Dear Colleagues,

Aspine is an anti-inflammatory drug and also acting in coagulation:

- by contrast with corticosteroid inhibiting phospholipase A2, aspirin inhibits cyclo-oxygenases (see works on coxA), so synthesis of all prostaglandins,

- in coagulation, aspinin inhbiting cyclo-oxygenase, this one synthetizes in platelets thromboxane A2 (TXA2) and consequently agregation of platelet (TXA2 is pro-coaguant) is inhibited (risk of bleeding with aspirin).

So, you have the explanation of the use of aspine in prevention of recidive of myocardial infaction, arterial thrombosis and so on....

Prostaglandins are inflammatory mediators with wide effects on cells and organs, according to prostaglandins synthetized by each cell in each organ: ie PGE1 in stomach is protective against acidity; if inhibited= risk of stomach bleeding; PGE2 in uterus tract , leading to the use of profenid, another anti-inflammatory drug , during menstruation pains in women.

Indirectly, these two effect (anti-inflammatroy and anti-aggregant) can interact with processes found in cancer, independently of evental actions on other intracellular pathways:

-cancer is often associated with thrombosis, and this is one of the mechanism used by cancer cells for metastasis (venous thrombosis on microvessel , then cancer cell bolus can migrate in others organs),

- but anti-inflmmatory effect can also be negative for the fight of the body against cancer cells, because inflammation is often the first step for further processes of immune response.

And I think they are a lot of added reasons in relation with your question.

I also think you can find, with these first elements and others , a lot of papers in litterature.

I hope it will be helpfull for you.

Best regards

Didier J

Aspirin has also been use to prevent heart attack, what can you say about that ?

Dear Colleagues,

Aspine is an anti-inflammatory drug and also acting in coagulation:

- by contrast with corticosteroid inhibiting phospholipase A2, aspirin inhibits cyclo-oxygenases (see works on coxA), so synthesis of all prostaglandins,

- in coagulation, aspinin inhbiting cyclo-oxygenase, this one synthetizes in platelets thromboxane A2 (TXA2) and consequently agregation of platelet (TXA2 is pro-coaguant) is inhibited (risk of bleeding with aspirin).

So, you have the explanation of the use of aspine in prevention of recidive of myocardial infaction, arterial thrombosis and so on....

Prostaglandins are inflammatory mediators with wide effects on cells and organs, according to prostaglandins synthetized by each cell in each organ: ie PGE1 in stomach is protective against acidity; if inhibited= risk of stomach bleeding; PGE2 in uterus tract , leading to the use of profenid, another anti-inflammatory drug , during menstruation pains in women.

Indirectly, these two effect (anti-inflammatroy and anti-aggregant) can interact with processes found in cancer, independently of evental actions on other intracellular pathways:

-cancer is often associated with thrombosis, and this is one of the mechanism used by cancer cells for metastasis (venous thrombosis on microvessel , then cancer cell bolus can migrate in others organs),

- but anti-inflmmatory effect can also be negative for the fight of the body against cancer cells, because inflammation is often the first step for further processes of immune response.

And I think they are a lot of added reasons in relation with your question.

I also think you can find, with these first elements and others , a lot of papers in litterature.

I hope it will be helpfull for you.

Best regards

Didier J

The machanism of anticancer and anti-inflamatiory action of aspirin is related to inhibition of prostaglandins. Aspirin inhibited prostaglandin synthase (cyclooxygenase) and inhibited proglandin production. Many studies showed that there is the level of prostaglandins increased in inflammation and cancer tissues and animal experiments confirmed that aspirin reduced swelling and inhibited cancer cell growth.

Dont believe everything you read about this drug its not that good in the pharma drug world as a cure

Why? If the clinical study shows the results? :)

I hope, it does help

Inflammation is a central point in cancer. Indeed, cancer give rise to inflammation and inflammation prepare the soil for cancer development and progression. It's a vicious circle !

Aspirin inhibits COX enzymes bloking the first step of PG synthesis. Among the PGs, seems to be the more effective in cancer. This PG is pro-proliferative and pro-angiogenic. This is the first explanation of the anti-cancer activity of aspirin.

