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Mode of Action of Aspirin as a Chemopreventive Agent

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Book cover Prospects for Chemoprevention of Colorectal Neoplasia

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 191))

Abstract

Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. The finding of aspirin benefit at low-doses given once daily, used for cardioprevention, locates the antiplatelet effect of aspirin at the center of its antitumor efficacy. In fact, at low-doses, aspirin acts mainly by an irreversible inactivation of platelet cyclooxygenase (COX)-1 in the presystemic circulation, which translates into a long-lasting inhibition of platelet function. Given the short half-life of aspirin in the human circulation(approximately 20 min) and the capacity of nucleated cells to resynthesize the acetylated COX-isozyme(s), it seems unlikely that a nucleated cell could be the target of aspirin chemoprevention. These findings convincingly suggest that colorectal cancer and atherothrombosis may share a common mechanism of disease, i.e. platelet activation in response to epithelial(in tumorigenesis) and endothelial(in tumorigenesis and atherothrombosis) injury. Activated platelets may also enhance the metastatic potential of cancer cells (through a direct interaction and/or the release of soluble mediators or exosomes) at least in part by inducing the overexpression of COX-2. COX-independent mechanisms of aspirin, such as the inhibition of NF-kB signaling and Wnt/β-catenin signaling and the acetylation of extra-COX proteins, have been suggested to play a role in its chemopreventive effects. However, their relevance remains to be demonstrated in vivo at clinical doses.

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Abbreviations

15R-HETE:

15R-hydroxyeicosapentaenoic acid

5-LOX:

5-lipoxygenase

ADP:

Adenosine diphosphate

apaf-1:

Apoptotic protease activating factor-1

AA:

Arachidonic acid

CRC:

Colorectal cancer

COX:

Cyclooxygenase

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular signal-regulated kinase

FAP:

Familial adenomatous polyposis

FGF:

Fibroblast growth factor

IGF:

Insulin-like growth factor

IL:

Interleukin

LPS:

Bacterial endotoxin

MPs:

Microparticles

mPGES-1:

Microsomal PGE2 synthase-1

NK:

Natural killer

NSAID:

Nonsteroidal anti-inflammatory drug

NF-kB:

Nuclear factor kappa B

PDGF:

Platelet-derived growth factor

PDGF:

Platelet-derived growth factor

PGI2 :

Prostacyclin

PG:

Prostaglandin

PKC:

Protein kinase C

Ser:

Serine

S1P:

Sphingosine-1-phosphate

Lef:

T-cell factor (Tcf)/lymphoid enhancer factor

TX:

Thromboxane

TIMP:

Tissue inhibitor of metalloproteinases

TCIPA:

Tumor cell-induced platelet aggregation

TXAS:

TXA2 synthase

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This work was supported by research funding from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to Paola Patrignani. We would like to thank, for fruitful discussions and suggestions, Dr Carlo Patrono (Catholic University, Rome, Italy), Luis A Garcia Rodriguez (CEIFE, Madrid, Spain) and Angel Lanas (University of Zaragoza, Spain). We apologize to our colleagues for not being able to reference all primary work due to space limitations.

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Authors and Affiliations

  1. Center of Excellence on Aging (CeSI) and Department of Neuroscience and Imaging, G. d’Annunzio University, School of Medicine, Via dei Vestini 31, 66100, Chieti, Italy

    Melania Dovizio, Stefania Tacconelli & Paola Patrignani

  2. Center of Excellence on Aging (CeSI) and Department of Medicine and Aging, G. d’Annunzio University, School of Medicine, Via dei Vestini 31, 66100, Chieti, Italy

    Annalisa Bruno

Authors
  1. Melania Dovizio
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  2. Annalisa Bruno
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  3. Stefania Tacconelli
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  4. Paola Patrignani
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Corresponding author

Correspondence to Paola Patrignani .

Editor information

Editors and Affiliations

  1. Massachusetts General Hospital, Gastrointestinal Unit, Harvard Medical School, Fruit Street 55, Boston, 02114, Massachusetts, USA

    Andrew T. Chan

  2. BSP-GD-GMA-CVRM, Berlin, S101, 09, 140, Bayer Schering Pharma AG, Müllerstraße 178, Berlin, 13351, Germany

    Elmar Detering

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Dovizio, M., Bruno, A., Tacconelli, S., Patrignani, P. (2013). Mode of Action of Aspirin as a Chemopreventive Agent. In: Chan, A., Detering, E. (eds) Prospects for Chemoprevention of Colorectal Neoplasia. Recent Results in Cancer Research, vol 191. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30331-9_3

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  • DOI: https://doi.org/10.1007/978-3-642-30331-9_3

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  • Print ISBN: 978-3-642-30330-2

  • Online ISBN: 978-3-642-30331-9

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