Sunday, 26 November 2017

WORTH REPEATING!- Drug cocktail approach against cancer stem cell-like cells

'Mitochondrial ROS and H2O2 production may be a trigger, for driving mitochondrial oxidative stress, ultimately leading to increased mitochondrial oxidative metabolism in CSCs. Pharmaceuticals, chemical inhibitors, or natural products that we have identified to target CSCs, which interfere with a specific metabolic process or function, are shown in BLUE.'

Sunday, 8 October 2017

Evidence for use of Stiripentol and other agents to effectively inhibit cancer stem-like cell activity.

A few months ago (in March, in a previous post in my blog), I theorised that stiripentol (the 'ketogenic diet pill') may be of use as an anti-cancer agent for brain cancer and perhaps others due to inhibition of Lactate Dehydrogenase activity. I think I have just found recent evidence that this theory may be valid.
Stiripentol

Stiripentol by Diatomit enhances beneficial effects of therapeutic ketosis for cancer management by inhibiting lactate dehydrogenase and offers neuroprotection and increased seizure threshold by enhancing central GABA neurotransmission.
Here is an extra from the paper with reference to stiripentol and complimentary agents that could possibly offer a safe, synergistic therapeutic benefit.
'We have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffein acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit cancer stem-like cell activity.'
The study can be found here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400535/

Saturday, 7 October 2017

Probiotics experiment- VSL#3. Gut dysbiosis and cancer, epilepsy.

I am currently on day 5 of a 30 day experiment using myself as a human guinea pig to test these high potency probiotics from Visibiome.

I first heard about this product from Dr. Rhonda Patrick and I trust her judgement. She stated how Visibiome contains 8 strains of live bacteria in concentrations of 450 billion bacteria per packet and I had this confirmed by the company that produces it. 

Why is this so important?

This is impressive as many probiotics only contain about 100 million bacteria (often dead as they should ideally be kept cold). I decided to investigate further and try these probiotics myself to see if I may benefit so I contacted the sister company based in the U.K. (Vivomaxx). 



The gut micro biome. You are only 10% organically human. (9)


Let's begin...

I received them promptly in pill l form, placed in an ice packed package. I chose the capsules because the carbohydrate content is negligible so should not interfere with my ketogenic diet to manage my epilepsy. I could experience some 'turbulence' as I adjust to it, which may or may not result in increased seizure activity temporarily. I have no idea, but I'm prepared for anything. So far so good.



The formulation used in these products is said to be the same as VSL#3, a probiotic that has been the subject of over 60 human clinical trials as a medical food in the dietary management of gastrointestinal and liver disorders.

From reading about the capsules, I found that they contain 112 billion bacteria per tiny capsule, and you can take up to 4 a day! It is said that these quantities are necessary to properly colonise the gut, which contains up to 10-100 billion bacteria/ml of faeces material. Optimal conolisation is achieved in 2-3 weeks so I have personally chosen to do this for 30 days, consistent with some interesting studies I have read. More information on the product can be found here: 


https://www.vivomixx.co.uk/faq.php 



I became interested further by studies suggesting novel mechanisms of action accounting for deficiencies of the endocannabinoid system (which is implicated in several chronic conditions) to regulate inflammation. It has also been established that endocannabinoid signalling is a key regulator of synaptic neurotransission throughout the brain (7), allowing for improvements in seizure control if you are able to target the appropriate receptors.

'The endocannabinoid system plays an important role in regulating inflammation in several chronic or anomalous gut inflammatory diseases. In vivo and ex vivo studies showed that 30 days treatment with a probiotic mix activated the endocannabinoid system in zebrafish.' (4)





The endocannabinoid system controls a variety of gastrointestinal functions. (10)


I decided to attempt to replicate this protocol in similar fashion, for 30 days. Obviously I am not a zebrafish, but I know that they are commonly used in research as they posess a similar genetic structure to humans. They share 70 percent of genes with us and 84 percent of genes known to be associated with human disease have a zebrafish counterpart. (5)


Orthologue genes shared between the zebrafish, human, mouse and chicken genomes, using orthology relationships from Ensembl Compara 63. (1)


Back to the experiment:


I began with just 1 capsule in case I experienced any gastrointestinal disturbance and from day 3, I had begun to take 2 capsules with food as I seem to tolerate it well. 


