted targets. To visualize which molecular functions arerelated to those miRNAs, an annotation network was created by ClueGO, a Cytoscape plug-in.

Project description:Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA + 1% CUR were given to mice from 1 week prior to the AOM injection until the experiment was terminated 22 weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.

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Acetylsalicylic Acid and Colorectal Cancer Prevention: Exploring the Platelet Function of Its Mechanism of Action

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