I should start this post by highlighting that generally cancer and autism are not caused by parasites.
I
have to be a little careful because we now know that certain types of virus and
bacteria are involved in the initial trigger to initiate some types of cancer.
This is why many females are now offered human
papillomavirus (HPV) vaccines to minimize the chance of several different
cancers. I noticed recently that in the US this vaccine is advertised on TV. I used to know a woman who like most people had the HPV virus as a child, but did not have this vaccine. She developed a rare oral cancer that the vaccine would have protected against and died very young. We saw in a previous post how a specific gut bacteria blocks the
initiation of childhood leukemia.
The pharmaceutical industry does not seem to like the idea of
repurposing existing drugs to treat a different disease. There are some exceptions; it is OK to treat
females with acne, using the diuretic drug Spironolactone. Nobody seems to object to the treatment of
intractable headaches with drugs actually approved to lower blood pressure (Verapamil,
Amlodipine etc).
When investigating cancers you have to look at the specific
underlying mechanisms, just as you do with autism.
As we saw long ago in this blog, it has been suggested to
classify autism as either over-active pro-growth signaling pathways, or under-active
pro-growth signaling pathways. Most is the over-active type.
Cancer is very clearly another example of over-active
pro-growth signaling pathways, so it is not surprising that there is an overlap
between therapies for autism and cancer.
The difference is that they are far more likely to be effective in
autism.
So, a cheap anti-parasite drug for kids like Mebendazole, which just happens to also be a Wnt inhibitor, may slow down the growth of some cancers, but it is sadly not curative. In an autistic brain where Wnt signalling might be overactive, a lower dose of Mebendazole, might well provide a long-term benefit.
My old posts that mention Wnt signaling are here:-
https://www.epiphanyasd.com/search/label/Wnt
Wnt signaling interestingly plays a role in how your hair
will go gray/grey. If you reduce Wnt signaling, your hair will go gray and so
this is an inevitable side effect of a potent Wnt inhibitor.
Premature graying might indeed indicate reduced Wnt activity.
Pyrantel pamoate
Our reader Dragos recently fined tuned his adult son’s anti-aggression
therapy and he recently shared his latest innovation:-
"you
have to give him 20mg of propranolol 2-3 times a day, pyrantel pamoate 750mg in
the evening for 2-3 days, and you will see that his anger will disappear, stay
on propranolol. After 3 weeks repeat with antiparasitic, you will see that I
was right, you don't use psychotropic drugs"
Propranolol is a normally used to lower blood pressure, but
it does this in a way that also reduces anxiety. At the low doses used by Dragos, it has been
used to treat actors with stage fright. It can be used before exams or driving
tests, to calm the person down.
Propranolol has been trialed in autism. Some people use a low
dose and some use a higher dose.
Pyrantel pamoate is used to treat hookworms and other
parasites that can be picked up by young children. It works by paralyzing the
worms. This is achieved by blocking certain acetylcholine receptors in the worm.
As is
very often the case, pyrantel pamoate likely has other modes
of action that are entirely different. Is it a Wnt inhibitor like the other
hookworm treatment Mebendazole?
I did a quick search on google and it gave me the wrong pamoate.
Pyrvinium pamoate is able to kill various cancer cells, especially CSC. The drug functions through the reduction of WNT- and Hedgehog-dependent signaling pathways (Dattilo et al., 2020).
Pyrvinium
pamoate is yet another anti-parasitic drug, but not the one Dragos is using.
So pyrantel pamoate may not be a Wnt inhibitor, unlike many anthelmintic drugs, but it is used by the “anti-parasitic re-purposer in chief” Dr
Simon Wu. He publishes his
findings/thoughts, which is good to see.
He likes to combine different anti-parasitic drugs.
I did look up the effect of pyrantel pamoate on gene
expression. There is data, but you
really need to see the source material to know whether anything is valid.
Inhibiting GSTP1 (glutathione
S-transferase pi 1) is suggested and that is a feature in common with an
anti-parasite drug class called Thiazolides (e.g. Nitazoxanide). That would make pyrantel pamoate a potential
therapy for triple-negative breast cancer, where the cancer cells rely on
vigorous activity by the enzyme glutathione-S-transferase Pi1 (GSTP1). Cancer cells are highly vulnerable to
oxidative stress, and as we know glutathione is the main way the body
extinguishes it. Glutathione
S-transferases
P1 protects breast cancer cell from cell death. So you want to inhibit GSTP1.
