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Mack
Member since Jan-9-09
12 posts
Jan-15-09, 00:10 AM (PST)
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"DCA and acetyl l carnitine"
 
   While going through my science feeds today I came across this article:

http://www.sciencedaily.com/releases/2009/01/090112093334.htm

An interesting extract:

Boston College biologists and colleagues at Washington University School of Medicine found new evidence to support Warburg's theory by examining mitochondrial lipids in a diverse group of mouse brain tumors, specifically a complex lipid known as cardiolipin (CL). They reported their findings in the December edition of the Journal of Lipid Research.

Abnormalities in cardiolipin can impair mitochondrial function and energy production. Boston College doctoral student Michael Kiebish and Professors Thomas N. Seyfried and Jeffrey Chuang compared the cardiolipin content in normal mouse brain mitochondria with CL content in several types of brain tumors taken from mice. Bioinformatic models were used to compare the lipid characteristics of the normal and the tumor mitochondria samples. Major abnormalities in cardiolipin content or composition were present in all types of tumors and closely associated with significant reductions in energy-generating activities.

The findings were consistent with the pivotal role of cardiolipin in maintaining the structural integrity of a cell's inner mitochondrial membrane, responsible for energy production. The results suggest that cardiolipin abnormalities "can underlie the irreversible respiratory injury in tumors and link mitochondrial lipid defects to the Warburg theory of cancer," according to the co-authors."

Diabetics have cardiolipin defects in their heart which can lead to heart disease.

http://www.eurekalert.org/pub_releases/2007-08/wuso-afm081007.php

"These results suggest that cardiolipin alterations underlie heart dysfunction in diabetic heart disease and may be a useful biomarker for diagnosing cardiovascular disease in diabetes," Gross says. "Measuring alterations may be a way to tell the severity of heart disease and to evaluate how well therapies work. In addition, these findings suggest potential new therapeutic approaches."

Even though the research team found a depletion of an important type of lipid in diabetic heart tissue, diabetic heart muscle cells actually take in excess lipids. But as these lipids enter cells they activate lipid-digesting enzymes. In previous studies, Gross and colleagues identified a particular lipid-digesting enzyme that becomes more active in diabetic heart muscle and contributes to the breakdown of cardiolipin."

Cardiolipin (at least in the (rat) heart) can be normalised by acetyl l carnitine:

http://www.ncbi.nlm.nih.gov/pubmed/10431808?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"The effect of aging and acute treatment with acetyl-L-carnitine on the pyruvate transport and oxidation in rat heart mitochondria was studied. The activity of the pyruvate carrier as well as the rates of pyruvate-supported respiration were both depressed (around 40%) in heart mitochondria from aged rats, the major decrease occurring during the second year of life. Administration of acetyl-L-carnitine to aged rats almost completely restored the rates of these metabolic functions to the level of young control rats. This effect of acetyl-L-carnitine was not due to changes in the content of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was markedly reduced (approximately 40%) in aged rats. Treatment of aged rats with acetyl-L-carnitine reversed the age-associated decline in cardiolipin content. As the changes in cardiolipin content were correlated with changes in rates of pyruvate transport and oxidation, it is suggested that acetyl-L-carnitine reverses the age-related decrement in the mitochondrial pyruvate metabolism by restoring the normal cardiolipin content."

Finally my suggested link the DCA, it may significently increase acetyl carnitine after exercise:

http://jap.physiology.org/cgi/content/full/87/5/1747

Postexercise, PDH-a in AC and Con trials had increased significantly but was still significantly lower than in DCA trial. Acetyl-CoA did not increase in any trial, whereas acetylcarnitine increased significantly only in DCA"

It is clear to me from this site that DCA works fantastically for some people and not in others. Given it's suggested methodology of action it should work for everyone unless something is interfering (stating the bleeding obvious I know). We need to know what the differences are and correct them so it is effective for all cancers that use glycosis for energy.

For instance if you are diabetic with cancer perhaps your cardiolipin levels are already very low and this prevents DCA working effectively at the levels that don't cause neuropathy. If you are overweight your blood lipids may also lower cardiolipin because the excess fats entering cells trigger the cardiolipin digesting enzyme. Perhaps when taking DCA you need to exercise to trigger levels of ACL or to get enough oxygen into the reactived mitochondria that it triggers apoptosis, but given age and sickness and neuropathy, some patients are unable to do so.

This is a hypothesis only and there is so much we don't know! I can't find a single paper that ACL is enough to kickstart the mitochondria in cancer cells into causing apoptosis by restoring cardiolipin levels. It is however much less toxic than DCA. Given it helps with neuropathy and fatgiue (and has been used for this in trials of patients on chemo) maybe a lower dose of DCA with chronic administration of ACL is worth a try to see if it can enhance DCA's effects.

My regards to you all. Please add to or challenge this hypothesis if you find other data. It all helps!

antony


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Mack
Member since Jan-9-09
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Jan-15-09, 04:07 AM (PST)
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1. "RE: DCA and acetyl l carnitine"
In response to message #0
 
   A further addendum to my post focusing on Cardiolipin.

Conjugated Linoleic acid has been observed in studies to impair the growth of breast cancer. A possible mechanism is that it inhibits fatty acid synthase enes.
http://www.ncbi.nlm.nih.gov/pubmed/19116881?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Linoleic acid also appears to be a component of cardiolipin and studies on cells in vitro show that it increases cardiolipin.
http://www.ncbi.nlm.nih.gov/pubmed/12562862?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum


Melatonin, another underutilised compound that is showing promise in impairing cancer growth also protects cardiolipin.
http://www.ncbi.nlm.nih.gov/pubmed/18928424
Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection.