The second point is the production of "aspirin-triggered lipoxin" (ATL) who are anti-inflammatory.

Cheers

we no that... thats all good and fantastic But really!!! if you are reported of having a grade 3, cancer asprin arnt going to do much for you, The idea that asprin is the next cancer cure is reported from one lab result, who just happn to have the study payed for by the makers of guess who?

the studies for col cancer and asprin is like every other drug reported to do sumthing to really think that asprin alone is the next wonder dug hmmm it will only be in the news till something else pops up... dont forget the cure for cancer has allready been reported to be developed and approved it just cost to much and for all those great lab personal who are right now doing the same work, we all know that that the time the FDA TGA approve this its 15 years plus away so in the mean time eat asprin yay

Go through, DrugBank and KEGG Drug Databases, it has the info on drug and its related pathway, hope pathway could be of your use.

Yes, over-the-counter pain reliever, Aspirin can be considered a powerful tool in cancer prevention because of its potent anti-inflammatory action.

But the main undesirable side-effects of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, daily intake of aspirin increase the risk of Reye's syndrome. So all these needs to be taken into consideration as well.

Yes in deed Pinaki,

Dear Colleagues,

Just a detail: use of aspirin in prvention can be good (proof on a long time to be done), but with already formed tumors, remember that aspini is an power anticoagulant, because anti-agregant, even at low doses; so, it favours bleeding of a tumor that can be very deleterious according to localisation (ie brain).

Always " inconvenients of advantages", to be in consideration, and wise use of therapeutics ; also in medicine the reason for no ideal treatment for one disease.

Regards

Didier

Clem Imrie Emeritus Professor - Lister Dept of Surgery- Royal Infirmary, Glasgow

This important subject has been largely neglected since 1994 when the Swedish prospective study of the comparison of outcome for 3 groups each having 48 patients with advanced irresectable cancers treated with a) standard supportive measures; b) additional low dose prednisolone or c) daily oral indomethacin was published by Lundholm et al. in Cancer Research 54, 5602-6. Prednisolone treated patients had a modest extension of survival, but the indomethacin treated group survived greater than 200 days more than the 276 days of those with standard supportive measures. They not only had this considerable survival benefit, but had less pain.

When this data and the host of > 100 publications showing all the common solid cancer patients can be simply stratified into better prognosis ( with normal inflammatory markers) and poor prognosis ( with elevated systemic inflammatory markers ) it is inexplicable why this subject is being largely ignored. Recent publications for those interested include Proctor et al Euro J Cancer 47,2633-41(2011); Allin & Nordestgaard in Crit Rev in Clin Lab Sci 48,155-170 (2011) . These papers will fire you in the right direction and lead you to many more publications.

Check it out

Chronic inflammation is linked to development of some cancers. Acute inflammation and fever have been associated with spontaneous remissions from cancers in some patients. I hypothesis that asprin may reduce chronic inflammation and reduce the incidence of cancers developing in the first place but asprin may take on a pro-tumor role for established cancers. Would be interesting to consider these possibilities.

It is likely that the mechanisms may depend on the type of cancer. In some tumors there are expansions and activation of myeloid-derived suppressor cells (MDSC) that suppress adaptive immune responses and confer a poor prognosis. One of the mechanisms of MDSC activation is mediated by PGE2 production. In such cases, aspirin and other COX inhibitors could be of help.

As to potential antineoplastic mechanisms of aspirin beyond cyclooxygenase inhibition, aspirin has been found to inhibit NF-kB (Kopp and Ghosh, Science 1994, 265: 956-959) and to acetylate p53 (Alfonso et al, Int J Oncol 2009, 34: 597-608).

(1) the inhibitory effect of Cox-inhibitors like aspirin (colon carcinoma) has been linked in part to COX-2 inhibition. But other metabolic pathways can also be influenced by NSAIDs, such as survivin down-regulation (Anticancer Res 2006, 26:4103-14)

(2) Development of metastases is highly dependent upon formation of microthrombi. Studies from 20-30 years ago in breast carcinoma (in Italy?) demonstrated that another coagulation inhibitor like coumarin, could lower the incidence of metastasis, but this beneficial effect was abolished by the much higher risk of brain bleedings.

