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Sunday, 9 July 2017

More Wnt Modulation for Autism and More Inexpensive Potential Cancer Therapies


This blog is of course meant to be about autism, but today it is again more about cancer, since I keep coming across interesting potential therapies while researching Wnt/PAK/hedgehog therapies for autism.

On their way to visit a pharmacy?

It really looks like daily use of Mebendazole should be beneficial in some types of autism and perhaps a little short term bioavailability boost from cimetidine might help get things started. There are anecdotes on the internet of people with autism using it for its anti-parasite properties and showing a behavioral improvement.
Wnt signalling is highly complex and yet still only partially understood. One interesting role of Wnt signalling is in controlling the flow of calcium ions within cells. The non-canonical Wnt/calcium pathway helps to regulate calcium release from the endoplasmic reticulum (ER) in order to control intracellular calcium levels. Wnt ultimately causes the release of IP3 which then binds to the receptor IP3R which causes calcium to be released from the ER. Problems with this calcium release triggered by IP3R were put forward by Prof Gargus as a possible nexus where different genetic types of autism come together, but he does not translate this thinking into potential therapies. IP3R has been covered in earlier posts.  

Is dysregulated IP3R calcium signaling a nexus where genes altered in ASD converge to exert their deleterious effect?

The Excitatory/Inhibitory Imbalance – GABAA stabilization via IP3R

Wnt signalling also plays a role in dendritic spine morphology, which I wrote about at length previously. In autism the synaptic pruning process does not result in the optimal structure, but even after this process has been completed it is possible to fine tune brain function by changing the shape of the dendritic spines that remain. This dendritic spine morphology can be modulated by Wnt signalling. 
It appears that either a Wnt activator or a Wnt inhibitor may be required to improve dendritic spine morphology depending on the person and the nature of their dysfunction. In a bipolar mouse model, lithium was used as a Wnt activator to create a denser structure of dendritic spines and a more functional mouse. My assumption is that in my case I need a Wnt inhibitor. This is the same situation we have observed with the better known mTOR pathway, where some people are hypo while others are hyper.
Many drugs that have some effect in autism do play a role in Wnt signalling, even Atorvastatin, in my Polypill, has an inhibitory effect.
Wnt signalling is a conserved evolutionary pathway so it is present in everything from fruit flies to humans. It plays a role in many cancers, type 2 diabetes and it seems in neurological conditions such as autism, bipolar and schizophrenia.
My earlier posts on Wnt and PAK1 ended up with 3 options:-

·      Ivermectin

·      FRAX486

·      Bio30 Propolis

The Bio30 propolis is put forward as a PAK inhibitor, but I think it is too weak unless used in huge quantities. I did try BIO 30 and I think it may have had a marginal effect, but it is expensive and you need a lot of it.
So I think Mebendazole, as a Wnt inhibitor, looks like an alternative more practical route to achieve the same thing.

Roche do not seem to be commercializing FRAX486, whereas Mebendazole is sitting in the OTC part of most pharmacies across the world (excluding the USA). Under the brand name Vermox, pharmacies in New Zealand legally sell it worldwide.
If Mebendazole has potency to have an anti-cancer effect, like FRAX486, then it should have potency to give an autism effect.

Note that some people may need a Wnt activator.
You can read all about Wnt at this Stanford lab here.


Back to Cancer
Cancer appears to be more common among people with autism and so it was to be expected that some readers of this blog are treating both autism and some type of cancer.

It does seem that there is scope to repurpose some very common generic drugs to improve the prognosis of many cancers. As with autism, there is great resistance among mainstream clinicians to do this.
As with autism, there are hundreds of sub-types of cancer and so it is not easy to collect relevant evidence, even in the best circumstances, so often it is a case of anecdotes. It is hard to prove anything conclusively, but some very expensive cancer therapies are only minimally effective. As with autism, even a moderate chance of success is worth pursuing and none of the mentioned potentially “repurposable” drugs have more than trivial side effects. Many ultra-expensive dedicated cancer drugs have side effects that are far from trivial and some have very limited benefit.

