Aspirin, Salicylate, and Cancer

Following are some thoughts on aspirin, salicylate, and cancer.

Executive Summary:

  • Aspirin prevents cancer
  • Aspirin has two modes of action, due to acetylation and salicylate
  • Salicylate prevents cancer through iron chelation and AMPK activation
  • Willow bark contains a high amount of salicylate
  • Polyphenols in willow might be important
  • Salicylate may prevent cancer without the side effect of bleeding

Aspirin prevents cancer

Aspirin is well known to prevent cancer. A number of epidemiological studies, as well as randomized controlled trials have found that people who take aspirin, and especially those who’ve taken it longer than 5 years, have much lower cancer rates.

How much lower?

In randomized controlled trials, the biggest decrease was in cancers of the gastrointestinal tract, which were 54% lower after 5 years of aspirin use; with 7.5 years of use, 20-year gastrointestinal cancer rate was 59% lower. (Note: this is a bit confusing; what it means is that someone who used aspirin for 7.5 years benefited over 20 years, even though they didn’t necessarily take aspirin the entire time, i.e. aspirin decreases cancer even after you stop taking it.)

For all cancers, the decrease in risk was 34% with 5 years of aspirin use.

Why does aspirin decrease cancer? Lots of ideas have been floated, perhaps the most popular being that aspirin inhibits the enzymes COX-1 and COX-2 (cyclooxygenase 1 and 2), which is involved in inflammation and pain. Another possible mechanism is that aspirin lowers levels of iron, such that people who take it for years have substantially lower body iron stores.

To understand how aspirin might protect against cancer, we need to know something about its pharmacology.

Pharmacology of aspirin

Chemically, aspirin is acetylsalicylic acid, hence it’s often referred to as ASA. When aspirin is ingested, enzymes rapidly remove the acetyl group, leaving salicylate and acetate.

 

Image result for aspirin metabolism

 

The acetyl group then attaches to COX-1, the dominant COX enzyme in blood platelets, disabling them. Platelets are responsible for forming clots after a bleeding episode.

One low-dose aspirin tablet irreversibly disables platelets, because the platelets are unable to synthesize new enzymes. The inhibition of platelet function is antagonized by newly formed platelets, which enter the circulation at the rate of 10 to 15% daily. (Hence platelets turn over every 7 to 10 days.) A loading dose of one regular dose (325 mg) aspirin disables platelets faster, which is why a regular size aspirin is used when a patient is having a heart attack. The arrival of new platelets daily means that, in order to maintain an optimal anticlotting effect, aspirin must be taken daily.

So, after the acetyl group is jettisoned, salicylate remains, and this molecule is also active. The active ingredient of willow bark, from which aspirin was originally derived, is salicin, and when ingested, salicin becomes salicylate, the active drug. Taking salicin or salicylate does not cause an anti-clotting effect; salicylate is responsible for the effect of diminishing pain and inflammation.

Back to cancer. It turns out that salicylate activates AMPK, the master metabolic switch that increases mitochondrial biogenesis and fat-burning. This makes salicylate similar to exercise and calorie restriction as well as resveratrol and berberine. Both cancer and atherosclerosis may be inhibited by activating AMPK. Oddly, the protective effect of aspirin against coronary artery disease may be due partly to this mechanism of salicylate, and not entirely because of the anticlotting effect of the acetylation of COX-1 in platelets.

Both aspirin and salicylate inhibit colon cancer cells in vitro. Salicylate also inhibits pancreatic cancer cells and breast cancer cells.

Both aspirin and salicylate inhibit UV-B radiation-induced skin cancer in mice.

While the acetyl group of aspirin isn’t necessary to provoke cell cycle arrest and apoptosis (cell suicide) of cancer cells, platelets themselves may have a great deal to do with the progression of cancer. That means that aspirin could have two separate ways of preventing cancer, through the action of salicylates and by inhibiting platelet aggregation.

Salicylates activate AMPK only at relatively high doses, higher than could be expected through a daily low-dose (81 mg) aspirin.

