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Thursday, 30 October 2014

Statins for Cancer and Autism? Another case for PTEN?







When I first started this blog and my investigation into the biology of autism, I did shy away from the more complex areas like genetics.  I assumed that this would be best left to the “experts” and be beyond the powers of those without fancy laboratory tools.

My literature review took me early on to oxidative stress and then neuroinflammation.  I deduced that in the case of neuroinflammation, it might be possible to control inflammatory cytokines using statins.  I also noted the use of statins in TBI (Traumatic Brain Injury). I thought it would be harmless to do a quick trial, not really expecting anything to happen; but it did, and from the very first dose.

The literature is full of references to lipid dysfunction in autism and one large sub-group in autism is known to have high cholesterol.  Cholesterol and inflammation are now known to go hand in hand.  When inflammation is present, the body can react by laying down a protective layer of cholesterol.  The problem is that too much cholesterol is not good for you either.  The real culprit is not the cholesterol, it is the inflammation.

If you are in the high cholesterol autism group, a cholesterol lowering drug that is also anti-inflammatory may be “just what the doctor ordered”.

Be warned that another subgroup in autism has very low cholesterol.  In a study at the Kennedy Krieger Institute, 19% of children had extremely low cholesterol, meaning lower than 99% of typical children.


There is a rare condition, leading to autism called Smith-Lemli Opitz syndrome (SLOS).  SLOS is caused by a mutation in an enzyme involved in cholesterol synthesis; the resulting biochemical characteristics may be predictable. Most patients have lowered plasma cholesterol levels.

Since cholesterol testing is cheap and widely available, you can easily determine which group you are in.

This post is for the high cholesterol cohort.

Note well how meaningless a figure for the "average cholesterol level" in autism would be. In the autism literature they frequently take the mean average for all data, thus missing the point. 



Why Statins for Autism?

My initial logic was that since inflammatory markers are often elevated in autism and that oxidative stress and inflammation are self-reinforcing, it would be logical to find an effective anti-inflammatory agent.  Steroids might fit the bill, but they cause plenty of side effects in long term use; their short term use in autism can be remarkably effective.  So I looked further, and having screened the literature, ended up convincing myself of the potential of statins.  Read all about cytokine storms in the old posts, if you are interested.

I choose  Atorvastatin (also known as Lipitor or Sortis), since it freely crosses the blood brain barrier (BBB) and is safely used my tens of millions of people around the world.

It worked.


Explaining Statin Therapy to others.

The most important thing is to have a therapy that works;  but then you have to explain it to others.

I was recently explaining it again to a doctor relative, who was asking how I could be sure it works.  I explained that every time I stop using it, within a day behaviour changes in the same predictable way.  It is as if people with autism have an inhibitory barrier; there are things they can do, want to do, but something is blocking them from doing them.

Examples are numerous.  Speech being one.  Plenty of kids with autism are non-verbal, everything is physically functional, yet they do not talk, even when they want to communicate.

At the age Monty, now aged 11 with ASD, tried the statin he was relatively verbal.  The immediate change in him was that he suddenly started to play the piano, by himself.  Odd it may sound.

In his earlier years he would often get “stuck”.  He would be upstairs and unable to come downstairs, somebody had to go up and get him.

When I now stop the statin, he will again get “stuck”.  He will stand in the kitchen and want to leave and just say “go that way”, but not move.  You have to take his hand, so that he can “go that way”.


A Better Explanation?

Now I have another explanation of why statins may be effective in one large sub-group of autism.

Statins up-regulate a known key dysfunctional autism gene, and protein, called PTEN.  I mentioned PTEN in a previous post, since one chemical released by eating broccoli also up-regulates PTEN.

Science has already shown that things that down-regulate PTEN (like seizures) make autism worse.

The full science behind PTEN will come in a later post.


Statins and Cancer

Regular readers will recall that PTEN is also a tumor suppressor gene and is therefore a target for cancer research.

Thinking the way I do, I know that statins increase PTEN and that this should slow cancer growth.  Hundreds of millions of people take statins and many millions get cancer, so what about people on statins getting cancer?

A quick check on google and there we have studies showing that people on statins get less cancer and that in common cancers like that of the prostate, the outcome is better when statins are taken.

Now this is not a cancer blog, but you do not have to dig very deep to uncover a wealth of supporting evidence.



Conclusion
In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomized controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.






 Conclusions This meta-analysis suggests that statin is associated with a significant risk reduction of liver cancer when taken daily for cardiovascular event prevention. However, this preventive effect might be overestimated due to the exposure period, the indication and contraindication of statins and other confounders. Statins might be considered as an adjuvant in the treatment of liver cancer.


