Does an Aspirin a Day Keep Cancer Away? — #GeneOTW with PTGS2

With over 100 billion tablets produced (and consumed) yearly,1 aspirin has come a long way from its humble beginnings as the active ingredient in willow bark—a medicinal remedy used since ancient times, by the likes of Hippocrates and Pliny the Elder.  Since its first patented formulation in 1897, aspirin has been heralded as a Wonder Drug, has provided the foundation for Nobel Prize-winning research, and has even played a part in a WWI conspiracy involving Thomas Edison!

 

A pre-1904 Bayer advertisement, promoting Aspirin, Lycetol, Salophen, and Heroin. (Yes, that’s right—heroin. As a cough suppressant. And a “non-addictive morphine substitute”…)

More recently, aspirin has re-entered the scientific spotlight as a potential preventive treatment against colorectal cancer.  But first, to understand how aspirin might mediate this effect, there’s another key biological component to introduce—PTGS2.

PTGS2 (Prostaglandin-Endoperoxidase Synthase 2) is an enzyme responsible for production of prostaglandins; synthesis of these compounds is stimulated in cases of trauma and stress, leading to numerous cellular processes like local inflammation and pain at sites of tissue repair.  Since aspirin (and other NSAIDs like Advil) inhibits PTGS2, its anti-inflammatory and pain-relieving properties result from suppression of prostaglandin levels.

 

3D structure of a PTGS2 dimer—after it’s been inactivated by aspirin.

Unfortunately, the same prostaglandin-induced processes that are so helpful during post-injury repair can occasionally be co-opted by some unwanted guests—tumor cells.  In fact, PTGS2 expression is increased in 86% of colorectal carcinomas, and this elevation of PTGS2 levels is associated with decreased survival of colorectal cancer.2  Besides being pro-inflammatory, prostaglandins are involved in multiple signaling pathways that happen to benefit cancer cells:3

 

Downstream Signaling Target  Function
Cyclin D1 Promotes proliferation
VEGFR Promotes angiogenesis
Bcl-2 Inhibits apoptosis 

Ultimately, abnormal over-expression of PTGS2 can result in the increased proliferation, migration, and invasion of tumor cells, along with new blood vessel growth that supplies the required nutrients for further expansion.4

Aspirin, as a PTGS2 inhibitor, is thus a natural choice to test for prevention of colorectal cancer.  Previously, randomized controlled trials have had mostly positive results, demonstrating decreased risk with aspirin treatment—though not always with statistical significance.5  A recent study, published within the past two weeks, offers an explanation for these mixed outcomes; regular aspirin use is associated with reduced risk of colorectal cancer, but only in certain populations—specifically, in individuals with normally high levels of HPGD, an enzyme that’s enriched in the colon.6

 

Crystals of acetylsalicylic acid (aspirin).

Furthermore, before you start popping pills, consider this:  long-term use of aspirin (and NSAIDs, in general) comes with other problems, including gastrointestinal bleeding and ulcers.  These unintended side effects may arise from the fact that aspirin inhibits not only PTGS2, but also a related protein, PTGS1.  Since tumor-promoting properties are generally only attributed to excessive PTGS2, pharmaceutical companies have tried creating PTGS2-specific inhibitors, in hopes of reducing these side effects:7

Drug Outcome

Vioxx

Approved by the FDA in 1999, this drug did significantly reduce risk of colorectal adenomas, but was ultimately pulled from the market in 2004, due to severe risk of heart attacks and strokes.

Celebrex

Approved by the FDA in 1998, this drug also significantly reduces risk of colorectal adenomas.  It has similar gastrointestinal and cardiovascular side effects, so Celebrex (known generically as Celecoxib) is only recommended for chemopreventive treatment in specialized cases.   

Given the importance of PTGS2 to normal body function, PTGS2-inhibitors are only recommended to patients for whom the potential benefits outweigh the dangers; for instance, Celebrex use is approved for those with Familial Adenomatous Polyposis—an inherited condition that leads to colon cancer.  Despite these limitations, PTGS2 still remains a critical topic of research focus, and the basis for future clinical therapies.  So in the end, this story is a little complicated (like much of science)… Can an aspirin a day keep cancer away?  Possibly.  But only if you don’t mind ulcers.

 

References:

  1. Aspirin Foundation. Supported by Bayer AG and Reckitt Benckiser PLC. Retrieved 01 May 2014 from http://www.aspirin-foundation.com/index.html. []
  2. Temraz S, Mukherji D, Shamseddine A. (2013) Potential targets for colorectal cancer prevention. Int J Mol Sci. 14(9):17279-303. []
  3. Temraz S, Mukherji D, Shamseddine A. (2013) Potential targets for colorectal cancer prevention. Int J Mol Sci. 14(9):17279-303. []
  4. Temraz S, Mukherji D, Shamseddine A. (2013) Potential targets for colorectal cancer prevention. Int J Mol Sci. 14(9):17279-303. []
  5. Temraz S, Mukherji D, Shamseddine A. (2013) Potential targets for colorectal cancer prevention. Int J Mol Sci. 14(9):17279-303. []
  6. Fink SP, Yamauchi M, Nishihara R, Jung S, Kuchiba A, Wu K, Cho E, Giovannucci E, Fuchs CS, Ogino S, Markowitz SD, Chan AT. (2014) Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD). Sci Transl Med. 6(233):233re2. []
  7. Temraz S, Mukherji D, Shamseddine A. (2013) Potential targets for colorectal cancer prevention. Int J Mol Sci. 14(9):17279-303. []

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  1. Why’s it gotta be so complicated? — #GeneOTW with HER2 | The Su Lab - [...] Last week, Melissa discussed the use of aspirin as a preventative measure against colorectal cancer.  While the risks may…

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