As written by other visitors of this forum: design of more specific formulations of drugs to inhibit various pathways being blocked by NSAIDs is needed, as are studies that can inhibit thrombosis (thrombocyte aggregation / tissue factor?) with formulations / dosages that carry lower risk for complications of bleeding disorders. Will not be easy.

Dear Colleagues,

Aspirin as a chemical chaperon and having the ability of protein inhibition from several structure-function damages can be useful in cancer therapy. But consideration of its advantages and disadvantages for this significant field of medicine is almost difficult and regarding complications of its usage is necessary.

t's important to realize that aspirin is a drug, just like other over-the-counter and prescription medications. It is a nonsteroidal anti-inflammatory drug, or NSAID. As such, there are definitely adverse reactions to contend with.

So me of the most common aspirin side effects are stomach pain, heart burn, nausea and vomiting. An aspirin overdose or higher dosage than recommended can cause very serious health issues

With short-term use for specific problems, aspirin has been shown to be effective and does not present significant health risks. However, long-term use can lead to many problems.

It is one of the leading causes of gastrointestinal tract complications, including micro-bleeding and ulcers. There is also a small but very serious risk of hemorrhagic stroke.

According to a new study in the British Medical Journal, many people who regularly take aspirin still suffer from heart problems, giving birth to a new condition: aspirin resistance.

So as far as a preventative measure, you are probably much better off with a safer alternative to an aspirin blood thinner that can reduce inflammation without aspirin side effects.

Aspirin is contraindicated for use in children younger than age 18 with viral syndromes because of an increased risk of Reye’s Syndrome.Especially when used in high doses aspirin causes tinnitus, or ringing in the ears. Irreversible ototoxicity can be an aspirin side effect. The common aspirin side effects related to the anti-platelet effect include bruising and bleeding. Gastrointestinal aspirin side effect symptoms include dyspepsia, nausea, vomiting, constipation, diarrhea and abdominal pain. Aspirin can also lead to reduced excretion of uric acid and hyperuricemia. Dizziness is also common, likely related to the ototoxicity.

Unusual Aspirin Side Effects: Tinnitis is among the more unusual and yet common aspirin side effects. Nasal polyps can be caused by aspirin allergy as another unusual aspirin allergy

Pregnancy and Lactation Class: Aspirin is category D in pregnancy, meaning there is a possible risk shown to fetus with aspirin use. Aspirin is considered possibly unsafe for use in lactation.

Dear colleagues,

Aspirin as an anti-inflammatory agent inhibits cyclooxygenases and may induce apoptosis. Aspirin affects the mu-type calpain gene. Recent gene mediates the anticancer effect.

Hi Dear ,

Aspirin (acetylsalicylic acid) is an aromatic compound containing both a carboxylic acid functional group and an ester functional group. Aspirin is a weak acid that is only slightly soluble in water. Aspirin (acetylsalicylic acid) contains three groups: carboxylic acid functional group (R-COOH) ester functional group (R-O-CO-R') aromatic group (benzene ring) .

Plant-derived anticancer agents also have same functional group (R-COOH) ester functional group (R-O-CO-R')

http://www.bdjpharmacol.com/journalbdps0102/2006010235.pdf

Is it any role if Aspirin to down-regulate the over expression certain genes in Cancer..?

Inhibition of the β-catenin/TCF signaling pathway in glioma cells is also reported as an anticancer role of aspirin.

we have to look first what kinds of cancers were supressed by aspirin and then look in to molecular mechanisms which generate these types of cancers let us read more and check what kind of trials have reached at above conclusion that aspirin supresses cancer, Till the time there is real evidence we can not reach at any conclusions, it will remain at best guess work. When one is learning a new language one starts with alphabet, so in case of aspirin's effectivity in cancer supression we will have to first read how does aspirin act and where does it act in cellular molecular mechanisms , what are those factors in CANCERS ( rather a broad term , I dont think any body believes that cancers as such are a single entity with a single etiology) which were supressed.