Salicylate chelates iron

Interactions with iron may explain much of the anti-cancer effect of both aspirin and salicylate. Aspirin can result in lower iron levels either through direct iron chelation or the promotion of largely invisible intestinal microbleeding. Aspirin users typically lose small amounts of blood, perhaps on the order of 1 ml, daily, and that adds up over time and depletes iron stores.

Aspirin’s iron-chelating action stems from the salicylate moiety. Salicylate is such a powerful iron chelator – it binds and removes iron – that several species of bacteria make salicylate to use as a siderophore, a molecule that complexes with iron in the host or elsewhere in the environment and makes it available for bacterial growth. Iron is the limiting element for most pathogenic bacteria, and bacteria and their hosts battled each other in an evolutionary arms race for iron.

Willow bark, which is rich in salicylate (salicin), has anti-cancer properties; it suppresses growth and induces apoptosis in human lung and colon cancer cells. Willow bark is also rich in polyphenols and these appear to contribute to its painkilling and anti-inflammatory effects. Aspirin, at physiologically relevant doses, kills cancer cells by causing pro-oxidation reactions in mitochondria, and this does not affect normal cells with normal mitochondria. Aspirin and/or salicylate possibly could, from this viewpoint, be used in the metabolic therapy of cancer.

Willow bark has been known and used as a drug for thousands of years. Hippocrates himself recommended it.

An extract of willow bark was recently found to be the most potent plant extract in the extension of lifespan in yeast. While yeast may not be the most relevant model of lifespan extension, they’re commonly used in aging research and many substances and interventions that prolong their lives also prolong the lives of mammals.

Whether the polyphenols or the salicylate in willow bark are responsible for the lifespan effect in yeast is not known, but I suspect that both are involved. Aspirin extends lifespan in a number of models, including mice, but the results are not so spectacular that they make aspirin the most potent life-extension molecule. Salicylate, on the other hand, perhaps along with the phytochemicals in willow bark, just might be among the most powerful.

Salicylate appears to offer many of the anti-cancer and anti-aging properties of aspirin without as many side effects, mainly the tendency to bleed when that’s not wanted. However, at least some of the protective effect of aspirin against heart disease is necessarily entwined with the bleeding tendency, since inhibition platelet function both increases the risk of bleeding and prevents clots from forming in arteries. Aspirin has another mode of protection against atherosclerosis though, and that’s the ability of salicylate to chelate iron and lower body iron stores. The first, anti-platelet, mode works quickly, which is why aspirin taken by people having a heart attack; the second, iron-chelation mode is longer term, over a period of months to years if low-dose aspirin is used.

Just to be clear, I’m not recommending anything, whether aspirin, salicylate, or willow bark. Apparently some people (especially over on Twitter) think you’re not supposed to talk about this stuff, or if you do, you’re making some kind of recommendation. I’m just spreading the knowledge, my friends.

PS: To learn how you can live longer, you might want to invest a couple (OK, more than a couple) bucks in my book, Stop the Clock: The Optimal Anti-Aging Strategy.

PPS: Check out my Supplements Buying Guide for Men.

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Leave a Comment:

41 comments
Al Becker says March 31, 2017

Very interesting and informative — as are so many of your articles. Thanks

Reply
    P. D. Mangan says March 31, 2017

    Thank you, Al.

    Reply
Bill says March 31, 2017

Yes PD thanks for spreading this information. I am interested as the baby aspirin does I took daily for years lead to anemia. So I have stopped. But information about achieving the anti-cancer & anti-aging affects via willow bark or salicylate is very useful.

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Randall Parker says March 31, 2017

So does vinegar reduce blood clotting? It contains acetic acid…

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    P. D. Mangan says April 1, 2017

    Randall, funny about that. According to what I’ve read, the acetylation effect of aspirin is non-specific; it just acetylates anything around it that’s capable of receiving an acetyl group. So maybe vinegar would do that?

