Sulfarlem / Anethole trithione (AOL) for Autism secondary to Mitochondrial Dysfunction (AMD)? Not to mention Metastasis

Sulfarlem has been used to treat dry mouths for half a century

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Sulfarlem is a drug containing a chemical called Anethole trithione. Anethole is an organic compound used as a flavouring, it contributes a large component of the odour and flavour of anise and fennel.

Anise seed, or aniseed, contains a large amount of Anethole. The popular Greek drink Ouzo turns cloudy when diluted with water because of the Anethole. For the French it is called Pastis.   

                                                                      

Ouzo has been used to treat dry Greek mouths for seven centuries, particularly after a good meal.

For Anethole without the alcohol, a good source would include aniseed or fennel.

Aniseed

Today's post was prompted by a comment made before Christmas by our reader Claudia; she highlighted some recent French research that repurposes a drug developed by Solvay half a century ago.  The drug is Sulfarlem / Anethole trithione and it is used to treat people with a dry mouth, mainly in French speaking countries (including Canada) and in China, particularly Taiwan.

Sulfarlem appears to have secondary effects that include inhibiting oxidative stress in mitochondria which might benefit a long list of diseases, though they do not mention autism secondary to mitochondrial disease.

The other effect is a reduction in metastasis in people with cancer. This effect was written about in 2002 in the mass media.

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. 

Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer’s diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.


Here is the associated patent:-

Compounds for the treatment of diseases linked to mitochondrial reactive oxygen species (rose) production

  

SUMMARY 

The present invention relates to an inhibitor of production of reactive oxygen species (ROS) for treating or for use in the treatment of free oxygen-radicals related diseases. In one embodiment, said inhibitor is anethole trithione (AOL). In one embodiment, said inhibitor inhibits mitochondrial production of ROS. In a preferred embodiment, said inhibitor inhibits mitochondrial production of ROS at site IQ of complex I of mitochondria. 

In one embodiment, said free oxygen-radicals related diseases are selected from the group comprising: age-related macular degeneration, Parkinson's disease, Alzheimer's disease, ischemic and reperfusion injury, pulmonary arterial hypertension, scleroderma, atherosclerosis, heart failure, myocardial infarction, arthritis, pulmonary toxicity, cardiopulmonary diseases, inflammatory diseases, cancer, metastasis, cardiac toxicity of anthracyclines, heart failure regardless of origin, ischemia, heart attack, stroke, thrombosis and embolism, asthma, allergic/inflammatory conditions, bronchial asthma, rheumatoid arthritis, Inflammatory Bowel Disease, Huntington's disease, cognitive disorders, Progeria, progeroid syndromes, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia, HIV-1-associated dementia, post-stroke dementia, Down's syndrome, motor neuron disease, amyloidosis, amyloid associated with type 11 diabetes, Creutzfelt-Jakob disease, necrotic cell death, Gerstmann-Straussler syndrome, kuru and animal scrapie, amyloid associated with longterm hemodialysis, senile cardiac amyloid and Familial Amyloidotic Polyneuropathy, cerebropathy, neurospanchnic disorders, memory loss, aluminum intoxication, reducing the level of iron in the cells of living subjects, reducing free transition metal ion levels in mammals, patients having toxic amounts of metal in the body or in certain body compartments, multiple sclerosis, amyotrophic lateral sclerosis, cataract, diabetes, cancer, liver diseases, skin ageing, transplantation, ototoxic secondary effects of aminoglycosides, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals, innate immune responses, and, Friedreich's Ataxia.

In one embodiment, said inhibitor is for preventing or for use in the prevention of metastasis.

                                                                                                   

From way back in 2002: -

Dry-Mouth Drug Joins Cancer Fight

Stephen Lam, director of the lung cancer prevention program at the British Columbia Cancer Research Center in Vancouver, British Columbia, found that one of Solvay's drugs, marketed as Sialor or Sulfarlem, also significantly reduces the spread of lung-cancer tumors.

Lam's study completed the second phase of trials necessary for the FDA's consideration. Over six months, 101 smokers and former smokers took the dry-mouth drug. It reduced the progression of their lung cancer tumors by an average of 22 percent.