Inhibition of the β-catenin/TCF signaling pathway in glioma cells is also reported as an anticancer role of aspirin.

it is right but only for some specific type not for the all .it has a some functional group like anti cancer agent so its work like that not for all thing

The role of Aspirin in inhibiting inflammation agents is not well understood yet, it needs more research, it may be the way it acts as anticancer.

Cancer is linked to inflammation in many cancers. The microenvironment was hypothesized to contribute to tumor progression via multistep process in which massive inflammatory angiogenic reactions represent the first step. Asprin as an anti-inflammatory drug is more likely to have a preventive role in cancer development via its effect on COX and TLR pathways.

It is becoming evident that some NSAIDs other than aspirin (Sulindac for example) have the same preventive action, most probably through the COX inhibition.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562783/

Http://www.jbc.org/content/281/39/29228.full

Basically it blocks beta catenin/lef1 complex formation in which is an active component in many cancers. given that its anti inflammatory role, it can also act by oxidative stress inducer leading to apoptosis or even necroptosis.

Aspirin can enhance the doxorubicin-induced apoptosis. It diminishes the growth of tumor.

As aspirin may act as a chemo-preventive. Asprin as an anti-inflammatory drug may be preventive in cancer control.

Recently, the chemopreventive property of aspirin, independent of its COX inhibition effect, was noticed. This pathway has cleared the new aims and facilities for cancer therapy. Aspirin reduces the microsatellite instability in colorectal cancer cells. It may alter the expression of DNA mismatch repair (MMR) proteins.

Aspirin gives stomach problems. Natural components e.g. mangosteen is the solution. Much info on pubmed for cancer research.

Http://her2support.org/vbulletin/showthread.php?t=41755

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824519/

Http://jnci.oxfordjournals.org/content/94/4/252.full

Http://www.jbc.org/content/281/39/29228.full

Lactic acidosis was seen in chronic consuming mangosteen juice. This problem may be related to the interaction of this supplement with other drugs.

It is AMPK and AMP signaling effects. See: http://www.dundee.ac.uk/pressreleases/2012/april12/ancientmedicine.htm

Cancer terapy by aspirin looks to be interesting

Here are papers regarding aspirin and metformin effects on AMPK (same is true for exercise) and cancer prevention:

Fay JR, Steele V, Crowell JA. Energy homeostasis and cancer prevention: the AMP-activated protein kinase. Cancer Prev Res (Phila). 2009 Apr;2(4):301-9.

Banko MR et al., Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis. Mol Cell. 2011 Dec 23;44(6):878-92. Epub 2011 Dec 1.

Song CW et al., Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362. Epub 2012 Apr 12.

Low-dose aspirin can not be useful for colorectal cancer prevention. Its high-dose is necessary. Therefore, consideration of following digestive complication is choice and Unfortunately, it is a paradox.

Asprin can be used for esophageal cancer

Its correct, but resolving this paradox is interesting.

http://www.nature.com/nrclinonc/journal/v9/n5/full/nrclinonc.2011.199.html | Nature Reviews Clinical Oncology 9, 259-267 (May 2012)

This is a recent publication on cancer prevention by aspirin and may be of interest.

Altered coagulation is detected in 50% of cancer patients and in 90% of those with metastases. Systemic inflammation leads to the activation of the coagulation system and these proinflammatory cytokines down regulate important anticoagulant pathways. Tissue factor is the main activator of this coagulation pathway which leads to thrombin formation and can be induced by inflammation. Tissue factor then contributes to tumour growth, angiogenesis, metastasis and thrombosis. Certain oncogenic activities in cancer cells such as expression of EGFR, PTEN, or P53 also increase tissue factor. Diet and lifestyle which does not include ASA use is of course the first preventative approach and poor nutrition and toxic lifestyle is indeed often the main cause of gene expression. A few alternatives and or integrative approaches to aspirin therapy, which in some cases may need to be used initially, are omega 3, curcurmin, bromelain, grapeseed extract, nattokinase, quercetin, resveratrol and supporting endothelial function and strengthening matrix with lysine, proline, vitamin C and EGCG.