    PS: Look what I found: Improvement of Haemostasis Mediated by Anti-Platelet Activities by Plant Vinegar

    We investigated the effects of plant vinegar on platelets and blood coagulation system. Plant vinegar inhibited in vitro platelet aggregation in a concentration dependent manner, when platelets were activated by thrombin and collagen. In addition, plant vinegar showed inhibitory effects on the serotonin secretion induced by thrombin in a concentration dependent manner. However, treatment with plant vinegar to platelets did not induce any cytotoxicity, as determined by the release of lactate dehydrogenase. Plant vinegar did not change the coagulation parameters such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) using rat citrated plasma.

    Acetic acid in aged vinegar affects molecular targets for thrombus disease management

    To elucidate the mechanism underlying the action of dietary vinegar on antithrombotic activity, acetic acid, the main acidic component of dietary vinegar, was used to determine antiplatelet and fibrinolytic activity. The results revealed that acetic acid significantly inhibits adenosine diphosphate (ADP)-, collagen-, thrombin-, and arachidonic acid (AA)-induced platelet aggregation. Acetic acid (2.00 mM) reduced AA-induced platelet aggregation to approximately 36.82 ± 1.31%, and vinegar (0.12 mL L−1) reduced the platelet aggregation induced by AA to 30.25 ± 1.34%. Further studies revealed that acetic acid exerts its effects by inhibiting cyclooxygenase-1 and the formation of thromboxane-A2. Organic acids including acetic acid, formic acid, lactic acid, citric acid, and malic acid also showed fibrinolytic activity; specifically, the fibrinolytic activity of acetic acid amounted to 1.866 IU urokinase per mL. Acetic acid exerted its fibrinolytic activity by activating plasminogen during fibrin crossing, thus leading to crosslinked fibrin degradation by the activated plasmin. These results suggest that organic acids in dietary vinegar play important roles in the prevention and cure of cardiovascular diseases.

    Reply
      Randall Parker says April 5, 2017

      My pre-existing suspicion is that vinegar is beneficial. I feel especially good if I soak thin slices of cauliflower in vinegar and eat it.

      Reply
        Bill says April 6, 2017

        How does vinegar survive passing through the hydrocloric acid in the stomach?

        Surely it is completely dissolved & broken up.

        Reply
          P. D. Mangan says April 6, 2017

          No, probably not. Vinegar is 5% acetic acid, and I don’t think that stomach acids would modify it at all.

          Reply
          Bill says April 7, 2017

          Well PD traditionally I always had apple cider vinegar on ‘fish and chips’. ( not quite french ‘fries’ ). But then I eased off eating deep fried food entirely and i only have vinegar in salad dressing now.

          When I was young I remember a good friend saying how Bragg’s boasted about the benefits of Apple cider vinegar in honey & water every morning. Tasted yuk ! But maybe it’s a way to go ?

          Reply
      Bill says April 29, 2017

      Bugger ! I used to love eating baked wedges with lots of organic cider vinegar. Delicious ! And so much healthier than tomato sauce – Ketchup to Americans.

      But since switching to a low carb diet I stopped eating wedges and now hardly take any vinegar except in salad dressings. So maybe some wedges occasionally with apple cider vinegar is the go, especially with Winter coming on ! :- )

      Reply
Montgomery says March 31, 2017

I was under the impression that ASS is metabolized to salicylic acid anyway – so free salicylate should be available systemically by just taking ASS – no need to eat salicylic acid.

Actually, the latter is causing trouble to many people, producing stomach irritation.
ASS was specifically invented to give the advantages of the salicylic acid without causing that problem – ASS
is not irritating to the stomach to most people.

Reply
Montgomery says March 31, 2017

https://en.wikipedia.org/wiki/History_of_aspirin

“However, the unpleasant side effects, particularly gastric irritation, limited their usefulness,[2]:46–55 as did their intense bitterness.”

“In 1897, Hoffmann started working to find a less irritating substitute for salicylic acid. It is generally accepted that he turned to this idea because his father was suffering the side effects of taking sodium salicylate for rheumatism.”