It seems that while many clinicians are aware of the potential benefit of these off-label therapies, very few prescribe them. Some seem quite happy if you get them somewhere else, which in the case of Prof Williams (see below) from San Diego means regular trips across the border to a pharmacy in Tijuana, Mexico.

Cimetidine for cancer
I did mention cimetidine in my last post.

Cimetidine (Tagamet) is an H2 antihistamine that lowers acidity in your stomach, but cimetidine does much more, it even increases your level of estrogen, which may help some autism. The anti-cancer effects of cimetidine are well documented, they come in part from its own actions and in part from interfering with how the prescribed cancer drugs are metabolized. Cimetidine increases the plasma concentration of numerous drugs including some anticancer drugs.
There are various different theories to explain the anticancer effects of cimetidine itself, but what looks clear is that it improves the prognosis of many types of cancer.
You might expect it to have a negative effect on the types of cancers that have estrogen receptors.

Desloratadine for cancer
On the subject of antihistamines, the OTC second generation antihistamine Desloratadine (Clarinex, Aerius)  has been shown to improve outcomes in breast cancer. As usual drugs have multiple modes of action and so the anticancer effect may have nothing to do with histamine. The data to support this anticancer effect comes from Sweden and the data is presented in the patent application below.


Perhaps one mode of anti-cancer action is the following one:-



Generic drugs with anti-cancer properties
So far we have covered in the last post and this one:

·      Ivermectin

·      Mebendazole (Vermox)

·      Albendazole

·      Cimetidine (Tagamet)

·      Statins (particularly Simvastatin, but also Atorvastatin)

·      Metformin

·      Desloratadine (Clarinex, Aerius)

·      Suramin (but use is limited by toxicity at high doses)

An antifungal treatment, Itraconazole, has an effect inhibiting hedgehog signaling, relevant to many cancers and has been shown to have some effect on prostate and breast cancer in particular. This might also have an effect in some autism where hedgehog signalling is elevated.
Itraconazole does not work well with drugs that lower stomach acidity, like H2 antihistamines and PPIs.


The Polypill approach to cancer
I was looking for information to support the possible effect of Mebendazole in autism and I came across a great example of someone with my approach treating his brain tumor. With good sense he was seeking to follow mainstream therapy, but to supplement it with science based off-label therapies.


The Drugs in Question: the evidence for and against

Metformin: Several studies suggest that tumors grow more slowly in cancer patients who take this anti-diabetic drug. Early-stage clinical trials are investigating its potential to prevent various cancers including prostate, breast, colorectal and endometrial.

Statins: Preclinical studies suggest these cholesterol-lowering heart drugs may prevent various cancers and stop them spreading. One recent meta-analysis associated a daily statin with a significant risk reduction of liver cancer.

Mebendazole: There is evidence this drug – usually prescribed to treat parasitical worm infections — may inhibit cancer cell growth and secondary tumors, though no clinical trials have been completed.

Cimetidine: This over-the-counter antacid has direct anti-proliferative effects on cancer cells, inhibits cell adhesion, reduces tumor angiogenesis (growth of blood vessels essential to a developing tumor) and also boosts anti-cancer immunity in various cancers.

Itraconazole: The common anti-fungal treatment is also thought to be anti-angiogenic and has shown promise as an agent for prostate cancer, non-small cell lung cancer and basal cell carcinoma, the most common kind of skin cancer.

Isotretinoin: This acne drug, marketed as Accutane, is occasionally used to treat certain skin cancers and neurological cancers as well as to prevent the recurrence of some brain tumors, although some studies suggest it is ineffective.

Professor Williams is not a doctor, but that did not stop him reading the research.
His choice of cheap generic off-label anti-cancer drugs looks pretty smart to me. He is still alive two decades after he “should” have been dead. It may all be a happy coincidence and perhaps he would have survived his orange-sized brain tumor without his own interventions. 

