The Biology of Aspirin

This is an oldie but goodie article from GRACE's archives. Enjoy!
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There is newfound excitement in the world of cancer over the role of aspirin, thanks to a recent study in the journal Lancet on the chemopreventive effects of aspirin.  This article was published on the heels of a media frenzy surrounding the invention of a new “super aspirin” called NOSH-aspirin.   Because of all the renewed interest in a century old drug, we thought it would be a good time to revisit the biology of aspirin for those of you who may be interested.  Aspirin is one member of a drug class called non-steroidal anti-inflammatory drugs, or NSAIDs.  Aspirin is primarily used as an analgesic (pain-reliever) and an anti-inflammatory drug.  The effects of aspirin in combatting pain and inflammation arise through the ability of aspirin to inhibit the formation of a molecule called prostaglandin 2, PGE2. https://cancergrace.org/post/cox-2-inhibitor-therapy-potential-relevance-cancer-treatment

PGE2 is an important signaling molecule in your body that can cause all sorts of physiological effects from muscle contraction to pain and blood clotting.  Aspirin blocks PGE2 to relieve pain and prevent inflammation by thinning your blood, among other things.  Aspirin blocks PGE2 by directly inhibiting cells from making PGE2, a function which is normally carried out by the enzyme cyclooxygenase (COX).  There are two main forms of cycooxygenase in the body, COX-1 and COX-2.  Aspirin is capable of inhibiting both COX-1 and COX-2, depending on the dose, and it can exert a great effect in cells like blood cells because platelets can’t regenerate COX once it is rendered dysfunctional by aspirin.  This is helpful for the blood thinning functions of aspirin such as preventing stroke, but this is also where the serious bleeding side effects of aspirin are derived.  Further, PGE2 has known protective effects in the gastrointestinal tract which is why many people suffer gastrointestinal irritations with frequent aspirin use.

So what exactly does aspirin have to do with cancer?  COX-2 and PGE2 levels are increased in many solid tumor types, so I would refer you to Dr. West’s post on COX-2 inhibitors for more information on the rationale behind targeting COX-2 in the treatment of cancer.  Aspirin will inhibit COX-2 at high doses and the most active metabolite of aspirin (salicylate) is preferentially a COX-2 inhibitor.  While aspirin and other COX-2 inhibitors can reduce PGE2 levels through COX-2 inhibition, aspirin inhibits COX-2 in such a way that it drives the formation of an anti-tumor molecule called aspirin-triggered lipoxin, or ATL. Forcing the generation of ATL by COX-2 is a unique function of aspirin compared to other NSAIDs based on the unique way that aspirin switches the function of COX-2 rather than inhibiting it completely.  The formation of ATL may also account for some of the antitumor effects of aspirin.

Aspirin exerts special anti-tumor effects specifically in the gastrointestinal tract, making it ideal for chemoprevention in people who are susceptible to colon cancer.  For example, many colon cancers arise through mutation of the adenomatous polyposis coli (APC) tumor suppressor gene.  This gene, when mutated, can activate an oncogenic signaling pathway called  b-catenin/Wnt.  Inhibiting PGE2 can work to suppress the b-catenin/Wnt pathway and provide an extra benefit in colon cells with mutated APC.  Aspirin can also activate a protein involved in the regulation of the cell cycle, NFkB.  Interestingly, aspirin can only activate NFkB in certain cell types including colorectal cancer cells.

Aside from these functions, aspirin can also activate other anti-tumor signaling molecules such as NSAID-activated gene 1, NAG-1.  The exact role of NAG-1 in the cell is still unknown, but it is thought that NAG-1 may suppress COX-2 expression thereby contributing to the chemopreventive effects of aspirin.  Additionally, aspirin can inhibit the affect of some carcinogens by reducing the peroxidase activity of certain enzymes in the cell which can reduce the amount of damaging free radicals in the cell.  Aspirin can also indirectly inhibit other signaling molecules such as sphingosine-1-phosphate, which is known to have many cellular functions like metastasis, angiogenesis, and promoting drug resistance.  Aspirin has still other effects that are known to us in the cell that are simply too numerous to list here. 