My main curiosity with this experiment in general, is to see how taking these probiotics may affect my epilepsy- positively, negatively, or no change. Personally I'm not sure if there will be any difference, but my general health may be improved. I will have a stool sample analysed after the experiment.


I also suffered a brain haemorrhage as a result of the tumour and have had brain surgery so it was interesting to find research on how the gut micro biome becomes altered as part of the inflammatory response, impacting both short and long term recovery. The simplest explanation I found came from this study on the inflammatory response to stroke in the Journal of Neuroscience. (12) A brain haemorrhage is not too dissimilar to a stroke, especially if the blood brain barrier integrity has been further affected by having had brain surgery. I still have invisible disabilities as a result of the assault on this area of my brain and I am able to control it to a large degree with diet and lifestyle adjustments but I am always looking to improve this.


Schematic showing how stroke alters gut microbiota,
which primes the immune system to exert further damage. 
(6)
I realise that the gut and brain have a complex, fascinating connection through these trillions of bacteria, that is only just starting to be understood at a higher level. This is exciting and provides us with so many opportunities to learn more and investigate all posibilities. 

The gut brain connection is facilitated via the vagus nerve, which is very important to note for individuals with epilepsy. The vagus nerves are a pair of nerves running from the brain throughout the body to send electrical messages around all physiological systems. The central nervous system can become spontaneously overstimulated with epilepsy, but it is possible to attempt to regulate these electrical impulses with Vagal Nerve Stimulation or with microbial and/or nutritional stimuli.

'...distinct microbial and nutritional stimuli activate the vagus and the nature of the signals transmitted to the brain that lead to differential changes in the neurochemistry of the brain and behaviour.' (2)

Vagal Nerve Stimulation (VNS) device (13)

I am now probably a little too aware of how every thought we have and every action we make impacts on gut health in profound ways as a 2 way feedback system between the gut and brain via the vagus nerve.

It is interesting to think how many individuals suffering with drug resistant epilepsy will attempt to put an end to their suffering with Vagal Nerve Stimulation (VNS), by which a small electrical device similar to a pacemaker is implanted under the skin to the left vagus nerve in the next with the aim of reducing seizure activity. Its pretty invasive and only appears to give significant, but partial relief at best, with a review stating that of those who responded (54%), there was a reduction in seizure frequency of around 45-63%. (3)

This is significant, but frustration will remain for these patients, especially the non responders. I wonder if we could find kinder solutions to this complex electrical circuitry that makes up our brain and central nervous system through modulation of the gut microbiome. Could probiotics help us to find some kind of solution here for non responders and perhaps even in combination with VNS for the responders?


Gut dysbiosis and cancer:

As a secondary aim of my investigation, I would like to learn more about the clear association between gut dysbiosis and a number of cancers (17), focusing on the brain and central nervous system of course.

I have recently transitioned into a more 'mediterranean' style ketogenic diet so that the probiotics have more of a variety of prebiotics to feed off. I have also increased amounts of ginger and turmeric in my diet, which should help, theoretically at least. 

I still have ghee because it is high in butyric acid, a short chain fatty acid which the microbes love. It is at a high concentration in this food, but is also produced in the intestines by bacteria that ferment non-digestible carbohydrates. (8) I feel it would be helpful for people to remember this fact when discussing carnivorous ketogenic diet ('zero carb') approaches. It has been suggested that high levels of dietary fat decrease levels of butyric acid, but this information would shed some doubt on these findings when viewed in different contexts.- how much fat, what source, what is 'high fat', what is carb/fat ratio, etc. 

I knew early on that the ketogenic diet acts partly by shifting the gut microbiome to result in favourable changes in the gut and brain chemistry, and I attempted to optimise this effect in creative ways when I was on a 'zero carb' ketogenic diet- eg. entomophagy (insect fibre), adding specific supplements, digestive enzymes.