Statins and PTEN

I am no cancer expert, but I can read the literature and the evidence is pretty compelling to me.  It is not enough, however, for doctors to prescribe statins to avoid cancer.  They are so busy prescribing statins to over 50s for other reasons, it does not really matter.

We came across PPAR previously.  PPAR gamma is a pathway to treat type 2 diabetes and the old type 2 diabetes drug Pioglitazone has shown promise in an autism study.



 Effect of pioglitazone treatment on behavioral symptoms in autistic children

At that time I was more interested in PPAR-alpha, due to its role in mast cell stabilization.

It is via PPAR-gamma, that statins up regulate PTEN.

You do not want to overdo it, because at very high doses too much PPAR gamma protein will be produced and you risk causing type 2 diabetes.

Low doses of statins are trouble free for most people, but high doses are associated with increased risk of diabetes and all kinds of aches and pains.

The statin effect in autism does not increase with higher doses, only a small dose is required.



Abstract
Germline mutations in the tumor-suppressor gene PTEN predispose to heritable breast cancer. The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. We previously demonstrated that lovastatin may signal through PPARgamma and directly upregulate PTEN expression at the transcriptional level. In our current study, we show that simvastatin, pravastatin and fluvastatin can induce PTEN expression in a dose-dependent manner. This resulted from an increase in PTEN mRNA indicating transcriptional upregulation. In addition, we observed, for the first time, that upregulation of sterol response element-binding protein (SREBP), known to induce PPARgamma expression, can increase PTEN expression. Using reporter assays, we observed that both the statins and SREBP could specifically induce PPARgamma-mediated transcription. However, the statins do not appear to signal through SREBP. Furthermore, our results indicate that SREBP utilizes PPARgamma's transcriptional activity to induce PTEN transcription, whereas the statins signal through PPARgamma's protein activity to upregulate PTEN expression. Overall, our observations suggest that statins signal through another transcription factor, in a PPARgamma-dependent manner, which in turn induces PTEN transcription. We, therefore, studied the full-length PTEN promoter through serial deletion reporter assays and electromobility shift assays and identified a region between -854 and -791 that binds an as-yet-unidentified transcription factor, through which the statins induce PTEN expression. Since PTEN is constitutively active, our data indicate it may be worthwhile to examine statin and SREBP stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies in cancer, diabetes mellitus and cardiovascular disease


PTEN dysfunction in Cancer and Autism

I will cover this point in more detail in the post on PTEN, but note that the PTEN gene dysfunctions found in 10% of people with autism are generally different to the ones found in cancer.  We also have the difference between whether the PTEN gene is mutated or there is PTEN loss.

There should be two identical copies of the PTEN gene. When one copy is mutated, the protein it produces was found to inhibit the protein produced by the good copy. In other cases, one copy of the PTEN gene is OK, but the other got deleted.   This turned out to be better than having one mutant version.

Different mutations in PTEN are linked to different outcomes.  The known autism mutations are called H118P, H93R and H123Q.  If you have a C124S mutation you would be at risk of something called thyroid follicular carcinoma and not autism.

It is all very complicated and I have to say some conclusions in the research are contradictory.

But it is reported that about 10% of people with autism have an identifiable PTEN mutation.  I am more interested in whether PTEN is an interesting protein in the other 90%.

We saw in the fragile X research that even though this affects only 1% of cases with autism, some experimental therapies for fragile X worked on people with autism, but without fragile X.  At the time I thought that very odd.

My assumption is that PTEN is interesting for more than the 10%.



Conclusion

So there are now 2 plausible reasons why statin therapy may be effective in people with classic autism and elevated cholesterol:-

·        Reduction in inflammatory cytokines 
·        Up-regulation of PTEN

Maybe it is both.

It may be that in people with autism and low cholesterol, and so not suited to statins, they may also have low levels of PTEN.

We saw in a recent post that when you eat fresh broccoli in addition to Sulforaphane, you also produce Indole-3-carbinol (I3C).   I3C also up-regulates  PTEN.

Using Peter logic, if statins have an immediate effect then quite likely so would I3C.


Whatever Next?

Well, for those few of you who have discovered the “magical” beneficial effects of mast cell stabilizers, like Verapamil and Cromolyn Sodium, on both autistic behaviours and severe allergies, here is a preview of what is coming next:-


Recent studies have indicated that PPAR-gamma plays an important role in anti-inflammatory responses and that PPAR-gamma signaling is associated with regulation of PTEN expression. It is known that up-regulation of PTEN expression reduces asthmatic pathogenesis.

These findings suggest that PPAR-gamma uses PTEN to modulate asthmatic responses The signaling mechanism by which stimulation of PPAR-gamma with the agonists regulates PTEN expression as well as Akt phosphorylation remains to be lucidated. However, our results agree with the observation that the anti-inflammatory action of PPAR-gamma agonists is mediated via up-regulation of PTEN.