I wonder how the serum level of salicylate is comparing a given dose of salicylic acid or the mol-equivalent of ASS.
If the bodie’s metabolism just snaps off the acetyl group and releases the salicylate, both should be equal?

Reply
    P. D. Mangan says April 1, 2017

    Yes, molar concentration of AAS and salicylate relate to each other 1:1. As for stomach irritation, while I realize aspirin was invented in part to overcome this, a dose of salicylate for “rheumatism” is very high, several grams daily.

    Reply
Aspirin, Salicylate, and Cancer says March 31, 2017

[…] post Aspirin, Salicylate, and Cancer appeared first on Rogue Health and […]

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    Bill says April 1, 2017

    Wow that link is really interesting Peter. I don’t take aspirin because it causes intestinal bleeding and anemia.

    But it looks like I am getting a good high dose of salicylates from my food : olive oil, macadamias, coconut oil, and lots of the fruit & vegetables that I already eat.. Makes sense that lots of plants, not just willows should produce salicylates, as toxin to deter predation..But then we have also evolved resistance to the toxin.. Interesting !

    Reply
Frank Liu says April 1, 2017

Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement.
http://annals.org/aim/article/2513179/aspirin-use-primary-prevention-cardiovascular-disease-colorectal-cancer-u-s

https://www.ncbi.nlm.nih.gov/pubmed/27064677

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    P. D. Mangan says April 1, 2017

    Thanks, Frank.

    Reply
Brandon says April 1, 2017

I read an article a few years ago about the oldest man in the world crediting his longevity to Anacin, a combination of aspirin and caffeine. I looked up the article again and apparently he was taking 6 a day which equals 2400mg of aspirin and 186mg of caffeine.

http://nypost.com/2013/07/26/upstater-oldest-man/

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    P. D. Mangan says April 1, 2017

    Thanks for reminding us, Brandon, I definitely recall him. “Shorty”.

    Reply
MickD says April 1, 2017

Mangan–did you come across anything in research weight benefits of aspirin vs risk of GI bleeds/ulcers?

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    P. D. Mangan says April 1, 2017

    Yes, risks need to be weighed against benefits.

    Reply
Herman Rutner says April 1, 2017

As an organic chemist familiar with the chemistry and medical applications of both aspirin and salicylate. Aspirin has a reactive acetyl group that rapidly reacts with amino groups on platelets in the blood stream and reduces the damage to cardiac tissue in heart attacks. The quickest way to get it is to the heart is to take at least five 81 mg chewable baby aspirin as sodium aspirin which will disperse in stomach contents and quickly get absorbed into the blood stream. In contrast regular aspirin each about 360 mg is not soluble in stomach acid.and may sit there for about 2 hrs before gastric emptying. Worse yet it may contact the delicate gastric mucosa and being mucolytic can dissolve the mucosa make a hole causing bleeding.by “tablet kiss” with the aspirin tablet visible in the hole.

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    Herman Rutner says April 1, 2017

    My prior comment was accidentally sent incomplete and without editing from my temperamental iPad.
    Further comments: And even worse after a heart attack is taking enteric coated aspirin, as foolishly recommended by Bayer and others, which dissolves only after reaching the alkaline intestinal medium needed to release and solubilize the aspirin.
    Re gastric or intestinal bleeding requiring localized mucolysis it appears highly unlike to me that it would occur even with 10 chewed baby aspirin that would convert to insoluble aspirin in the gastric acidity, at worst causing transient irritation of the stomach lining. Dispersed aspirin from baby aspirin would be more rapidly absorbed into the blood stream than a regular slowly disintegrating aspirin tablet, obviously a critical factor in reducing damage from heart attacks. But 10 baby aspirins contain about 100 mg sodium.

    Reply
      Bill says April 1, 2017

      Herman, I am interested in your comments as I have a history of having gastro-intestining bleeding when I take regular aspirin. I use to break the regular 300 “Aspro Clear” adult dose tablet up into quarters and take a quarter a day dissolved in water.

