Summary
Born in 1897 as an analgesic and antipyretic drug, Aspirin is conventionally regarded as a drug that prevents arterial thrombosis through the inhibition of platelet COX-1.
In the last five years Aspirin has been taken into new fields: Cancer, Dementia and Gynaecology.
This work try to consider how can aspirin be active in cancer prevention through the hypothesis that inhibition of platelet activation may mediate both the cardio-protective and cancer-preventive effects.
Effects of Aspirin on cancer incidence and mortality
After years of anti-inflammatory use, Aspirin has been shown to be effective in preventing atherothrombotic vascular complications (myocardial infarction, stroke and vascular death).
More recently, long-term follow-up of randomized trials of daily aspirin vs. control in cardiovascular prevention has shown that low dose aspirin reduces the incidence and mortality due to colon rectal cancer after a delay of 5-10 years and reduce death due to several others common cancers after delays of 5-15 years.
Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials., 2012
In September 1995 prof Edward Giovannucci published in The New England Journal of Medicine an article about Aspirin and the risk of colorectal cancer in women (2). In the conclusions he reported that regular Aspirin use reduces the risk of colorectal cancer however the benefit is evident after at least a decade of regular aspirin consumption.
In the last five years, some new pieces of evidence have awakened interest in aspirin and cancer.
First: Fifty-one randomised trials that compared the use or nonuse of Aspirin were reviewed, with almost 77,000 participants. (3) There were fewer instances of cancer in subjects who had taken daily low-dose Aspirin for three years or more, and a reduction of 31% in cancer deaths on aspirin after more than five years. The reduction was not just in cancers of the gastrointestinal tract, but also in breast, prostate, and lung cancer.
Second: Patients with Lynch (4) syndrome (a hereditary predisposition to colorectal and other cancers) were randomised into taking either aspirin 600 mg or placebo. Those who had taken Aspirin for more than two years were significantly less likely to develop cancer.
Third: The effects of Aspirin, in terms of reducing metastases in the primary prevention trials and on follow-ups are encouraging.
More data are also needed on the apparent Aspirin effects on metastasis and their impact on death due to cancer. (5)
There is limited evidence of an effect on overall cancer incidence before five years, and no effect on colorectal cancer before 10 years, so there must be long-term post-trial follow-up to detect such effects.
The Non Vascular outcome on Aspirin team are trying to add data with ongoing trials to increase the reliability of these effects beginning after five years. For example the long-term follow-up from the Scottish trial of Aspirin for Asymptomatic Atherosclerosis (AAA) and Prevention Of Progress of Arterial Disease And Diabetes (POPADAD) may give more information on long-term cancer incidence.
The team is also working with the Women’s Health Study and the Physicians Health Study group to compare the effects of the alternate day and daily Aspirin, in long-term follow-up, to see whether the alternate day effects are similar to or smaller than those on daily Aspirin.
There are hints that other cancers may be prevented by ASA, for example Christina A Gamba et al., reported that aspirin is associated with lower melanoma risk amang post menopausal Caucasian women. (6)
Chemoprevention of cancer
The mechanism of the chemopreventive effect of Aspirin against colorectal adenoma and cancer has long been related to the inhibition of Cox2 activity in various cell types of lower GI tract.
The molecular mechanism that defines Aspirin and other NSAIDs as a class is their ability to block the metabolism of arachidonic acid through the prostaglandin H (PGH) synthase or cyclooxygenase (COX) pathway.
Two distinct isoforms of PGH synthase, derived from different genes, have been identi¬fied and designated COX 1 and COX 2.
COX 1 is con¬stitutively expressed in most tissues and has a central role in platelet aggregation and gastric cytoprotection. COX 1 is the only isoform present in mature platelets where it is the source of TXA2;
COX 2 is constitutively expressed in several tissues (vascular endothelium, kidney and brain) and expression is induced in other tissues during inflammation, wound healing, and neoplasia.
Direct inhibition of COX 2 activity is the main mecha¬nism by which Aspirin and other NSAIDs have been pro¬posed to inhibit the development of certain cancers, although other mechanisms have been hypothesized.
The hypothesis that the effect of Aspirin on colorectal cancer is mediated by COX 2 inhibi¬tion is also supported by results from an epidemiologic study that found aspirin use was associated with lower risk of colorectal cancers that overexpressed COX 2, but was not associated with lower risk of colorectal cancers that showed weak or absent COX 2 expression. (7)
Mature platelets, which contain only COX 1, are particularly susceptible to the long-lasting effects of low-dose aspirin treatment, because they lack a nucleus.
Other nucleated cells can resynthesize COX isozymes within a few hours.
The Aspirin regimen for cardioprotection (once daily administration of 75–100 mg) has negligible and tran¬sient effects on extra-platelet targets.
Figure 1 | Mechanism of action of high-dose and low-dose aspirin depicted on a simplified schematic of the cyclooxygenase pathway.