I read an interesting study recently revealing how the ketogenic diet is able to mitigate symptoms of epilepsy at least partly by correcting an imbalanced gut microbiota in epileptic infants. (15)

I also looked at effects of how other fasting mimicking diets, including intermittent fasting and time restricted feeding, will also alter the composition of microbiota, specifically in relation to cancer, but this was harder to find. Maybe we are still learning.  



How we might determine the composition of the microbiota in patients with cancer compared to healthy volunteers. (16)


My conclusion is that, in light of the data, from what we know and what we have yet to understand, it would not be unfeasible to suggest that taking probiotics at appropriate times may help to reduce risk of recurrence of a high grade glioma. I understand (in basic terms), the close relationship between the vagus nerve and microbiome-brain-gut-axis communication and so this may have an additional or stand alone benefit for epilepsy management and improved quality of life. Its fascinating stuff.- most of the more interesting research I found is on colon cancer, but there are obvious potential applications for a host of other cancers. Its a new area to look into, we can't make any definitive conclusions, but I'm looking forward to learning more.



References:



1. Collins, J. E.White, S.Searle, S. M. & Stemple, D. L. Incorporating RNA-seq data into the zebrafish Ensembl genebuildGenome Res. 2220672078 (2012)


2. Forsythe, P., Bienenstock, J. and Kunze, W.A., 2014. Vagal pathways for microbiome-brain-gut axis communication. In Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (pp. 115-133). Springer New York.


3. García-Pallero, M.A., García-Navarrete, E., Torres, C.V., Pastor, J., Navas, M. and Sola, R.G., 2017. Effectiveness of vagal nerve stimulation in medication-resistant epilepsy. Comparison between patients with and without medication changes. Acta neurochirurgica159(1), pp.131-136.


4. Gioacchini, G., Rossi, G. and Carnevali, O., 2017. Host-probiotic interaction: new insight into the role of the endocannabinoid system by in vivo and ex vivo approaches. Scientific Reports7.


5. Howe, K., Clark, M.D., Torroja, C.F., Torrance, J., Berthelot, C., Muffato, M., Collins, J.E., Humphray, S., McLaren, K., Matthews, L. and McLaren, S., 2013. The zebrafish reference genome sequence and its relationship to the human genome. Nature496(7446), p.498.

6. Lewis, T. (2016) Stroke Alters Gut Microbiome, Impacting Recovery. The Scientist Magazine. From URL: http://www.the-scientist.com/?articles.view/articleNo/46557/title/Stroke-Alters-Gut-Microbiome--Impacting-Recovery/ Accesed online, 07 Oct 2017.


7. Ludányi, A., et al., 2008. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. Journal of Neuroscience28(12), pp.2976-2990.


8. Maness, L.R., 2016. The Effect of Butyric Acid on GLUT4 and IRS1 Expression in Human Preadipocytes in vitro.


9. NeuroscienceNews.com image adapted from The Sociable Scientist. http://thesociablescientist.com  


10. Pinto, L., Capasso, R., Di Carlo, G. and Izzo, A.A., 2002. Endocannabinoids and the gut. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA)66(2-3), pp.333-341.


11. Schwabe, R.F. and Jobin, C., 2013. The microbiome and cancer. Nature Reviews Cancer13(11), pp.800-812.

12. Singh, V. et al., “Microbiota dysbiosis controls the neuroinflammatory response after stroke,” The Journal of Neuroscience, doi:10.1523/jneurosci, 2016.

13. Vagus nerve stimulation. Epilepsy Society. from URL: https://www.epilepsysociety.org.uk/vagus-nerve-stimulation#.WdaI0a2ZM_U Accessed online, 07 Oct 2017.

14. Vivomixx. from URL: https://www.vivomixx.co.uk/faq.php Accessed online, 07 Oct 2017.(12)


15. Xie, G., Zhou, Q., Qiu, C.Z., Dai, W.K., Wang, H.P., Li, Y.H., Liao, J.X., Lu, X.G., Lin, S.F., Ye, J.H. and Ma, Z.Y., 2017. Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy. World Journal of Gastroenterology23(33), p.6164.