In other words, increasing PTEN minimizes allergies.  Perhaps, via feedback loops, increasing allergies reduces PTEN?

Seizures also reduce PTEN.

Reduced PTEN leads to increased autistic behaviours.

Not surprisingly we will come back, yet again, to mast cells.

For us, it really does seem that PTEN is a key piece in the puzzle;  but a puzzle with a solution.









7 comments:

  1. Your case on statins gets stronger and stronger.
    But I worry about trying it, specially with younger kids.
    Besides low cholesterol, any other "known comorbities" would be a showstopper?
    Regards,
    J.

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  2. Statins have been trialled in children as young as 8 to lower cholesterol. Kids younger than that would not normally get tested for cholesterol or be obese. Nobody has thought about Statins and autism. A brief test for a week is unlikely to do harm, only if it works do you then need to worry. The chief side effect is a headache at higher doses. I used 10 mg with no side effects, at 20mg there was no behavioral change, but there were headaches. I should try 5mg. The maximum dose suggested for children is 20mg.

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    1. Thanks for your reply.

      Delete
  3. Hi Peter,

    This is a very interesting finding. Way to go in once again being on the cutting edge of autism research. Among other things, your finding highlights something which is truly under appreciated which is that autism in most cases is in part a vascular disease. Here is one reference: http://www.ncbi.nlm.nih.gov/pubmed/16908745.

    Another substance one might try to improve vascular function and hence symptoms in autism is silymarin. Here is a reference for silymarin improving vascular function: http://www.ncbi.nlm.nih.gov/pubmed/24123505. I have been giving small doses to my son and I think it helps him.

    Your findings on statins are terrific. If you are going to provide them over a long time period, you may want consider whether it makes sense to supplement with some CoQ10 as well. Evidently statins decrease the production of CoQ10 which can result in side effects in some: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096178/. As many with autism already have some inefficiencies of energy production this seems like something that one may want to watch out for.

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    1. Thanks for the comment, Seth.

      Statins are known to deplete co-enzyme Q10 and this may cause the side effects some older people suffer with high dose statins. However adding back extra co-enzyme Q10 does not seem to help:-

      Coenzyme Q10 and Statin-Induced Mitochondrial Dysfunction
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096178/

      “The statin medications routinely result in lower coenzyme Q10 levels in the serum. Some studies have also shown reduction of coenzyme Q10 in muscle tissue. Such coenzyme Q10 deficiency may be one mechanism for statin-induced myopathies. However, coenzyme Q10 supplements have not been shown to routinely improve muscle function.”

      People with mitochondrial disease should not take statins. This would perhaps imply that many people with regressive autism should not take statins. Perhaps the small number of older people who experience side effects at large doses of a statin actually have an undiagnosed pre-existing mitochondrial disease?

      I did try giving coenzyme Q10 in addition to the statin. There was no noticeable effect, but it is a harmless supplement and perhaps should be take routinely as you suggest.

      You certainly could make a case that statins should make autism worse, via mitochondrial effects, but in my son they make it better. I guess it all depends on which sub-type of autism you are dealing with; in this case a cholesterol test may give a good indication.

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  4. Peter,
    My grandson has low total cholesterol (132). 25 Hydroxy vitamin D is also low. For a 2.5 year old 12kg child he eats 2 eggs daily and takes vitamin D drops. He has normal bowel movements and stool colour is brown. His CRP is normal. Liver and renal function and glucose are normal. He has been prescribed with sonic cholesterol and to increase his Vitamin D to 2000 IU per day. Some parents from other forums say that sonic cholesterol and Vitamin D bring significant improvement in behavior. So Cholesterol is the precursor for Vitamin D too. Before blood tests I was thinking about statin. But with low cholesterol? While searching the net I came across this article. They are trying to increase low cholesterol by using cholesterol lowering drugs and say that they are only trying to treat the symptom. You said the same no?Cholesterol is only the consequence. So what is the cause? Oxidative stress? Neuroinflamation? It seems cholesterol, vitamin D,immune system and mast cells are all interrelated. May be along with sonic cholesterol we can add biotin and niacin? He is already on fish oil. Here is the article.
    http://www.niams.nih.gov/news_and_events/spotlight_on_research/2006/low_cholesterol_syndrome.asp

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    1. Yes, I also found it intriguing that SLOS can be treated with cholesterol + simvastatin.

      Cholesterol is produced in response to inflammation. Statins have numerous modes of action.

      I would suggest you consider using a probiotic that raises 25-hydroxy vitamin D. It is available in several commercial products (just google L. reuteri NCIMB 30242). I think it may also help in other ways.

      Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial.

      https://www.ncbi.nlm.nih.gov/pubmed/23609838

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