Ty kathleen and didier plz tell if there any animal studies or toxicity/ safety /efficacy studies with the drug or is it still in the realm of theorization????

Dear Nina,

Aspirin as being used since a lot of years for different pathologies (probably also in Antic time because found in some plants in a natural form) , with three mains effects: anti-inflammatory, against fever and anti-agregant (platelet effect); mainly, as already said, by effects on eicosanoid synthesis. Eicosanoid (ie prostaglandine (PG), leukotrienes ...) are secreted and used as intercellular messengers at at short distance, by contrats to hormones which can act on other cells at distance, by blood.

So, in litterature you can find all experimental, animals and human study demonstrating its use in different pathology ( my descriptions was based on these general knowledges found in litteratue).

In the past, against fever was its main utilisation (as quinin in some country, treating malaria), then as inti-inflammatory drug (rhumatism), more recently in cardiovascular diseases (acute myocardial infarction AMI), as prevention for seconday accident.

As for a lot of drug, and before for natural products from plants, observation conduts to a description of drug effects; then with arival of molecular biology and genetic, we could also explain their mechanism (prostaglandin discover; ; then cloning of the different cyclo-oxygenase COX genes). And these discoveries allows us to understand probable effects in other pathologies as cancer.

By counterpart, power effects lead always to correspondant side effects by the same mechanisms , but on other body system (bleeding= aggregation, first step of coagulation; stopmach pains and bleeding by ihnibition stomach PGE1, protective for stomach epithelial cells).

So, William gave you some refrences, and you can find wide studies in human treatment study, ie and even if it's an old one, when where discovered new treatment for AMI prevention similar to aspirin: ticlopidine, clopidogrel (platelet ADP receptor inhibitors). And you have the CAPRIE study wich compared prevention of infacrtus recidivism, inferior leg arteritism and cerebral vascular thrombosis. And in parallele, and necessary for pharmaceutical industries to pursue drug development and to obtain authorisation for commercialisation, comparison of side effects.

Best regards

Didier J

The link: http://www.clinicar.ca/etude.php?q=19

Great, thanks for all your interesting answers and point of views. Very helpful. Maybe great to test aspirin on cancer stem cells, what do you think?

I think yes; especially if you are able, in case of a visible effect, to analyse mechanisms at a molecular level.

Best wishes for that.

Regards

Didier J

Yes; of course: salicylate or acetyl salicylic acid.

In general, salts are more "physiological" for cells; and also different forms have to be studied in case of internalisation needed for action.

Regards

thanks farrid my point of view exactly - need to test it specifically on different forms of neoplastic disorder, as there is wide variety of these all earlier studies which were carried out in other contexts may not have tested the drug specifically for molecular mechanisms of its action on cancer cells. @ Didier Yes what u have written is correct and well studied but all these effects of aspirin were studied as an antii - inflammatory drug, for its properties (that is how it effected cells to produce anti inflammatory and analgesic and anti aggregation effects at a molecular level In normal cells / inflammatory conditions etc) most of the work was done on its effect on platelet and its aggregation, a cell without nucleus. We must specifically test it on cancer cell lines of different types and also then think of studying it in more details as a chemotherapeutic agent.

I am sorry if am sounding as a skeptic but some body has to present a contrary view.

great discussion

thanks all

I agree Nina for the future studies on aspirin and others cellular effetcs than those already known.

And it can lead to new indications in cancer, as it has been the case for others drugs (ie arsenic and thalidomide in leukemia and myelodysplastic syndrom).

Didier

Aspirin is not only an anti-inflammatory drug, but also a chemical chaperone. According to this opinion, this natural substance can be able to change the abnormalities which are related to both inflammation and structure-function of protein. This scenario would be happen in cancer and investigation with recent approach will be useful for application of aspirin in cancer.