Cardiolipin deficiency leads to decreased cardiolipin peroxidation and increased resistance of cells to apoptosis.
http://www.ncbi.nlm.nih.gov/pubmed/18375209?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

And finally this:

Apoptotic interactions of cytochrome c: redox flirting with anionic phospholipids within and outside of mitochondria.
http://www.ncbi.nlm.nih.gov/pubmed/16740248?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed

"This conundrum has been resolved by establishing that mitochondria contain a pool of cyt c, which interacts with CL and acts as a CL oxygenase. The oxygenase is activated during apoptosis, utilizes generated ROS and causes selective oxidation of CL. The oxidized CL is required for the release of pro-apoptotic factors from mitochondria into the cytosol. This redox mechanism of cyt c is realized earlier than its other well-recognized functions in the formation of apoptosomes and caspase activation. In the cytosol, released cyt c interacts with another anionic phospholipid, PS, and catalyzes its oxidation in a similar oxygenase reaction. Peroxidized PS facilitates its externalization essential for the recognition and clearance of apoptotic cells by macrophages. Redox catalysis of plasma membrane PS oxidation constitutes an important redox-dependent function of cyt c in apoptosis and phagocytosis. Thus, cyt c acts as an anionic phospholipid specific oxygenase activated and required for the execution of essential stages of apoptosis"

Regards

antony


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billn
Member since Apr-27-07
98 posts
Jan-15-09, 07:14 PM (PST)
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2. "RE: DCA and acetyl l carnitine"
In response to message #1
 
Regards the final paragraph,

This is part of the reason that caffeine is suggested - it stimulates Cytochrome C release, while inhibiting CYP1A2, which is a Cytochrome C suppressant.

Billn


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didierphmartin
Member since Apr-16-08
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Jan-15-09, 08:03 PM (PST)
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3. "RE: DCA and acetyl l carnitine"
In response to message #1
 
   If we pay close attention to the cardiolipin synthesis pathway we can notice that the cell membrane composition is also important. In other words, the type of polyunsaturated lipid contained in the cell membrane may potentially be important in the process.

For ref about the cardiolipin synthesis pathway see: http://www.biocarta.com/pathfiles/cardiolipinPathway.asp

Another dimension to consider is the type of microenvironment where the cancer cells evolve. People having a low omega 3 to 6 ratio have an environment that sustain inflammation. It has been observed that in some diseases like lipus (an auto immune disease) the concentration of cardiolipin antibodies is quite high.

This is an hypothesis too. But I personally think we cannot disconnect the inherent inflammation micro-environment and the mithocondria disfunction. Maybe it only two facets of the same disorder (in the tumor I mean , not in sane tissues).

Cheers
Didier PH Martin, PhD.


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Mack
Member since Jan-9-09
12 posts
Jan-15-09, 11:49 PM (PST)
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4. "RE: DCA and acetyl l carnitine"
In response to message #3
 
   Excellent points. I wonder if low level systemic inflammation (that shouldn't be there) is the thing that makes us more susceptible to cancer rather than causes it? For instance it may cause insulin resistance, which leads to diabetes which appears to lead to degradation of the cardiolipin and thereafter when a cell becomes defective it doesn't die. It would imply that diabetics should have a greater incidence of cancers.

We are here though because we, our family and friends have cancer and usually of a stage where mainstream therapy hasn't worked as well as we'd hoped. We need a treatment that addresses fast growing and unresponsive tumours and to kill these suckers we want all the cells of that tumour to have the proper cellular amounts in their proper place of cardiolipin, cyt C and phosphatidylserine (PS) to trigger apoptosis when we use dca at levels that won't cause side effects.

One thing that puzzles me that maybe you can help me with. DCA is a small molecule which can get into cells. In a cancer cell DCA blocks PDK because it resembles pyruvate. This increases PDH, which converts pyruvate to acetyl CoA. Is it the presence of this acetyl CoA which restarts the mitochondria? This is said to generate a much greater than usual ROS because acetyl CoA becomes unlimited and these ROS oxidise cardiolipin and leads to the release of the cyt c which results in the apoptosis of the cell. Adequate levels of PS might be required as well.

As I understand this theory, it won't happen in normal cells because acetyl CoA is a self regulating mechanism, the mitochondria will burn through it if it is there, generating ROS that would kill the cell but at a certain concentration it activates PDK which shuts down the conversion of pyruvate until acetyl CoA levels are used up. Is this correct?

If so, then cancer cells must not allow the production of acetyl CoA at all. what is the mechanism by which its production is blocked in cancer? (I'm betting there is a complicated answer to that one)

I was also wondering if instead there was any research to show that it is the combination of free radicals produced by the glycosis energy mechanism combined with the ROS produced by the reinvigorated mitochondria that might be the cause of dca's potency? I thought I had read such some years ago but now can't find the reference. Its relevance to treatment with DCA is that if both energy pathways are activated and cause cell death, it might be beneficial to take extra glucose at the same time as DCA (putting fuel on the fire).