There are numerous alternative therapies for cancer and some people do even forgo conventional therapies to treat themselves, which looks very foolish to me.
Personally I would put my faith in science and that does not necessarily mean just medicine. Medicine is based on an evidence-based selective interpretation of often out of date science. So in some fields, medicine works just great, but in complex areas like cancer or anything to do with the brain, medicine lags decades behind science.

As Prof Williams learned, evidence is great as long as you are not going to die before someone collects it. If you have only a year to live what do you really care about any minor side effects metformin, simvastatin or cimetidine may have?
There are some apparently nutty therapies for cancer, just as there are for autism; I think someone should investigate them anyway, just in case someone has stumbled upon something effective by accident.




10 comments:

  1. Totally off-topic, but I couldn't find a fitting blogpost to put this.

    "Controlling a single brain chemical may help expand window for learning language and music"
    https://www.sciencedaily.com/releases/2017/06/170629142919.htm

    I can't decide if this is interesting news for the ASD community or just more unusable science.

    /Ling

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    Replies
    1. Hi Ling,

      Thanks for posting! I actually read up on new papers dealing with Autism, and any neurology papers that may now or later be relevant, so if you think a paper or article even remotely connects to ASD, please share.

      AJ

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  2. Hi everyone,

    I just ran across a paper from a few years ago that I found interesting so wanted to share:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959772/

    "Mitochondrial membrane mass was higher in ASD brain, as indicated by higher protein levels of mitochondrial membrane proteins Tom20, Tim23 and porin. No differences were observed in either mitochondrial DNA or levels of the mitochondrial gene transcription factor TFAM or cofactor PGC1α, indicating that a mechanism other than alterations in mitochondrial genome or mitochondrial biogenesis underlies these mitochondrial abnormalities. We further identified higher levels of the mitochondrial fission proteins (Fis1 and Drp1) and decreased levels of the fusion proteins (Mfn1, Mfn2 and Opa1) in ASD patients, indicating altered mitochondrial dynamics in ASD brain. Many of these changes were evident in cortical pyramidal neurons, and were observed in ASD children but were less pronounced or absent in adult patients. Together, these findings provide evidence that mitochondrial function and intracellular redox status are compromised in pyramidal neurons in ASD brain and that mitochondrial dysfunction occurs during early childhood when ASD symptoms appear."

    I'm going to dig a bit into the altered fission and fusion protein status in the mitochondria (and see if there are any natural treatments to increase what is low or decrease what is high) but if anyone has any insights to share on this topic, please do so, and I too will share any findings.

    Have a great Saturday!

    AJ

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    Replies
    1. Hi everyone,

      So I'm just starting my research and I've already found something interesting:

      https://www.ncbi.nlm.nih.gov/pubmed/28669827

      "Here we show that nicotinamide (NAM), an inhibitor of sirtuin deacetylases, promotes degradation of mitochondria fusion protein mitofusin 1 (MFN1), suggesting that acetylation status of MFN1 is important for its protein stability. TIP60 but not PCAF acetyltransferase caused a reduction of MFN1 level. Meanwhile, siRNA-mediated knockdown of SIRT1 deacetylase caused a significant reduction of MFN1 whereas over-expression of SIRT1 increased its level in 293T cells. In vitro acetylation experiments showed that TIP60 increased the acetylation of MFN1 that was abolished by co-existence of SIRT1. Notably, MFN1 and SIRT1 levels were accumulated, along with mitochondria elongation under hypoxic conditions. Thus, the data suggest that mitochondria elongation under hypoxic condition is regulated through SIRT1-mediated MFN1 deacetylation and accumulation. The data provide an insight in the maintenance of cellular homeostasis through mitochondria morphological change."

      So why this is interesting to me is that I was just gong through the following paper a few days ago:

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491272/

      The title of the paper is "Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder", and again, through multiple papers I'm coming up with SIRT1 (which Peter has mentioned on the blog).