I just know that Aspirin is an analgesic, anti-pyretic and anti-inflammatory drug. Aspirin inhibits the enzymes like cyclooxygenase (Cox), and there is a significant body of epidemiological evidence showing that regular aspirin use is associated with a decreased incidence of developing cancer. It also influences cellular processes such as apoptosis and angiogenesis.

James E. Trosko, Ph.D., Michigan State University

Given that inflammation plays a role in many chronic diseases, including the multi-stage, multi-mechanism process of carcinogenesis[ “initiation, promotion, & progression phases”] and the inflammatory endogenous ( cytokines) and exogenous (phorbol ester) compounds affect the promotion phase by inhibiting gap junctional intercelluar communication (GJIC) , aspirin, as an anti-inflammatory agent, probably affects promoting afgents from inhibiting GJIC. See my many articles on this topic, including: Trosko, J.E., and Tai, M.H., “Adult stem cell theory of the multi-stage, multi- mechanism theory of carcinogenesis: Role of inflammation on the promotion of initiated cells”. In: Infections and Inflammation: Impacts on Oncogenesis, T. Dittmar, K.S. Zaenker, and A. Schmidt, eds., S. Karger AG, Publisher, Contributions to Microbiology , Vol. 13 Infection and Inflammation: Impacts on Oncogenesis”, pg. 45-65, 2006

.

Aspirin as a chemical chaperone may affect on proteins involved in cancer cells' membrane.

Chronic inflammation has been linked to colon carcinogenesis in mice (Meira et al., Journal of Clinical Inivestigation, 2008), vis-a-vis inducing DNA damage. The anti-inflammatory properties of aspirin may help prevent this.

I think the anti-inflammatory properties of aspirin must be interpreted according to its chaperone character. In addition to aspirin activity and its effect on COX pathway, the folding of some proteins involved in inflammation may be protected by it.

I like the comments of Mr.James E. Trosko, Ph.D., Michigan State University,which is very informative.

DEAR COLEAGUES

The following paper will give to you a clue (or insights?) for the molecular mechanisms of aspirin as anti-cancer agent:

Yin MJ, Yamamoto Y, Gaynor RB.The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998 Nov 5;396(6706):77-80.

Abstract

NF-kappaB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-kappaB is sequestered in the cytoplasm by inhibitory proteins, I(kappa)B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I(kappa)B, leading to its degradation and translocation of NF-kappaB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-alpha or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response

Please see recent paper of salicylates and AMPK activation

We found that NSAIDs, including aspirin, inhibit Ras signaling. As we know, Ras is an important protein in cancer biology. Mutation in Ras proteins is one of the most common genetic alterations found in human cancers and is found in ~20% of all mammalian tumors, with particularly high frequency in pancreas (90%), thyroid (55-60%), colon (45%), seminoma (45%) and non-small-cell lung (35%) cancers (Downward, Nature Reviews, 2003). Of these cancers, lung and colon cancer are the first and second leading cause of cancer-related death in the US, respectively (Jemal, et al. CA Cancer J. Clin. 2010). The C-terminal hypervariable regions (HVR, ~20% homology) of the otherwise highly homologous Ras proteins are posttranslationally prenylated and guide the proteins to highly dynamic and spatially segregated lipid assemblies within the inner leaflet of the plasma membrane, termed nanoclusters (Prior, et al. Journal of Cell Biology, 2003). This lateral segregation within the plasma membrane is absolutely essential for the signaling of Ras proteins. In a recently published study, we found that NSAIDs, which are amphiphathic and associate strongly with phospholipid membranes, stabilizes cholesterol-dependent nanoclusters, or lipid rafts, in the plasma membrane. Most Ras isoforms, such as H-ras and K-ras, preferentially segregate to the non-raft domains when bound to GTP and activated. We found that NSAIDs trap these GTP-bound and activated Ras isoforms in lipid rafts and thus prevent the binding of downstream effectors, such as Raf. This action attenuates the phosphorylation and activation of Raf and MAPK signal transduction.

http://www.jbc.org.ezproxyhost.library.tmc.edu/content/287/20/16586.full

Additionally, we found that the ability of NSAIDs to inhibit Ras nanoclustering and signaling is completely independent of their COX-inhibition effects, but dependent upon their membrane partition coefficients.