Recent research is beginning to show that when cells are deprived of oxygen for more than 3 minutes, they don't necessarily die right away but enter a low oxygen state. It is actually the resumption of oxygen into the cell (reperfusion injury) that triggers apoptosis and kills the cell. Occasionally when young children fall into ice water and drown the cold somehow prevents this mechanism and they can be resuscitated without major damage after longer periods of time without oxygen. It's rare but can happen and increasingly in hospital settings cooling the body is being used in operations to prevent injury from oxygen deprivation.

So what drives this damage? Why does a short term lack of oxygen in cells appear to do the same job as DCA, does it inhibit PDK or is there another mechanism? And why does the cold sometimes prevent this- simple prevention of the apoptopic chemical reaction through the lower temperature?

Approaching it from a different direction for cancer treatment could there be some benefit for those taking DCA in subjecting themselves to short term increases of body temperature (spa/sauna) during treatment or even localised heat on tumours?

Antony


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didierphmartin
Member since Apr-16-08
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Jan-16-09, 03:35 PM (PST)
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5. "RE: DCA and acetyl l carnitine"
In response to message #4
 
   In fact, DCA re-activate the production of ATP by protein complexes located in the inner membrane of mitochondria. It allows pyruvate to get into the I to IV complexes. But something else may prevent the electrons to freely move from one complex to the other and therefore produce ATP as the end result. Cafeine stimulate the electron transport and so do Acetyl L carnitine and Coenzyme Q10.

It has been shown in some studies that the a P53 gene mutation induce a downregulation of SCO2(synthesis of cytochrome c oxidase 2) which is critical for the assembly of the cytochrome c oxidase complex embedded in the inner mitochondrial membrane. So not only pyruvate can be prevented to enter the mitochondrial complexes but also a genetic mutation (p53) can impair the electron transport in the mitochondrial complexes.

In conclusion: DCA alone is most likely unsufficient and the addition of other mitochondrial complexes "boosters" could be required. Among them, Acetyl L carnitine, cafeine and coenzyme Q10.

Cheers
Didier PH Martin, PhD.


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didierphmartin
Member since Apr-16-08
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Jan-16-09, 04:09 PM (PST)
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6. "RE: DCA and acetyl l carnitine"
In response to message #4
 
   Sorry, I could not edit the previous message to add a specific answer to your question, a system error occured on the server. So I'll do it in this message.

Normally when a good concentration of acetyl CoA is present in the mitochondria, it is enough to start the electron transport process. However that transport can be jeopardized by insufficient concentration of other enzymes like cytochrome c and coenzyme Q10.

Cytochrome c is present in the mitochondria intermembrane and coenzyme Q10 is present within the inner membrane. Both are required to fuel the electron transport process. Cafeine takes care of the cytochrome c but not of coenzyme Q10 which is less and less present as we age. Thus, both cytochrome c and coenzyme Q10 are required by the electron transport process (ref: http://en.wikipedia.org/wiki/Oxidative_phosphorylation).

Now, as soon as the electron transport process comes back to life, ROS and other process by products will occur and these byproducts create normal cell apoptosis (cell death). So, the cell comes back to a limited life cycle.

Cheers
Didier PH Martin, PhD.


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Mack
Member since Jan-9-09
12 posts
Jan-19-09, 05:02 AM (PST)
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7. "RE: DCA and acetyl l carnitine"
In response to message #6
 
   Thanks for your help. I should have realised that acetyl CoA production couldn't be the cause of dca's effectiveness as it would do this to all cells not just cancer and cause widespread apoptosis.

Two things I've noticed while trying to get up to speed on mitochonria and apoptosis research. A lot of people here are taking alpha lipoic acid (ALA) to deal with the neuropathy and it is used very effectively for just this purpose for diabetic neuropathy. However ALA is an excellent cellular anti-oxidant and reactive oxygen species (ROS) seem to play a major role in triggering or completing the apoptosis pathway- especially the one we hope dca activates. If we effectively scavenge ROS from the cells by ALA it may prevent cancer cell apoptosis from occuring. Would you agree?

The other is the involvement of Ca2+ ions in apoptosis, not too sure how or why yet but it seems mitochondria accumulate and release Ca2+ and this activates the (or a) apoptosis pathway. On this basis anyone who is taking calcium channel blockers for high blood pressure could be impeding the effectiveness of dca. Not suggesting that anyone discontinue if prescribed CCB's but it should be taken into account if there is no response to dca. I am also wondering if taking extra calcium of some form would be of benefit or harmful?

Finally I'm thinking of getting a very sick friend friend of mine on this dca and want the best protocol that has worked like a charm on anyone else here with metastacized breast cancer (lymph, brain, lung, arm, throat) - I have to persuade her that it will be better than the chemo that has devastated her life on and off for 20 years. She has put such faith in doctors to date and has felt that if she abandons following their advice that it will be like giving up but the cancer appears completely resistant now and I need something outside the box if she is to survive. All the doctors have done is double the dose of the ineffective chemo. It makes her very very sick.

From what I have read here and elsewhere I am thinking:
dca (dosage?)
co-enzyme Q10 (300mg a day enough?)
acetyl l carnitine (restore cardiolipin levels and boost mitochondria- say 3x500mg a day?)
conjugated linoleic acid (both as a cancer/fatty acid synthase inhibitor and also as a precursor to cardiolipin)
caffeine (to trigger cytochrome C)
phosphatidylserine or a precursor (when oxidized by Cyt C during apoptosis it is extruded from cell membrance and attracts macrophages to devour the cell)

Is there anything else I should add or consider? For instance Vitamin D3 and melatonin are said to be quite good but I don't know if they will interefere with or enhance the dca apoptosis approach. And melatonin in Australia requires a prescription. Resveratrol, the red wine component that is getting some good reports in the press I'm not sure about- some studies say it kills cancer, others that it provents apoptosis.