To participate in the study, the smokers had to have smoked at least a pack a day for 30 years, or two packs a day for 15 years.

Those who took a placebo had 53 percent more new lesions or lesions that got worse than those who took the drug.

The billion-dollar question is, who will pay for more clinical trials? Lam's study was paid for with grants from the National Cancer Institute, and the money has run out. The final stage of clinical trials can cost hundreds of millions of dollars.

The French have recently followed up :-

Mitochondria ROS blocker OP2-113 downregulates the insulin receptor substrate-2 (IRS-2) and inhibits lung tumor growth

They go further in their patent and propose Sulfarlem as a blocker of metastasis.

A recent Chinese paper sets out the mechanism of action.

CXCR4 and PTEN are involved in the anti-metastatic regulation of anethole in DU145 prostate cancer cells

Taken together, anethole demonstrated to act as the CXCR4 antagonist and as the PTEN activator which resulted to PI3K/AKT-mediated inhibition of the metastatic prostate cancer progressions.

Regular readers will know that PTEN is both a cancer gene and an autism gene.

PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat.

Activating PTEN should also help some types of autism.

A recent Japanese study has a different take on the anti-metastatic mode of action.

Anethole Exerts Antimetastatic Activity via Inhibition of Matrix Metalloproteinase 2/9 and AKT/Mitogen-Activated Kinase/Nuclear Factor Kappa B Signaling Pathways

Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-kB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-kB signal transducers.

Metastasis

There is quite a lot in this blog about cancer, due to the overlapping signalling pathways with autism, so follows a little digression about metastasis.

Metastasis is a pathogenic agent's spread from an initial/primary site to a different/secondary site within the host's body.

Often it is the metastasis that ultimately kills people; indeed this just happened to the mother of one of Monty's friends with autism.

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension.

Source: Mikael Häggström 

If a cheap substance could reduce metastasis that would be a big deal.  Cancer is currently the second most common cause of death.  If you can take cheap/safe chemoprotective agents to reduce cancer’s occurrence and a cheap substance to reduce its spread/metastasis you would be pretty smart.

Cheap Cancer Drugs

Numerous cheap drugs have known anti-cancer properties (Metformin, Aspirin, Statins, plus many more) but absolutely no serious interest is shown to apply any of them.  Instead, some hugely expensive drugs have been developed that often extend life by a matter of months.

Sulfarlem certainly is cheap, costing 3 euros (USD 3.3) a pack in France, where it seems to be sold OTC.

It looks like the world of cancer research is as dysfunctional as the world of autism research, when it comes to translating existing knowledge into beneficial therapies.  Nobody wants a cheap cancer drug and I think nobody wants a cheap autism drug.  

Most people still believe autism cannot be treated and some even think it should not be treated. 

Conclusion

Sulfarlem has been around for 50 years and so there is plenty of safety data regarding its use.

It does look like a significant number of people with autism have a problem with Complex 1 in their mitochondria.  This subject has been covered extensively in this blog in regard to regressive autism and what Dr Kelley, from Johns Hopkins, termed autism secondary to mitochondrial disease (AMD).  Unfortunately for us, he has retired.

https://epiphanyasd.blogspot.com/p/regressive-autism.html

Dr Kelley’s mito-cocktail of antioxidants is used by many, but even he makes clear that it is far from perfect and it is not so cheap. 

Sulfarlem looks like an interesting potential add-on, or even a potential replacement.

The fact that Sulfarlem also activates PTEN means that an entirely different group with autism might see a benefit.

Who might carry out a trial of Sulfarlem in autism?  I think the one likely group are those irrepressible autism researchers in Iran, who have trialed so many off-label drugs.  Since Sulfarlem is already licensed in Canada, one of those more enlightened researchers in Toronto might like to investigate.

If you live in France you can skip your early morning expresso and go down to the pharmacy with your three euros and then make your own trial.

Sulfarlem, or just plain anethole, seems a cheap/safe way to potentially reduce metastasis once cancer has been identified. Probably not worth waiting another 20 years for any possible further clinical trials.