16. Zitvogel, L., Daillère, R., Roberti, M.P., Routy, B. and Kroemer, G., 2017. Anticancer effects of the microbiome and its products. Nat Rev Microbiol15, pp.465-78.


17. Zitvogel, L., Galluzzi, L., Viaud, S., Vétizou, M., Daillère, R., Merad, M. and Kroemer, G., 2015. Cancer and the gut microbiota: an unexpected link. Science translational medicine7(271), pp.271ps1-271ps1.


Friday, 6 October 2017

Biochemical individuality. Thoughts on the effectiveness of dichloroacetate as an anti-cancer agent from DNA testing and analysis

I have been using Prometheus to extract raw data from my 23andme raw data in an attempt to personalise my approaches moving forward. You can find out more here: https://promethease.com

https://www.britannica.com/science/DNA

Interestingly, following on from my post about DCA, I decided to determine what SNPs I had relating to specific nutrients, metabolic therapies, and drugs. I have explored this before, but not in as much depth as I have recently.

From pouring over the exhaustive amount of data detailed in my Prometheus report I found that I appear to be a slow metaboliser of DCA, which is interesting for a number of reasons.



DCA is an interesting chemical compound, because it can be a chlorine byproduct from chlorinating swimming pools and tap water, and the 'poison' could be in the dose, with some arguing that it may be a major environmental hazard, or a 'panacea for human ills'- This has not yet been proven definitively either way, as the study below has concluded, but perhaps never will be because it seems to be either helpful or harmful depending on the context. 


I came across this study when investigating if being a slow metaboliser could allow me to have greater harm from drinking chlorinated water, or, conversely, derive less potential benefit from treatment with DCA if I ever go down this route as a back up plan should I have a recurrence. In that case I may benefit more from intravenous DCA or I may not benefit significantly at all! Its interesting, harmful or helpful? Or both? Here is what I found...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040600/

And my own personal conclusion? Well, I often say with these things that whenever we have seemingly extreme views, the truth often lies somewhere in between and this seems to be the case with DCA.



There is biochemical individuality with any drug, diet, or drug, whether it be 'natural' or synthetic. This is why I value genetic testing and a personalised approach to any treatment protocol. It is also why I chose to discontinue chemotherapy a few years ago not long after starting. It was a personal decision based on the fact that my tumour was not chemosensitive and I was unlikely to benefit from progression free survival. Even if you believe cancer is a metabolic disease, it is our genetics that can help us to determine what might potentially be the most beneficial approaches for us as individuals. You are as unique as your cancer and we are all different despite the many things we can have in common.

So with all this in mind, what is your view of DCA? Effective for some but not all? Personalised application and dosages? Breakthrough effective metabolic cancer treatment or major environmental hazard? The truth probably lies somewhere in between these two main ideas. 





Wednesday, 23 August 2017

DCA and glioma

Human glioblastoma patients require at least a 6.25 mg/kg oral, twice-a-day dose of DCA (Dichloroacetate) to inhibit PDK (Pyruvate dehydrogenase kinase) and kill cancer cells as indicated in the study below (5).

http://artemisinin.pbworks.com/f/Metabolic+Modulation+of+Glioblastoma+with+Dichloroacetate.pdf



A reliable source of DCA can be found here:

https://www.dcalab.com


It comes in tablet form as well as a powder.



The main problems I see here is that you would need to have enough of the product to get the appropriate therapeutic dose and it is not cheap!


Simple background as to why DCA might be useful:

As many reading this will already know, most tumours display unique metabolism described as the 'Warburg Effect' which has long been associated with the resistance to apoptosis which characterises cancer. Even in tumours where glucose is maybe not the primary fuel, it appears to still play a key role as a major energy source. 

the Warburg Effect (9)


Cancer is clever, there are parallels with Darwinian natural selection (1), meaning it can adapt to use different fuels in the absense of others. With this in mind, I believe it is key to note that the best result is unlikely to come from a monotherapy approach. Nevertheless, this glycolytic phenotype in most cancers appears to be a common denominator and gives reason as to why all these molecular abnormalities occur, and as a result lead to defective mitochondria. The good news is that research suggests this suppression of mitochondrial function we see in cancer may be reversible with DCA at therapeutic doses.