The dose of aspirin necessary to necessary to inhibit COX 2 as well as COX 1 activity, is about 2,000 mg daily, but this inhibition can only be main¬tained in nucleated cells by repeated dosing three or four times daily.
Because low-dose Aspirin selectively inhibits COX 1 in platelets, and only marginally and transiently inhibits COX 2, it has been considered implausible that the daily low-dose regimen used to inhibit arterial thrombosis could also effectively inhibit the development and/or progression of certain cancers cox 2 dependent.
To address this inconsistency, we hypothesize that the antiplatelet effect of low-dose Aspirin might mediate both its cardioprotective and cancer preventive effects.
The chemopreventive effects occur at low doses (75–160 mg), as observed in secondary analyses of the cardiovascular trials and higher doses do not seem to provide greater protection.
Secondly, dosing at 24 h intervals seems to be adequate, despite the short half-life of aspirin and the ability of cells other than platelets to regenerate COX 1 and COX 2 within a few hours.
None of these features are compatible with a direct inhibitory effect of low-dose Aspirin on COX 2 or with various COX-independent mechanisms that have been proposed.
Despite the strong clinical and preclinical evi¬dence that implicates COX 2 expression in the promotion and progression of colorectal and other cancers, treat¬ment with low-dose aspirin once daily cannot achieve sustained inhibition of COX 2 in nucleated cells.
As noted above, higher doses of Aspirin (for example, 600 mg of aspirin administered three or four times daily) are needed to achieve sustained inhibition of COX 2.
Other proposed mechanisms that are independent of COX include inhibi¬tion of NF-κB19 and induction of polyamine catabolism. However, the potential relevance of these alternative mechanisms, there aren’t any evidence of low dose aspirin activity in this direction.
Now the only consistent hypothesis concerning how aspirin might inhibit colorectal carcino¬genesis, is that permanent inactivation of platelet COX 1 has a key role in suppressing the induction of COX 2 in adjacent cell types (for example, stromal cells) of the intestinal mucosa at sites of mucosal injury, where platelets are recruited and activated (Figure 2).
Such a platelet-dependent effect might work through paracrine lipid (for example, TXA2) or protein (such as interleukin 1β and PDGF) media¬tors.
Indeed, activated platelets induce COX 2 expression in monocytes by combinatorial signalling to transcriptional and post-transcriptional checkpoints involving adhesion and cytokine signalling.
Also, the generally similar effects of low-dose Aspirin in preventing sporadic adenoma recurrence are consistent with the hypothesis that the early transformation of a normal intestinal epithelium into an adeno¬matous lesion might be blocked, at least in part, either by interfering with platelet activation upstream or inhibiting COX 2 activity downstream (Figure 2). Platelet inhibition might also be important in later stages of carcinogenesis, as extensive experimental evidence shows that platelets are important, if not essential, in the development of tumor metastases from the bloodstream. It has been recognized that during metastasis platelets surround cancer cells in the bloodstream, which protect them from immune surveillance and promotes their colonization at distant sites.
Despite suggestive evidence for potential rule of Aspirin in cancer prevention all the authors evidence that all the data are pulled out from cardiovascular study and that
randomized interventional trials of the effect of Aspirin on the rate of recurrence of adenomas would be useful in establishing causality, data on dose response relations and the duration of treatment.
References
1. Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet http://dx.doi.org/10.1016/S0140-6736(12)60209-8.
2. Giovannucci, E. et al. Aspirin and the risk of colorectal cancer in women.
The New England Journal of Medicine Sept. 7, 1995; vol.333/609-614.
3. Rothwell, P. M. et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials www.thelancet.com Published online March 21, 2012 DOI:10.1016/S0140-6736(11)61720-0
4. Lynch HT, Lynch JF and Shaw TG (2011).Hereditary gastrointestinal cancer syndromes Gastrointest Cancer Res. 4 (4 Suppl 1):
5. Rothwell, P. M. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet Published online March 21, 2012 DOI:10.1016/S0140-6736(12)60209-8
6. Gamba C. A. et al. Aspirin is associated with lower melanoma risk amang post menopausal Caucasian women. Cancer 2013 Mar 11.doi: 10. 1002/cncr27817
7. Chan, A. T., et al Aspirin and the risk of colorectal cancer in relation to the expression of COX 2. N. Engl. J. Med. 356, 2131–2142 (2007).
8. Patrono, C., Patrignani, P. & Garcia Rodriguez, L. A. Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical readouts. J. Clin. Invest. 108, 7–13 (2001).
9. Thun M. J, Jacobs E. J. and Patrono C. The role of Aspirin in Cancer Prevention.
Nature reviews Clinical Oncology: 2012 May. Vol9; 259-267
10. Choe K.S., Liauw S. L., Effects of Aspirin on Cancer Initiation and Progression. Expert Rev. Anticancer Ther. 13(2), 115-117 (2013)
