A blog reader (thanks!) sent me the link to a food-for-thought 2003 Swedish study (see http://tinyurl.com/d4qc38) on nicotinamide, a water-soluble member of the vitamin B family (specifically, the amide derivative of vitamin B3).
Now, this study doesn’t examine myeloma but is still relevant to us because it shows that nicotinamide inhibits IL-1 beta (=SMM-MM progression factor), IL-6 and TNF-alpha by, tadaaa!, 95%. I repeat, by 95%. And it also inhibits IL-8, an angiogenesis cytokine in myeloma, by 85%. This is all most intriguing.
This was an in vitro experiment, conducted on healthy human blood incubated with endotoxin, which stimulated the response of the above-mentioned cytokines. Nicotinamide, when added to the mix, inhibited all four cytokines, which is great news. The researchers conclude: As the proinflammatory cytokine response of IL-1beta, IL-6, IL-8 and TNFalpha following endotoxin stimulation of human whole blood is profoundly inhibited by nicotinamide, nicotinamide may have a therapeutic potential as a modulator of cytokine effects in inflammatory disease. Super duper!
Now, the study kept mentioning this thing called PARP…no idea what that was, so I had to look it up. The acronym stands for “polyadenosine-5′-diphosphate-ribose polymerase.” Uhm. Okay, spelling it out doesn’t help matters. Forget the acronym.
Let’s see (flip flip flip…flipping virtual pages)…ah, here we go: PARP is basically a protein linked to DNA repair, cell proliferation and apoptosis. Interesting factoid: NF-kappaB cannot be activated unless PARP is also activated, as we can see by glancing at this 1999 abstract: http://tinyurl.com/b8hmsc.
And, of course, PARP is involved, not in a good way, in myeloma. Hah!
A 2005 abstract (http://tinyurl.com/dkyk39) tells us, in fact, that the outcome of PARP cleavage is the apoptosis (=programmed cell death) of myeloma cells. PARP whaaat??? Oh, okay, simply put, PARP cleavage has nothing to do with embarrassingly low necklines but is a typical manifestation of apoptosis. Basically, anything that induces PARP cleavage in myeloma (or any type of cancer) cells is a good…anything.
So…my next step was to check out PARP cleavage and curcumin. Well, quelle surprise!, curcumin induces PARP cleavage in myeloma cells (see, e.g., the 2003 MD Anderson curcumin-myeloma study to which I link from my blog): Suppression of NF-kB by curcumin also led to apoptosis of MM cells, as indicated by activation of caspases and cleavage of PARP. So this cleavage business is one of the ways that curcumin annihilates myeloma cells. Good to know.
I took this all a bit further. Not surprisingly, parthenolide also induces PARP cleavage in myeloma cells (see: http://tinyurl.com/bdbqzj): Parthenolide rapidly induced caspase activation and cleavage of PARP […]. Capital, capital.
Other substances that induce this important cleavage process (perhaps not specifically in myeloma, though; I would need more time to check that out) are:
DHA (omega-3), see: http://tinyurl.com/d4eje2
Quercetin: http://tinyurl.com/cusjx9
Resveratrol: http://tinyurl.com/alfd25
Capsaicin: http://tinyurl.com/dn325k
Okay, enough, enough, I don’t have the time to go down the list of supplements on my blog. But anyway, wanna bet that most if not all induce PARP cleavage in some type of cancer?
As soon as I finished reading the nicotinamide study, I went downstairs and took my vitamin B supplement (a gooey but tasty liquid with other things in it, too). I take it only now and again, when I need an energy boost…but perhaps now I will begin taking it more frequently. Hey, you never know…
Quick consideration. Funny how we tend to overlook things that we don’t understand or don’t think are important. Selective memory, eh? You see, I don’t remember any mention of PARP cleavage in the MD Anderson 2003 curcumin study, a study that changed my life. Yet PARP is mentioned in that study as many as 15 times (I just counted ’em)! But all that mattered to me back then was that curcumin killed myeloma cells. How this actually occurred was not important. Now, though, after three years of research, I am a bit more interested in understanding the mechanics of these apoptotic processes. Not easy…for an unscientific mind…like mine. Oh, how I wish I had a photographic memory!
Hmmm…well, interesting, but…
The concentrations they used of nicotinamide in whole blood to get the 95% inhibition were 4-40 mmol/L. The molecular weight of nicotinamide is 122.12g so 40mmol is about 4.88g. An adult male has about 5L of blood so I’d need to actually get close to 25g of this into me to get this effect, supposing it works in vivo. Even to get the 4mmol/L I’d need to ingest about 2.5g and that wasn’t very effective except in IL-6 according to the graphs in the study.
Just a quick look at the wikipedia page (http://en.wikipedia.org/wiki/Nicotinamide), the accuracy of which I can’t vouch for, indicates that it may produce liver toxicity at doses above 3g. This may be a problem.
In looking at the paper the inibition of cytokines was dose dependendent, meaning smaller doses still had an effect. I’d note that 10mmol/L had a greatly diminished effect – except on IL-6 -and that this amont may still be above what produces liver toxicity.
I think vit. B is still great stuff. We’re learning more and more about all the vitamins we should have been taking. I’m always suprised by these studies though that do things in vitro that would possibly be lethal if you tried to duplicate them.
Chris
Thanks Chris,
Studies very rarely translate in vitro quantities into in vivo ones, so what you did is very helpful. I wish I could do that!
25 GRAMS/day? Yikes. Say no more…
Too bad, though, eh?
Margaret,
Yes, this is one of my pet peeves. Sometimes you have to look at it and question the real scientific relevance. At the same time it’s interesting to know what a substance does so at least some limited studies like this are easy to justify. It’s also possible that, like curcumin, some of these substances actually do have some effect at much lower doses, so the research has merrit.
But the other thing that ticks me off is when paper after paper gets published and it’s clearly irrelevant. The best example of this I think is Quercetin. Quercetin is a known PI-3K inhibitor which is great. It was actually the template from which the compound LY294002 was designed. You can find a paper from 1994 from Lily that describes this process. So, we know what Quercetin can do and have for a long time.
Subsequently we have hundreds of papers on Quercetin. Great. One problem: It’s been established for a long time that absolutely no unconjugated Quercetin gets into plasma. So why do people keep publishing papers on this when they could do research on the comounds we can measure – and measure at pretty high quantities instead? I don’t know. I think it’s a waste of time and money but people get papers published and that really is their goal. At least one researcher who studied the bioabailability of isoflavones stated concisely that all the research is a waste. It’s terribly unfortunate.
So, for lots of things studied, they may not do a thing. Worse, I suppose it’s possible that some conjugated form of a compound could be harmful.
Chris
There was a large scale trial to ascertain whether nicotinamide would prevent type 1 (juvenile) diabetes. The participants were given 1.2 g/m2 for 5 years but unfortunately nicotinamide did not prevent diabetes at this dosage. See: http://www.ncbi.nlm.nih.gov/pubmed/15043959
Although the participants apparently suffered no ill effects at this dose, I understand that several of the B vitimins are toxic at high dosage.
Paul