Pyrantel has many other suggested
effects even reducing expression of the gene FXR2 (fragile X mental
retardation,2) and increasing expression of the gene MTSS1 (metastasis
suppressor 1).
Pyrantel is even suggested as an
epilepsy drug.
Drug repositioning in epilepsy reveals novel antiseizure candidates
Epilepsy treatment falls short in ~30% of cases. A better
understanding of epilepsy pathophysiology can guide rational drug development
in this difficult to treat condition. We tested a low-cost, drug-repositioning
strategy to identify candidate epilepsy drugs that are already FDA-approved and
might be immediately tested in epilepsy patients who require new therapies.
Expanding on these analyses of epilepsy gene expression
signatures, this study generated a list of 184 candidate anti-epilepsy
compounds. This list of possible seizure suppressing compounds includes 129
drugs that have been previously studied in some model of seizures and 55 that
have never been studied in the context of seizures. 91 of these 184 compounds
are already FDA approved for human use, but not for treating seizures or
epilepsy. We selected four
of these drugs (doxycycline, metformin, nifedipine, and pyrantel tartrate) to
test for seizure suppression in vivo.
Pyrantel tartrate is an antiparasitic agent that acts by
inhibiting fumarate reductase, and by directly acting on acetylcholine
receptors at the neuromuscular junction of infecting helminths. Pyrantel
tartrate is FDA approved for use in domestic animals and has been used to treat
human parasitic infections.73 Unlike nifedipine and metformin (for which some
rodent studies and human reports relate to seizures), a March 2018 PubMed
search for “pyrantel and epilepsy” and “pyrantel and seizure” found no
manuscripts that studied pyrantel in seizures. Thus, pyrantel tartrate represents a truly novel
antiseizure drug candidate yielded by our screen.
All in all it is not surprising that Dr
Yu is prescribing pyrantel pamoate.
Digging any deeper is beyond the scope
of a blog post.
What is clear is that pyrantel pamoate and mebendazole are
unlikely to be equally effective in Dragos’ son.
Other anti-parasite drugs work very differently.
In the chart the mode of action of some common drugs is presented.
Anthelminticsfor drug repurposing: Opportunities and challenges
Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).
Suramin is now quite well known as a potential autism therapy
and two different groups are trying to commercialize it. Suramin is the original anti-purinergic
drug (APD), it blocks purinergic receptors that have names
like P2Y2.
When I looked at PAK1 a long time ago, which was put forward
as a treatment pathway for neurofibromatosis, some schizophrenia and some
autism I came across Ivermectin as an existing alternative to the research drug
FRAX486, or the expensive BIO 30 propolis from New Zealand.
A decade later and the world goes crazy when the idea of using Ivermectin to treat COVID 19 gets well publicized. The good news is that now we know that regular use of Ivermectin is not as dangerous as people thought it would be. Many people have been using the veterinary version in the US, Brazil and elsewhere.
The supporting research:-
Effect of Pyrantel on gene
expression.
decreases expression of:-
FXR2 fragile X mental retardation, autosomal
homolog 2
(and many more)
Increases expression of
MTSS1 metastasis suppressor
1
BNIP1 BCL2/adenovirus E1B
19kDa interacting protein 1
BRAF B-Raf proto-oncogene,
serine/threonine kinase
(and many more)
https://maayanlab.cloud/Harmonizome/gene_set/Pyrantel+Pamoate/CTD+Gene-Chemical+Interactions
Glutathione
S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.
Pyrantel Pamoate Gene Set
Dataset CTD
Gene-Chemical Interactions
2 genes/proteins interacting with the
chemical Pyrantel Pamoate from the curated CTD Gene-Chemical Interactions
dataset.
GPR35
G protein-coupled receptor 35
GSTP1
glutathione S-transferase pi 1
Triple-negative breast cancer target is found
They discovered that cells
from triple-negative breast cancer cells rely on vigorous activity by an enzyme
called glutathione-S-transferase Pi1 (GSTP1). They showed that in cancer cells,
GSTP1 regulates a type of metabolism called glycolysis, and that inhibition of
GSTP1 impairs glycolytic metabolism in triple-negative cancer cells, starving
them of energy, nutrients and signaling capability. Normal cells do not rely as
much on this particular metabolic pathway to obtain usable chemical energy, but
cells within many tumors heavily favor glycolysis.