      However you seem to be suggesting that “chewable baby aspirin as sodium aspirin” will not cause bleeding. This is good news. But could you confirm that this is what you meant ?

      Reply
        P. D. Mangan says April 2, 2017

        Enteric-coated aspirin is safer for the stomach, but there’s no way around the bleeding problem, since that’s caused by the action on platelets, not on the stomach.

        As for 325 mg vs low-dose aspirin for heart attack, the solution is to chew the large aspirin.

        Reply
          Bill says April 2, 2017

          Thanks for the clarification PD.

          Reply
        Herman Rutner says April 2, 2017

        Hi Bill, from my chemical knowledge. of mucolytics like aspirin and the observed aspirin tablets embedded inside gastric ulcer cavities I disagree with conventional medical l wisdom that all types of aspirin cause gastric or intestinal bleeding, especially if taken as baby aspirins. I believe it is exclusively conventional aspirin tablets. But as mentioned by PD, platelet inactivation from repeated high dosing with aspirin may contribute to systemic bleeding. This should not occur with routine daily use of the minimum effective aspirin daily dose of 20 mg or 1/4 or better 1/2 baby aspirin.
        PS aspirin is not an iron chelator since it requires the free OH group in salicylic acid which forms a strong red iron Fe3 chelate but not with reduced Fe2. Note also that salicylic acid is a keratolytic, as used in wart removal, that is far more corrosive than a mucolytic. Hence taking salicylate as in old time Doan’s Magnesium salicylate tablets is more corrosive in the stomach where it forms free salicylic acid. Also aspirin slowly hydrolyzes to salicylate in water, faster at higher pH like about 7 in intestines.

        Reply
          Bill says April 3, 2017

          Herman, thanks for this comment. It provides some new insight into my own situation vis a vis aspirin. Previously I was using about roughly 75 mg a day significantly more than you suggest.

          Again thanks !

          Reply
Carole says April 2, 2017

So . . . if you don’t mind revealing: How much aspirin and what kind do you take each day? Thanks.

Reply
    P. D. Mangan says April 2, 2017

    Hi Carole – I take a low-dose (81 mg), enteric-coated aspirin about 5 days a week. I don’t mind telling what I take, but I can’t make recommendations for others due to aspirin’s potential adverse side effects.

    Reply
brbr says April 4, 2017

Hi P.D, just bought aspirin prevent 100mg (enteric coated) and i learned this this medicine is for people who got a heart stroke and now i’m wondering if i bought the wrong kind of aspirin… Would appreciate if you could help me with this, is it the same thing as taking aspirin for headache or something?

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    P. D. Mangan says April 4, 2017

    Enteric-coated aspirin helps protect the stomach lining against mucosal injury. Generally, doses of aspirin for pain relief (like a headache) are larger, from 325 to 650 mg.

    Reply
      brbr says April 4, 2017

      Thanks for the answer, so i can use this medicine for the motives exposed in your post right? Cheers.

      Reply
JP says April 24, 2017

Looking at all the nasty additives associated with “coated” aspirin. It is really, really hard to find aspirin that is NOT coated. Two options:
1. Take Willow Bark Extract (which is pure) instead of aspirin
2. Take “animal” aspirin (ANIPRIN P) which doesn’t have any weird fillers

What do you think?

Reply
    P. D. Mangan says April 24, 2017

    Here’s a thought if you want non-coated aspirin: take a regular aspirin tablet and cut it into quarters; each quarter is equivalent of a low-dose aspirin. I used to do that myself.

    Reply
      JP says April 24, 2017

      Doesn’t that just get you four small pieces that are also coated?

      Reply
        P. D. Mangan says April 24, 2017

        Not if you use regular aspirin.

        Reply
          JP says April 24, 2017

          I was at CVS, Target, and the grocery store today, and there was no “regular” aspirin at all. Closest I could get still had some additives in it.

          Looking like the horse powder might be the way to go…

          Reply
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