Further, COX is actually located downstream of Ras signaling pathway. So NSAIDs' COX inhibition may actually be linked to their ability to inhibit Ras signaling.

Eklou-Kalonji et al mentioned that " we identified polyamine biosynthesis as a cellular target of aspirin, since the treatment of HT-29 Glc(-/+) cells with aspirin reduced the flux of L-ornithine through ornithine decarboxylase, an effect that could not be explained by an acute action of the drug on the ornithine decarboxylase catalytic activity. Since polyamine biosynthesis is strictly necessary for HT-29 cell growth, our data suggest that reduced flux through ornithine decarboxylase may participate in the antiproliferative activity of aspirin towards colonic tumoral cells. It is concluded that in HT-29 Glc(-/+) cells that are not functional for prostaglandin production, aspirin can affect cell growth, cell cycle, and polyamine biosynthesis without affecting cell membrane integrity." . Today, polyamine has been known as chemical chaperone.

The direct effect of aspirin on platelets is often ignored. Considering the high abundance of platelets in the blood, inflammation mediated by platelets would likely be a crucial component of inflammation. Aspirin acts to directly reduce platelet production, as an anti-coagulant, and thus reduces inflammation. The link of inflammation and platelets can be easily found in Pubmed.

Dear Prem Subramaniam ,

Evidently, platelets are know to partcipate in coagulation (part of clot consitution; agregation after tisue factor pathway of coagulation activation or intrinseque pathway) but if you look at its constitution in term of mediator content, and it s interce"lular relation in term of membrane receptor, you can see why their activation (and so thrombosis) can participate in inflammation (presense of IL in granules ie), and also by changing of adhesive protein expression of blood cells (leucocytes) ; so, these underlines another relation with inflammation.

That explains that in inflatmmation, you increase the risk of thrombosis.

So, a drug like aspirin acting essentially by action on eicosanoid metabolism in platelet (prostaglandins, leukotrienes, HETE and thromboxane A2) possesses an indirect action on inflammation also via platelets.

Regards

Didier JAMBOU

second slide

DJ

Sorry if the pictures don't open. So you can find them by google search, image function and key words" platelet content" and "platelet receptors and inflammation".

Regards

DJ

I liked the amount of work going on aspirin as an anti inflammatory drug with its help in anticancer therapy

Dear Farid,

in some case aspirin inhibits tumour growth via inhibition of NF-kappaB and subsequent down-regulation of CyclinD1. However this issue must be investigated for each tumour type independently.

Cheers...

Dr. Jambou:

I fully agree with your explanation, and the mechanisms you outline. I think that really concisely sets out some of the most overseen aspects of aspirin function.

Best wishes,

-Prem Subramaniam

This idea that aspirin inhibits tumor growth due to inhibition of NF-kappaB, needs to valuable references. Please present them.

Dear Hossein, here we go (just few recently published evidences):

Aspirin itself:

http://www.ncbi.nlm.nih.gov/pubmed/21745758

http://www.ncbi.nlm.nih.gov/pubmed/20397022

Aspirin-derivatives:

http://www.ncbi.nlm.nih.gov/pubmed/22209867

http://www.ncbi.nlm.nih.gov/pubmed/22100881

http://www.ncbi.nlm.nih.gov/pubmed/21645153

http://www.ncbi.nlm.nih.gov/pubmed/18174252

cheers

P.S. Please keep in mind that COX2 is a prominent target gene of NF-kappaB....

Inded, NF-kappaB is an ubiquitous transcriptionnal factor used in a lot of ways of gene activation.

Regrads

Didier J

Agree... It is especially important in cancer development and progession (positively and negatively)

see e.g.

http://www.ncbi.nlm.nih.gov/pubmed/22586649

http://www.ncbi.nlm.nih.gov/pubmed/15313403

http://www.ncbi.nlm.nih.gov/pubmed/21772280

NF-kB is located downstream of ras signaling pathway. More specifically, H- ras activates NF-kB through the PI3K and Akt pathway. NSAIDs have been shown to directly inhibit ras signaling, which also sits upstream of COX.

http://www.sciencedirect.com/science/article/pii/S007668790133046X

Correct, but the blockade of NF-kappaB is sufficient to suppress proliferation of several tumour species (this is the modus operandi for anti-cancer effects of e.g. curcumin and its derivatives). Thus, at least a combined mechanism involving both can not be excluded at the moment. Ras is not the only known oncogene... In additon, Ras activity is not always necessery to activate NF-kappaB.