"Inhibiting GSTP1 impairs glycolytic metabolism," Nomura said. "More broadly, this inhibition starves triple-negative breast cancer cells, preventing them from making the macromolecules they need, including the lipids they need to make membranes and the nucleic acids they need to make DNA. It also prevents these cells from making enough ATP, the molecule that is the basic energy fuel for cells."
Anthelmintics for drug repurposing: Opportunities and challenges
It has been demonstrated that some of the anthelmintics are able to inhibit critical oncogenic pathways, such as Wnt/β-catenin, signal transducer and activator of transcription proteins 3 (STAT3), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; therefore, their application for cancer treatment has been considered.
Repositioning
of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System
Anthelmintics
for drug repurposing: Opportunities and challenges
Mode of action of albendazole (ABZ), ivermectin (IVM), levamisole (LV), mebendazole (MBZ), niclosamide (NIC), flubendazole (FLU), rafoxanide (RAF), nitazoxanide (NTZ), pyrvinium pamoate (PP), and eprinomectin (EP).
Thiazolides inhibit
growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in
human colon cancer cells
More research on the repurposing anti-parasite drugs:
Chronic inflammation is a new catch phrase for the explanation of all chronic degenerative diseases, from asthma, arthritis, heart disease, auto-immune disease, and irritable bowel disease to cancer. Occult infections from oncovirus, bacterial, and fungal infections as well as from lesser known parasitic infections are driving forces in the cellular evolution and degeneration of cancer cells. An approach using currently available medications that target both fungal and parasitic metabolism appears to interfere with the metabolic synergy that is associated with tumor growth and aggressiveness
The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs
Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent
A Pinworm Medication Is Being Tested As A Potential Anti-Cancer Drug
I did suggest long ago that Mebendazole, as a Wnt inhibitor, might be a cheap and effective treatment for some autism. I had envisaged that it would need to be given daily, as it is in the cancer trials.
Dragos’ use of pyrantel pamoate, for an average
of 4 days a month is interesting. It is cheap,
safe and practical.
One key issue with antiparasitic drugs is how much is
absorbed into the blood stream. If 100%
of the drug stays in the gut, its benefit will be limited.
About 20% of Mebendazole ends up in the blood stream and if
you take it often this figure is reported to increase.
The combo of propranolol + pyrantel pamoate is
an interesting option to treat self-injury and aggressive behavior. It works for Dragos and undoubtedly will for
some others.
Is the inhibition of Wnt signalling the reason why pyrantel
pamoate is effective for Dragos’ son? There
is no evidence to support that.
Are antiparasitic drugs going to be widely adopted to treat
any unrelated conditions, cancer included, I very much doubt it.
Cancer is better avoided, than treated. It is a much more achievable objective.
The Fragile X researcher Randi Hagerman takes metformin, as
her chemoprevention therapy. She is the medical director of MIND Institute at the University of California,
Davis.
You can raise IQ in people with Fragile X by 10-15% using Metformin. I guess Randi had been reading up on
Metformin and came across the anti-cancer effects.
If I had to suggest an anti-parasite drug for Randi to try in
Fragile X, I would suggest the PAK inhibitor Ivermectin, made (in)famous by
Donald Trump and Jair Bolsonaro during Covid. The research drug FRAX 486 is
called FRAX for Fragile X. It is a PAK inhibitor that never made it to market. Ivermectin is an existing drug that is also a
PAK inhibitor. Worth a try, Randi?
I expect Dr Yu might try and increases his chances and make a
combo with a second anti-parasitic drug.
Metformin is one of several anti-cancer choices, it depends
which type of cancer is of concern. For RAS-dependent cancer I think
Atorvastatin is the best choice.
If you read the research, like me and
Randi, chemoprevention
is the obvious choice for older adults. Dementia prevention is equally obvious.
Parkinson’s prevention may be achieved by blocking Cav1.3
(amlodipine etc)
Alzheimer’s prevention may be achieved using low dose fenamates
(Ponstan etc).
For vascular dementia and Alzheimer’s prevention/treatment
spermidine (in the form of modified wheatgerm) is promising.
Anti-parasite drugs for cancer and autism? Yes, it sounds
mad. But is it?
What is for sure is that your pediatrician will think you
have gone mad!
Our reader MG in Hong Kong will have got some new ideas to
think about.