Aspirin is clearly working on many known pathways in the cell and has some very definite anti-cancer properties.  However, I hope to have disseminated that the effects of aspirin are highly complex, and likely some still eluding doctors and scientists somewhat.  Therefore, it is always best to consult with your doctor before you consider starting an aspirin-containing regimen to be sure that it will not put you at risk for any complications based on your current health situation

 

7 Responses to The Biology of Aspirin

 
 
  •  
    certain spring says:

    Many thanks for this, Dr Quesnelle.
    May I ask your view of the work recently published in the Lancet by Peter Rothwell from Oxford University? He was suggesting that daily aspirin could not just help prevent cancer in the first place, but also prevent distant metastasis in patients who already have cancer. I am not competent to understand the research properly, but wondered if you find it convincing?
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60209-8/fulltext

     
     
     
  •  
    Dr Quesnelle says:

    Hi CS,

    I do find the research convincing and here’s why on the molecular level: over time, inhibiting COX-1 and COX-2 can change the levels of other prostaglandins and thromboxanes in your body to to compensate for the loss of PGE2. These are good changes to have happen in your body regardless of whether you already have cancer or not. They actually mimic taking fish oil supplements. I think that taking aspirin over a period of years can be beneficial in preventing cancer or its metastasis.

    The string of publications put out by Dr. Rothwell and his colleauges this week, of which you have pointed to one, show this by examining a large number of studies (this is called a meta-analysis) to provide a collectively very large data set. Large data sets and a robust algortihm are the key to getting people to believe your data, and they have both here. They show that taking aspirin results in reduced instance of cancer and distant metastasis, but not local spread of the disease. Importantly, they show that this seems to be most specific to adenocarcinoma metastases. They also show that the benefit of reducing cancer is initially outweighed by the increase in incidence of major bleeding, an important thing to remember before you start taking aspirin at home. They suggest that a low-dose, extended release aspirin is as effective as taking aspirin at higher doses.

    So yes, I find it convincing. However, do I pop an aspirin at home every day? No. I try to incorporate good fats in my diet instead because I think that does the same thing over time and won’t give me the increased risk of bleeding.

    Hope that helps,

    Kelly

     
     
     
  •  
    certain spring says:

    That’s really interesting – thank you Dr Quesnelle.

     
     
     
  •  
    ssflxl says:

    Dr. Quesnelle,

    thanks for this in-depth explanation. I think I read an article (maybe a bias one from some pharma company) that they have made a “super Aspirin” for chemotherapy. Have you heard about this?

    thanks

    ssflxl

     
     
     
  •  
    Dr Quesnelle says:

    I am guessing that you are referring to NOSH-aspirin. I discussed this with Dr. West in a thread a month back:

    While it sounds promising, it’s important to note that this work has been done mainly by one group, and only in laboratory animals. There have not been any published trials in humans. The idea behind the NOSH-aspirin is that scientists have added two extra molecules on the standard aspirin. One of the molecules protects your GI tract from the negative effects of daily aspiring use (excessive bleeding, GI distress) and the other molecule may have some additional anti-cancer benefits. I’m hoping this compound will turn out to be as effective as it seems!

    Best,

    Kelly

     
     
     
  •  
    ssflxl says:

    Dr. Quesnelle,

    Yes, that’s the one. What about other NSAID? Meloxicam has COX 1 along with mild COX 2 activity, and Celebrex is being tested in some trials too.

    thanks

    ssflxl

     
     
     
  •  
    Dr Quesnelle says:

    These inhibitors would work in much the same way as aspirin, keeping in mind that aspirin can also have some additional effects that are not carried out through the inhibition of COX-1 or COX-2. Celebrex is currently in many trials for cancer. I don’t believe that meloxicam is currently being tried as a cancer therapy in the U.S.

     
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