Regards and thanks

antony


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Sandra
Member since Feb-27-07
604 posts
Jan-19-09, 05:39 AM (PST)
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8. "RE: DCA and acetyl l carnitine"
In response to message #7
 
Fantastic posts! A long time ago I looked at supplements used by patients with Huntington's Disease, because (like cancer) it involves mito disfunction. Any comments from either of you on these?
http://www.thedcasite.com/dcaforum/DCForumID10/52.html

Thanks,
Sandra


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hardrock
Member since Jun-17-07
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Jan-19-09, 05:30 PM (PST)
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9. "RE: DCA and acetyl l carnitine"
In response to message #8
 
   In response to Mack' comment "the involvement of Ca2+ ions in apoptosis" there is a paragraph on page 157 in the book 'The Salt Solution' by Boynton, McCarty and Dr Moore that reads: "the rate at which cells divide is inversely proportional to their plasma membrane potential." Cancer cells have a very low potential while normal cells have a high potential.

Their point is we are consuming too much sodium and not enough potassium to get the proper cellular K/Na ratio(electrolytes).
Decreasing the K/Na ratio in cells leads to an increased level of intracellular Ca2.

This book is an eye opener but unfortunately interested biophysicists were unable to motivate cancer reasearchers. I found my copy on Amazon.


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Mack
Member since Jan-9-09
12 posts
Jan-20-09, 00:19 AM (PST)
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10. "RE: DCA and acetyl l carnitine"
In response to message #8
 
   I recently saw a study that suggests and old drug called clioquinol may reverse alzheimers, parkinsons and huntingdon's- at least in animals.

http://www.sciencedaily.com/releases/2009/01/090106170748.htm

However it may work on a process different to that relevant to dca.

Low dose Methylene Blue also seems to energise the mitochondria positively in Alzheimers and Parkinsons.

http://www.sciencedaily.com/releases/2008/08/080818101335.htm

"One of the key aspects of Alzheimer's disease is mitochondrial dysfunction, specifically complex IV dysfunction, which methylene blue improves. Our findings indicate that methylene blue, by enhancing mitochondrial function, expands the mitochondrial reserve of the brain."

Didier said earlier that "DCA re-activate the production of ATP by protein complexes located in the inner membrane of mitochondria. It allows pyruvate to get into the I to IV complexes", so perhaps DCA shares some chemical simularities with methylene blue.

I was interested to read your earlier thread that dca and ALA worked better together in shrinking tumours. I felt sure that a potent antioxidant would have detracted from triggering apoptosis by inhibiting ROS production. Perhaps it works due to ALA's role as an inhibitor of NF-KB, the inflammatory pathway that triggers growth and metatastis. I do know that some very many chemotherapy treatments while originally killing tumours, increase the NF-KB pathway which can drive the growth and spread of tumours. I privately believe this happened in my friends case but do not want to tell her that in case it breaks her spirit. On the positive side there are many studies that the compound curcumin shuts down the NF-KB pathway. For example:

http://www.ncbi.nlm.nih.gov/pubmed/16243823?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis.

"In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products."

The recent good claim on resveratrol is here:

http://www.ncbi.nlm.nih.gov/pubmed/18996091?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"Results revealed that inhibition of proliferation is associated with regulation of the JAK/STAT pathway, where resveratrol prevents phosphorylation of JAK, thereby inhibiting STAT1 phosphorylation. Furthermore, resveratrol treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. Consequently, an imbalance in the Bax/Bcl-2 ratio triggered the caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favor of apoptosis. These observations indicate that resveratrol treatment inhibits JAK/STAT-mediated gene transcription and induce the mitochondrial cell death pathway."

http://www.ncbi.nlm.nih.gov/pubmed/18850184?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"In this work we demonstrated that the stilbene trans-resveratrol was able to commit human breast cancer MCF-7 cells to apoptosis. Mainly, we evidenced a pivotal role of the mitochondria in this phenomenon as cytochrome c release into the cytosol was found after the treatment. We further showed that trans-resveratrol was able to affect cellular redox state. In particular, it induced an early production of ROS and lipid oxidation, and only later compromised the GSH/GSSG ratio. This mode of action was mirrored by a temporally different activation of JNK and p38(MAPK), with the former rapidly induced and the latter weakly activated at long intervals. The results obtained demonstrate a pro-apoptotic activity for trans-resveratrol, and suggest a preferential activation of different classes of MAP kinases in response to different oxidative stimuli (ROS versus GSH/GSSG alteration)."

The trick for us here is not simply to add everything that may work but narrow down the protocol to the smallest number of chemicals (nutrients, chemicals or pharma drugs) that has the greatest apoptopic effect for the least side effect.

The danger is by adding everything that sounds good, the interaction between chemicals may cancel out a positive effect and we might end up discarding something that may work. We may take too much of something and negate its good effect or take too little and see no response. Hopefully we can work this out based on pure science, where it is available from studies and reports, and where it is not, by shared protocols between list contributors.