Mitochondrial physiology (8)


DCA exerts its anti-cancer effects by inhibiting an enzyme called PDK (Pyruvate Dehydrogenase Kinase), a mitochondrial enzyme that is activated in a variety of cancers. Inhibition of PDK with DCA shifts the metabolism of cancer cells from glycolysis to glucose oxidation (7). As a result we would hope to see restoration of normal mitochondrial function and suppression of mitochondrial dependent apoptosis.



As I say, typically nothing works as effectively in isolation as with a multi-modal approach. Personally I would recommend a low carb, fasting mimicking diet, time restricted feeding and/or longer periods of just water fasting alongside DCA. 

Why?... 

Well, I get lots of people asking about how some tumours appear to be able to use fatty acids for energy after reading certain studies showing up regulation of lipogenic enzymes in cancer cells (4). It is well established that deregulated lipogenesis plays an important role in tumour cell survival (3) and as a result, FASN (fatty acid synthase) is also a therapeutic target. However... 

I wouldn't worry about this in the context of a continuous ketotic state or through implementation of a low carb diet and I will tell you why. Despite the fact that this phenomenon exists, research shows that the expression of FASN is highly dependent on nutritional conditions in lipogenic tissues. 

'FASN-catalysed endogenous FA biosynthesis in liver and adipose tissue is stimulated by a high carbohydrate diet, whereas it is suppressed by the presence of small amounts of FAs in the diet and by fasting.' (2,6) 




References

1. Greaves, M. and Maley, C.C., 2012. Clonal evolution in cancer. Nature481(7381), p.306.

2. Katsurada, A. et al. Effects of nutrients and hormones on transcriptional and post-transcriptional regulation of fatty acid synthase in liver. Eur. J. Biochem190, 427–433 (1990).

3. Mashima, T., Seimiya, H. and Tsuruo, T., 2009. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. British journal of cancer100(9), p.1369.

4. Menendez, J.A. and Lupu, R., 2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature reviews. Cancer7(10), p.763.

5. Michelakis, E.D., Sutendra, G., Dromparis, P., Webster, L., Haromy, A., Niven, E., Maguire, C., Gammer, T.L., Mackey, J.R., Fulton, D. and Abdulkarim, B., 2010. Metabolic modulation of glioblastoma with dichloroacetate. Science translational medicine2(31), pp.31ra34-31ra34.

6. Sul, H. S. & Wang, D. Nutritional and hormonal regulation of enzymes in fat synthesis: studies of fatty acid synthase and mitochondrial glycerol-3-phosphate acyltransferase gene transcription. Annu. Rev. Nutr. 18, 331–351 (1998).

7. Sutendra, G. and Michelakis, E.D., 2013. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Frontiers in oncology3.

8. Wallace, D.C., 2012. Mitochondria and cancer. Nature reviews. Cancer12(10), p.685.

9. Vander Heiden, M.G., Cantley, L.C. and Thompson, C.B., 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. science324(5930), pp.1029-1033.
  


Thursday, 22 June 2017

Analytics for my cryotherapy project.

I had a training session today at university with the Firstbeat Bodyguard, a sophisticated device I will be using to track activity and various health markers as I embark on my month long Whole Body Cryotherapy experiment. 

The equipment is also designed to assess how appropriate my diet and lifestyle is for my specific requirements alongside additional monitoring of sleep and how well I recover from personalised workouts throughout the duration of the experiment. It will be particularly interesting for me to assess just how much of my energy expenditure in each 24 hour period comes from fat and how this varies over the course of the day. 

I am looking forward to sharing more as I progress on this journey of discovery. 








Some examples of data collection:

http://www.henkpeteroonk.nl/en/firstbeat-bodyguard-2

http://www.wearethecity.com/professional-women-manage-stress-recovery-avoid-burn-firstbeat-life-assessment-insight-thrive-trial/