      I'm going to keep doing research, and will keep sharing, but my latest reading seems to keep coming back to SIRT1 (and PGC-1α) - it may be coincidence, but its just funny that multiple lines of my research come up to the same target in a matter of a few days.

      I love the self-hacked site as it often does the research on certain targets, and they just had one on SIRT1:

      https://selfhacked.com/blog/nad-and-sirt1-their-role-in-chronic-health-issues/

      I'll keep researching and sharing, but I hope people find the above helpful!

      AJ

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    2. Yes it is important to understand what the various forms of B3 do. In general, Nicotinamine (NAM) inhibits SIRT1 while nicotinic acid (Niacin) and Nicotinamide Riboside (NR) promote SIRT1.

      The sirtuins and especially SIRT1 are currently the most studied area of research in the anti-aging sphere at the moment, unless you consider research on lifestyle factors that greatly promote aging to be in that same camp (smoking, alcohol, obesity, diabetes, etc.).

      Delete
  3. Borrelia (a spirochete) causes 'autoimmune disorders' (Autism is 'autoimmune in nature' ie inflammation of the brain). Borrelia has been found in 100% of cancer tumours and the brains of deceased Alzheimer sufferers.
    Borrelia can be transmitted by ticks, fleas, mosquitoes, blood, sex, infected mother to fetus, vaccines (the latter if they contain infected animal cells) etc. Borrelia (aka Lyme Disease) is endemic. It can cause over 300 autoimmune disorders such as MS, diabetes, arthritis, asthma, cystic fibrosis, hypo/hyper thyroidism, IBS etc (depending on what part of the body it targets and how the body responds). IgeneX in America or the NIIM medical cwntre in Hawthorn, Victoria, Australia have specialist tests for the disease (local/mainstream tests are not accurate). Borrelia is the Autism Cancer comnection and why antiparasitics play a vital role to treat both. NIIM medical clinic specialise in treating Lyme like illness. I have personally witnessed reversal of the symptoms of diabetes 1, MS, psoriatic arthritis, asthma, autism etc with treatment for Borrelia. Gluten, dairy, sugar feed Borrelia and other parasites which is why Paleo is good for health.

    Borrelia's cork screwed shape allows it to corkscrew deep inside tissue thereby evading the immune system. Borrelia also coats tissue with protein. The immune system attacks the protein with inflammation thereby damaging the coated tissue. The inflammation destroys tissue in a futile attempt to catch and destroy the spirochete. However, the spirochete corkscrews deeper theteby perpetuating the 'autoimmune disorder.'

    Look up Lyme Disease Association of Australia for more information. Look up this FB page for a treatment protocol

    https://m.facebook.com/notes/will-wiegman/wiegman-pulsed-protocol-for-lyme-disease-including-congenital-lyme-and-vaccine-i/10154253003723139/

    ReplyDelete
  4. On the subject of cancer treatments relevant to autism. Have you looked into Dr. Michael Chez's use of Neupogen/Filgrastim? He is patenting the use of it for neuro-inflammation. https://www.google.com/patents/US20160228510

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    1. Anna, this relates to his ideas about stem cell therapy.

      Delete
  5. Hi Peter
    http://www.brightmindsinstitute.com/approach.html
    I would like to know the advantage of doing a DEEP EEG over 24 hr EEG.
    Have you done DEEP EEG for your son or the 24 hr EEG?
    Thanks
    SB

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    1. SB, I would see a neurologist who is knowledgeable about autism and take his advice. What tests are available depends on where you live. It makes sense to use a test that has been used many times before, rather than go straight to an unusual one.

      I think it is most relevant if you can identify people who are at risk of developing epilepsy, before their first big seizure. The first big seizure is thought to make epigenetic changes that lower the threshold for future seizures.

      By making GABA more inhibitory you might expect to lower the chance of a seizure.

      My son has not developed epilepsy. We had no EEG, but we have modified the effect of GABA. making it more inhibitory.

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