In theory acetyl l carnitine should help dca therapy by activating the mitochondria and restoring cardiolipin to youthful levels but does it? Should we load up our cells (cancer or healthy) with mitochondrial compounds such as Q10, ALC, etc before using DCA so as to prime them for DCA triggered apoptosis? Is there anyone here already using it with dca for a few weeks for neuropathy and having a better/worse response?

All the best to you all

antony


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parachute
Member since Mar-20-07
39 posts
Jan-20-09, 02:37 AM (PST)
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13. "RE: DCA and acetyl l carnitine"
In response to message #10
 
   Antony wrote,

"In theory acetyl l carnitine should help dca therapy by activating the mitochondria and restoring cardiolipin to youthful levels but does it? Should we load up our cells (cancer or healthy) with mitochondrial compounds such as Q10, ALC, etc before using DCA so as to prime them for DCA triggered apoptosis? Is there anyone here already using it with dca for a few weeks for neuropathy and having a better/worse response?"

When I began taking DCA 9 months ago I was already taking Acetyl L Carnitine in hope of relieving certain SE resulting from RT and 2 years of androgen blockade. I also take a lot of curcumin. Aside from a few days of PN following four days of dehydration and overexertion working in the desert, I've experienced no symptoms. And the benefits of DCA have been astonishing.

I've had no time off ALC for comparison so unfortunately this is merely anecdotal. But it's one more data point.

DCA 10mg/Kg/day 5 days on, two days off. Details:

http://www.thedcasite.com/dcaforum/DCForumID2/244.html

Best,

Randy



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Mack
Member since Jan-9-09
12 posts
Jan-20-09, 06:22 AM (PST)
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14. "RE: DCA and acetyl l carnitine"
In response to message #13
 
   It is so fantastic that what you are doing is working for you so well. Even to read one story like this gives me hope.

If I understand your linked post correctly the prostate cancer is still there but held almost completely in check, you feel great, you aren't on any chemo (other than dca and the listed supplements) and aren't suffering any side effects from the cancer or the dca. Is that right?

Can I ask why you never took coenzyme q10 as part of your protocol? Was it something you didn't know about? I'm thinking of trying my friend on 450mg a day split into three doses with meals. In Australia I can get 120 capsules of 150mg Q10 for $88 AUD which comes to about $2.20 AUD a day. It has small amounts of EPA and DHA in the capsule but nothing at the level you are taking.

I can also get 50 grams Musashi acetyl l carnitine powder from a health food store for about $50 AUD.

Also the curcumin you mentioned wasn't on the original list of supplements you were taking. Is that a recent addition and what amount do you take?

Regards

antony


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parachute
Member since Mar-20-07
39 posts
Jan-20-09, 08:19 AM (PST)
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15. "RE: DCA and acetyl l carnitine"
In response to message #14
 
   Responses interspersed:

Mack: If I understand your linked post correctly the prostate cancer is still there but held almost completely in check, you feel great, you aren't on any chemo (other than dca and the listed supplements) and aren't suffering any side effects from the cancer or the dca. Is that right?

Randy: Correct on all counts except that the supplements listed in my original post are only those which I feel minimize risk of PN. Full list below. I have never had chemo.

M: Can I ask why you never took coenzyme q10 as part of your protocol? Was it something you didn't know about? I'm thinking of trying my friend on 450mg a day split into three doses with meals.

R: What is her weight if you don't mind my asking? Or the proposed dose in mg/Kg?

M: In Australia I can get 120 capsules of 150mg Q10 for $88 AUD which comes to about $2.20 AUD a day. It has small amounts of EPA and DHA in the capsule but nothing at the level you are taking.

R: I believe EPA and DHA are critically important. I took CoQ10 for 3 or 4 years. I've been tracking PSA velocity against supplements and have decided that simple is good. Dropped CoQ10 recently however perhaps I should reconsider.

M: I can also get 50 grams Musashi acetyl l carnitine powder from a health food store for about $50 AUD.

Also the curcumin you mentioned wasn't on the original list of supplements you were taking. Is that a recent addition and what amount do you take?

R: I've been taking curcumin for about three years. However when the molecular oncology work showed potential efficacy as an adjunct to chemo I got serious about it, switched to a form with seven times the potency per milligram and increased dose from one capsule a day to 8.

http://www.lef.org/Vitamins-Supplements/Item00407/Super-Bio-Curcumin.html

My caffeine intake is about 1,000mg/day by longstanding preference.

Didier mentions inflammation and I believe it plays a role in etiology and progression. I had severe joint inflammation and BPH for many years prior to my PC Dx. I overdid the NSAIDs and caused damage to stomach lining. Incredibly, an herbal product called Zyflamend has completely relieved the joint pain and stiffness with zero SE. This non-Rx product "exhibits antiproliferative, antiinflammatory, antioxidant, antiangiogenic, and apoptotic activities; inhibited receptor activator of NF-kappa B ligand-induced osteoclastogenesis, suppressed tumor necrosis factor (TNF)-induced invasion, and potentiated the cytotoxicity induced by TNF and chemotherapeutic agents, all of which are known to require NF-kappa B activation..."

http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=retrieve&dopt=Abstract&list_uids=17516865

See also:

http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=retrieve&dopt=Abstract&list_uids=17218785

http://www.ncbi.nlm.nih.gov/sites/entrez?db=PubMed&cmd=retrieve&dopt=Abstract&list_uids=17351029