Correct. However, ras is one of the major oncogenes and it's mutations have been found in 20% of all tumors. So its inhibition should play a big role in cancer prevention/treatment.

additionally, although ras may not be essential to NF-kB activation, it definitely contributes significantly to NF-kB's activity. So inhibition of ras may play parts in the down regulation of NF-kB.

http://www.jbc.org/content/272/39/24113.long

http://www.jbc.org/content/274/20/13841.abstract

http://www.neoplasia.com/pdf/manuscript/v08i11/neo06574.pdf

That`s exactly the point... Both mechanisms may be involved, either via direct inhibition of NF-kB-activity, or by modulation of the upstream Ras. However, a correlation instead of a direct influence of Ras on NF-kB can not be excluded and should be tested (in vitro) in each tumour species independently.

Best regards,

Darius

Further, when studying the blockade of NF-kB, did they also measure the activities of elements upstream of NF-kB? Or they concluded that the inhibition is through direct binding to NF-kB?

It seems that curcumin also affects Akt, in addition to NF-kB. Akt is an effector of PI3K, which sits downstream of Hras. Akt is commonly used as an indicator of Hras activity.

http://www.springerlink.com/content/18n558v11ru33516/

Curcumin also seems to target multiple pathways, including the MAPK pathway.

http://www.sciencedirect.com/science/article/pii/S0304383508001936

Dear Yong,

I just realized that you are also working on the molecular effects of indomethacin. Does it act via Ras?

P.S. Sorry for hijacking of this discussion

It's quite all right.

Yes, indomethacin also inhibits ras. We hypothesize that this is a membrane-mediated effect. Since all NSAIDs are amphiphathic and associate strongly with lipids, they can potentially alter membrane protein functions by changing membrane properties. Indeed, we found that NSAIDs can trap GTP-bound ras isoforms in lipid rafts and negatively impact ras signaling.

I think the original question does point to one pitfall in use of aspirin in cancer. Hemorrhaging. The clinical effective dose of aspirin in cancer may well step into the region of severe hemorrhaging. Of course, this is also a short coming of even current therapies. This remains one of the connundrums of cancer therapy.

Slightly off topic !! :-)

Curcumin has been shown to directly interact with NF-kB preventing the nuclear translocation (Aggarwal Lab). Thus, the influence on other pathways may be indirect. Please keep in mind that, depending on the cellular context, NF-kB can activate more than 800 target genes.

However, to my knowledge there are no reports on such interaction between aspirin and NF-kB.

Dear Yong,

thank you for this information. We recently observed that indomethacin drives human neural crest-derived stem cells towards neuronal differentiation (unpublished)... The influence on ras may explain this phenomenon (=> link between ras and cAMP levels)...

Regards,

Darius

So, as you are discussing on intracellular pathways, I can indicate to you that I have worked on myocardial infarction and cell proliferation in case of atherosclerosis.

And GAS6 protein, the product of growth arrest specific gene, has been shown to be implicated in a lot of cellular process like proliferation, differentiation, division.

Polymorphisms in this gene could be implicated in different pathology (some havingbeen demonstrated) , and also cancer.

And GAS6 protein acts via TAM receptorrs (Tyro3, Axl and Mertk), with intracellular signal via Akt and then PI3 kinase. Indirect way of cell proliferation where the intracellular pathways also conduct to PI3K and RAS.

But I don't know the effect of aspirin on GAS6 protein ? remember that aspirin is used in myocardial infarction. So, another indirect possible effect ?

Regards

Didier J

There is an excellent review on MedScape: http://www.medscape.com/viewarticle/764274?src=top10