Caffeine, VEGF and IL-8

March 2 2008 post. Thanks to Sherlock, who sent me the full study that I will be discussing today, and to a Grouppe Kurosawa mailing, I found out something that I had not previously known about coffee. As it did for yours truly, the following should put a smile on the faces of coffee drinkers. This was meant to be a simple brief discussion of a study on caffeine, but it turned into a huge time-consuming bit of research. One thing led to another…I did my best not to go overboard!
 
An Italian study (see abstract: http://tinyurl.com/3862f5) published in May 2007 in “Molecular Pharmacology” states that caffeine inhibits VEGF and IL-8 (interleukin-8) in human colon cancer cells. Specifically, it inhibits HIF-1 alpha, or “hypoxia-inducible factor alpha.” Let’s take a closer look at HIF-1 alpha before proceeding.

I read that solid tumours are unable to grow beyond a certain size because of hypoxia, which means “insufficient oxygen.” What happens is that, as tumours grow, they need more and more nutrients and oxygen. At a certain point, though. the tumour microenvironment just can’t deal with this constant demand (if I got that right…) and becomes hypoxic. Under hypoxic conditions (less than 6% oxygen, I read), HIF-1 alpha, a transcription factor, becomes activated, and it in turn activates genes, dozens of them!, that keep tumours alive and well, via angiogenesis, glucose transport and whatnot. So tumour progression goes hand in hand with the increased activity of HIF-1 alpha.

Is this bothersome transcription factor present in myeloma, I wondered for just a split second? I really didn’t need to do a search to answer that question.  But I did do a search, and, quelle surprise!, it turns out that HIF-1 alpha is involved in myeloma angiogenesis as well. See this Italian study: http://tinyurl.com/36eywf. And see also this very colourful PDF presentation prepared by an Italian team for the 10th International Myeloma Workshop (Sydney, 2005): http://tinyurl.com/ytwej8 It also shows the involvement of HIF-1 alpha in myeloma angiogenesis.

Back to the Italian study on caffeine (see abstract): “Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression.” (Wait…adenosine? Uffa, another thing to look up…) Here we go: simply put, adenosine is a natural chemical, a neurotransmitter, released by brain cells to make us sleepy. The more we stay awake, the more adenosine gets released. But I should point out that adenosine is present also in all cells of the body, and, aha!, has the function of protecting cells from damage under conditions of hypoxia.  And it protects solid tumours from the attacks of NK cells and T-lymphocytes, as can be seen in this abstract (“International Journal of Oncology,” March 2008): http://tinyurl.com/yu7o72. It seems to be involved in a lot of mischief! Well, ok, not all the time!, for instance it mediates the damage caused by strokes…

Enough. You can read more about the importance of adenosine on the Grouppe Kurosawa public blog (February 29 post): http://tinyurl.com/23fbgo. The main thing we need to know is that, when adenosine is released, HIF-1 alpha and VEGF, the very best friends of cancer cells, are activated.

I started going through the Italian caffeine study with my usual (exaggerated!) attention to detail, then I decided that that didn’t make any sense. Do we really care that much about how this all works? Naaah. The important thing is the study’s clear message (well, to me, a morning coffee drinker, at least!): DRINK COFFEE! (yes, yes, YES…!).
 
Okay, just a few points (can’t help it, sorry! ):
  1. Hypoxic tumour cells are resistant to chemotherapy and radiotherapy. Eh!
  2. Hypoxia stimulates IL-8, which is involved with cancer progression (including myeloma progression, as we know from a previous post).
  3. HIF-1 “contributes to tumor progression and metastasis.”
This, according to the authors, “is the first report examining the in vitro effect of caffeine on hypoxic cancer cells.” Their “data suggest three potential chemopreventive targets for caffeine: 1) HIF; 2) VEGF and IL-8; and 3) cell migration.” They add: “our results indicate that, in tumor colon hypoxic cells, adenosine increases VEGF promoter activity via the HIF-1 pathway and that caffeine is able to block this effect.”
 
Now, while the cancer cells studied here were not myeloma ones, there is quite a bit of common ground, as we have seen (VEGF, IL-8 etc.). So I will be interested to read future studies on this topic. In the meantime, I will enjoy my usual morning homemade cappuccino with much more gusto!
Oh, I just can’t resist adding this lovely titbit at the end. Guess what other substance inhibits HIF-1 alpha? Any ideas? Yes! CURCUMIN! (I always check…). See this abstract, published in “Oncology Reports” in 2006: http://tinyurl.com/2aooud It suggests that “curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1 alpha-mediated angiogenesis.” And a “Molecular Pharmacology” 2006 study (full text: http://tinyurl.com/27q93o) also suggests that curcumin inhibits tumour growth by targeting this transcription factor.
 
HAH! Now I have TWO good reasons to be happy today!
June 20 2008 post: an item of interest to those of us, especially women!, who drink coffee is that apparently we will live longer. Have a look at this HealthDay article: http://tinyurl.com/3kojwq Okay, you may well object that this holds true probably only for healthy folks since all the Spanish study participants were free of heart disease and cancer, but hey, every little bit counts. And besides, I will never tire of repeating this!, caffeine inhibits angiogenesis, an important tumour-feeding process.

 

Another bit of recent research shows that drinking coffee lowers your risk of developing type 2 diabetes. Good!

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