In closing, hope you noticed this terrific report today:

http://www.thedcasite.com/Tim_McGough_lymphoma_case.html

Sorry, Excel does not paste gracefully here but you get the idea:

What Dose Morning Evening Empty Stomach
5-Loxin 75MG 1
7-HRM Lignans Swanson 40mg 1 1
Acetyl-L-Carnitine LEF 1
B 12 Sublingual 3000mcg 1 1
Benfotiamine 250mg 2 2
Bone-UP Jarrow 1 Bedtime
Capsibiol-T green tea & capsaicin 2 1
Carnitine 1400mg 1 1
Citrus Pectin Fractionated Tablespoon 1 Yes
Complete Vitamin B Complex LEF 1 1
Curcumin, LEF Super Bio 400mg 7x absorption 4 4
D3 10,000iu/day 5 5
DHA Jarrow Max 600mg 1 1
EPA- Nordic Naturals 1g 1 1
Green Tea Extract 725mg 1 1
Magnesium Glycinate 200mg 1 1
Melatonin 40mg Evening
Multi Vitamin no copper or iron 1
Pomegranate Extract 500mg 1 1
Quercetin 500mg 1 1
R-Lipoic Acid 300mg 1 1
SAMe 400mg 2 2
Se-Methyl-Selenocysteine 200mcg 1
Silymarin 900mg 1
Strontium 340mg 1 Bedtime
Turmeric Supreme ETOH extract turmeric root 400mg 1 1
Zyflamand large capsules 1 1


Best,

Randy



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Mack
Member since Jan-9-09
12 posts
Jan-21-09, 02:12 AM (PST)
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18. "RE: DCA and acetyl l carnitine"
In response to message #15
 
   Responses snipped & interspersed for brevity:
...
M: Can I ask why you never took coenzyme q10 as part of your protocol? Was it something you didn't know about? I'm thinking of trying my friend on 450mg a day split into three doses with meals.

R: What is her weight if you don't mind my asking? Or the proposed dose in mg/Kg?

About 50kg or under now. There was a study were 3 women with breast cancer including one that had spread to the lungs seemed to go into remission on high dose Q10. Critics contend the studies were unreliable as they also had chemo and other supplements. No-one appeared to follow up the early study with another. Other studies indicate that BC women are low in Q10 and as it appears non-toxic at high doses thought it might be worth a try.

R: I believe EPA and DHA are critically important. I took CoQ10 for 3 or 4 years. I've been tracking PSA velocity against supplements and have decided that simple is good. Dropped CoQ10 recently however perhaps I should reconsider.

Probably you could drop a few supplements without interfering with your results but since it is working so well, why take the risk? Just wish it could deliver a knockout punch to the PC. Other than their anti-inflammatory effects I wonder if EPA and DHA contribute to restoring cardiolipin levels? I will have to do some more research on that.

R: I've been taking curcumin for about three years. However when the molecular oncology work showed potential efficacy as an adjunct to chemo I got serious about it, switched to a form with seven times the potency per milligram and increased dose from one capsule a day to 8.

http://www.lef.org/Vitamins-Supplements/Item00407/Super-Bio-Curcumin.html

This is good to know. I love curries but not that much!

My caffeine intake is about 1,000mg/day by longstanding preference.

Didier mentions inflammation and I believe it plays a role in etiology and progression. I had severe joint inflammation and BPH for many years prior to my PC Dx. I overdid the NSAIDs and caused damage to stomach lining. Incredibly, an herbal product called Zyflamend has completely relieved the joint pain and stiffness with zero SE. This non-Rx product "exhibits antiproliferative, antiinflammatory, antioxidant, antiangiogenic, and apoptotic activities; inhibited receptor activator of NF-kappa B ligand-induced osteoclastogenesis, suppressed tumor necrosis factor (TNF)-induced invasion, and potentiated the cytotoxicity induced by TNF and chemotherapeutic agents, all of which are known to require NF-kappa B activation..."

Very interesting. The disclosed list of ingredient are

Holy Basil:
Turmeric:
Ginger:
Green Tea:
Rosemary:
Hu Zhang:
Chinese Goldthread and Barberry:
Oregano:
Scutellaria:

In closing, hope you noticed this terrific report today:

http://www.thedcasite.com/Tim_McGough_lymphoma_case.html

M: Did read that. Just fantastic. Sometimes I think if Doctors were co-administered the same chemo they give to patients, the research into dca or even 3-bromopyruvate would suddenly gain huge momentum...

I worry that the clinical trial of DCA may fail because patients will be instructed not to take additional supplements which enhance its effect because it will cloud the results. Thinking of this, it occured to me that this could be the reason why most drugs tested in mice routinely cure cancer but fail in human trials. The mice are young and healthy- at least until we transplant human tumours into them. The cancers then hijack their system and grow and ultimately kill the mouse. The medication might work because their underlying systems are still ok, apoptopic pathways intact, lipids normal etc. When you trial a single drug on humans, usually those who have been given no hope, their system is already compromised and may have led to the tumour in the first place. Inflammation, hyperlipidemia, high insulin, high glucose etc. They aren't testing the same thing. The equivalent (immoral) test would be like transplanting tumours into a healthy 22 year old in the prime of their lives and trying the drug on them. Just a thought...

All the best

Mack


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Sandra
Member since Feb-27-07
604 posts
Jan-21-09, 07:28 PM (PST)
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19. "RE: DCA and acetyl l carnitine"
In response to message #18
 
Mack,

Just a note on why its so easy to cure cancer in mice...

'Regarding the use of mice or rats as experimental models for chemotherapy of cancer, one big problem is the incredible ability to detoxify, their liver and kidney are powerful organs compared to humans. It is mostly because their basal rate of metabolism is 8-10 times higher than that of humans. The other big problem that misrepresents the results and conclusions is the size of the tumor as a ratio of body weight-namely the distribution of the drug in the tumor and rest of the body. In a mouse that weight about 25 grams, the smallest palpable tumor is 250 mg (bearly noticable). That would represent a ratio of tumor to total body weight of 1/100, which for a human would be huge, unheard of after surgical resection. Thus, the distribution of the drug between tumor and rest of body assuming that there is no specific accumulation at a particular site would favor the tumor in the animal. Namely, more of the drug would accumulate in the tumor area in the mouse than in a human. The relative size of the tumor to body does not affect the results of the drug activities on the tumor cells.'


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Sandra
Member since Feb-27-07
604 posts
Jan-20-09, 08:02 PM (PST)
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16. "RE: DCA and acetyl l carnitine"
In response to message #10
 
Just a side note on lipoic acid. I found what looks to be a great resource on it here, and there are large (free) excerpts:

Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects
edited by Mulchand S. Patel and Lester Packer

http://books.google.com/books?id=XmxJS2L1LO8C&printsec=frontcover&dq=DCA+lipoic+acid&source=gbs_summary_r&cad=0

I don't know why lipoic acid seems to work with DCA, but just for reference, I'll post a link here to the patent info:
http://www.thedcasite.com/alpha_lipoic_acid_and_dca.html

And why I use R+ lipoic acid:
http://www.r-lipoic.com/

I also found it interesting that Dr. Berkson got fantastic results using lipoic acid and LDN in a Pancreatic cancer patient:
http://www.thedcasite.com/Library/Berkson_Rubin_pape_%20pancreatic_cancer.pdf


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didierphmartin
Member since Apr-16-08
12 posts
Jan-20-09, 00:23 AM (PST)
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11. "RE: DCA and acetyl l carnitine"
In response to message #7
 
   I agree on the first point. Taking Lipoid acid, a strong anti-oxidant can do the opposite of the desired effect in tumor cells.

I have to think more about the calcium because there are some conflicting studies about it. I need to sort it out.

I would suggest high doses of EPA/DHA supplements. Something like 10g EPA and 10g DHA per day. The best route is to slowly increase the omega 3 supplements. The best supplement I found to date is medOmega from Carlson containing 1200mg per teaspoon of both EPA and DHA. Thus, a tablespoon would gives 3600 mg of EPA and DHA. A tablespoon can easily be taken just before meals. So the trick would be to start with a tablespoon per day and slowly increase the dosage. As documented in numerous studies (see in pubmed) EPA stimulate the production of anti-inflammation prostaglandins. On the other hand, DHA act on some apotosis pathways. EPA will also change the cell membrane composition and the added membrane flexibility will make more easy the job of the receptors. Several recent studies and in particular and soon to be published one by Dr Pardini from U of Nevada show that chemo effect is increased with omega and make the cell less resistant to it. This implies that high dosage of omega by changing the cell membranes makes the reception of several drug, notably DCA, more active. We should not forget that mitochondria also have an external membrane similar to the cell membrane and that the added flaxibility will facilitate the job of the pyruvate receptor.
The other goal is to reduce to its strict minimum omega 5 intake. Omega 6 is the precursor of arachidonic acid which itself is a precursor of pro-inflammatory prostaglandins.
In the January 2009 Nature journal we saw the proposal of a new property to be added to the now famous hallmark of cancer 6 properties. The last one to be added is an inflammatory micro-environment. This environment is needed by most of cancer cell to assure their growth. Anything that could modulate the inflammatory micro-environment will reduce the resitance of tumor cells.

Didier PH Martin, PhD.


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didierphmartin
Member since Apr-16-08
12 posts
Jan-20-09, 10:30 PM (PST)
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17. "RE: DCA and acetyl l carnitine"
In response to message #11
 
   The link between acetyl-L-cysteine, DCA and lipoid acid is not that obvious. I need to do a second check of the literature. Maybe here, the interaction of all these elements do not involve ROS to create apoptosis but other pathways. The question is not only the interaction but also the dosage of lipoid acid. So, Some of Sandra's post brought some doubts in my first conclusion.

Didier PH Martin, PhD.


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didierphmartin
Member since Apr-16-08
12 posts
Jan-20-09, 01:24 AM (PST)
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12. "RE: DCA and acetyl l carnitine"
In response to message #7
 
   giving second thought about acetyl-L-carnitin it may synergistically act with DCA on a different pathway. As we know, most of tumoral cells live by aerobic glycolysis. DCA's goal is to re-activate the full processing of glucose. However, cells also rely on lipids or proteins as mitochondrial fuel. Acetyl-L-carnitin act on a second energy pathway by "boosting" the usage of lipids for beta oxidation. Sandra mention this link (http://www.stanford.edu/group/hopes/treatmts/ebuffer/j6.html) explaining the acetyl carnitine metabolism pathway.

I tried to find a site to give you a ref to understand the second energy pathway based on lipid and was strucked by the fact that most of them illustrates only the glycolysis pathway. It seems that we are a society obsesed by glucose

I thinnk I need to explore more the relation EPA/DHA and acetyl-L-carnitine. Maybe you are into something. This could potentially be a second pathway to activate the slugish mitochondria of tumoral tissues.

Didier PH Martin, PhD.


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Mack
Member since Jan-9-09
12 posts
Jan-21-09, 11:45 PM (PST)
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20. "RE: DCA and acetyl l carnitine"
In response to message #12
 
   How about this:

http://www.jlr.org/cgi/content/full/39/8/1583

"Docosahexaenoic acid-enriched cells had increased mitochondrial potential and produced 5-fold more cellular oxidants than did cells enriched with any other fatty acid. Oxidant production in fatty acid-enriched HT-29 cells did not correlate with the degree of unsaturation for total membrane fatty acids. However, there was a strong correlation between the degree of fatty acid unsaturation of cardiolipin, a critical inner-mitochondrial membrane phospholipid, and oxidant production. Cardiolipin acyl composition is known to influence the activity of electron transport complexes, an effect that can increase mitochondrial oxidant production. Docosahexaenoic acid was enriched to 48 mol% of the fatty acids present in HT-29 cell cardiolipin.

These results demonstrate the importance of membrane acyl composition to mitochondrial potential and oxidant production in live cells. Additionally, results suggest that docosahexaenoic acid increases cell oxidant production by accumulating in cardiolipin, where its presence alters electron transport efficiency.—Watkins, S. M., L. C. Carter, and J. B. German. Docosahexaenoic acid accumulates in cardiolipin and enhances HT-29 cell oxidant production. J. Lipid Res. 1998. 39: 1583–1588."

cheers

Antony


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didierphmartin
Member since Apr-16-08
12 posts
Jan-23-09, 00:27 AM (PST)
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21. "RE: DCA and acetyl l carnitine"
In response to message #20
 
   That's a good one Antony! I read it at least 5 times to be sure I get it right.

So it seems that colon adenocarcinoma cells(1) can potentially be lead to apoptosis with DHA. This is the first document I encounter that describe the lipid content of cardiolipids and its impact on the mitochondria voltage. For mitochondria that can still use beta oxidation, this could lead to apoptosis even without the other pathway based on glucose and that are re-activated with DCA. It could also mean that DCA+DHA can induce apoptosis to at least stage II colon carcinoma cells like HT-29.

It also implies that several men following the Budwig diet rich in alpha linolenic acid but who have a low DHA conversion (2,3) do not experiment the same results as women do (4). For these men, a more concentrated form of DHA is required. Such as high concentration EPA/DHA fish oil supplements for example.

It can potentially explain why the Dr Pardini's case describing a 78 years old men who got into remission of a lung cancer with a high dosage ingestion of DHA. After 4 years, he was able to reduce to near zero his multiple tumors (5). He died 8 years later (86 years old) from natural death and not from his tumor or any metastasis.

Pardini as well as me believed that DH case tumor reduction was due to lipid peroxidation but without a more detailed mechanism. This document provides a potentiel one.

Many thanks Antony for that pearl. Keep doing your great foraging job and your focus on cardiolipin.

Cheers
Didier PH Martin, PhD.


References:
-----------
(1) HT-29 descriptions: http://www.biotech.ist.unige.it/cldb/totcl5292.html
(2) Budges & al. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men. Br J Nutr. 2002 Oct;88(4):355-63.
(3) ISSFAL Newsletter, Volume 14 Number 3, Winter 2007
(4) Budges & al (2003). Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr. 2003 Nov;90(5)93-4; discussion 994-5
(5)Pardini et al. Nutritional Intervention With Omega-3 Fatty Acids in a Case of Malignant Fibrous Histiocytoma of the lungs (ref:http://toosexyformyhair.com/nutritionandcancer-1.pdf)


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didierphmartin
Member since Apr-16-08
12 posts
Jan-23-09, 02:08 AM (PST)
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22. "RE: DCA and acetyl l carnitine"
In response to message #20
 
   The study you mention is interesting because of the detailed in-vitro reaction of the cells mitochondria to DHA. Here are two other IN-VIVO studies that give more info. I get these two in my research folder and best of all, they are freely accessible on the net.

a) http://carcin.oxfordjournals.org/cgi/content/full/23/11/1919?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%28cardiolipin+AND+DHA%29&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

b) http://carcin.oxfordjournals.org/cgi/content/full/26/11/1914?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=%28cardiolipin+AND+DHA%29&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

They mention butyrate acid and the local action of it because of its natural production by some gut bacteria from their metabolism of pectin and other polysacharides (fibers). But we can infer that this action could be also available elsewhere with sodium bytyrate and DHA. Hence, could not be limited to only colon tumoral cells.

Didier PH Martin, PhD.


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Sandra
Member since Feb-27-07
604 posts
Jan-23-09, 03:38 AM (PST)
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23. "RE: DCA and acetyl l carnitine"
In response to message #22
 
Jim also has quite a few links on DHA here:

http://www.thedcasite.com/Omega3/Omega3.html

and butyrate:

http://www.thedcasite.com/Butyrate.html


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billn
Member since Apr-27-07
98 posts
Jan-27-09, 10:04 PM (PST)
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24. "RE: DCA and acetyl l carnitine"
In response to message #23
 
Here is some interesting stuff on Serpins:

http://en.wikipedia.org/wiki/Serpin

SerpinA9 (Centerin)seems to be linked to lymphoid malignancy.

Seems these Serpins are in most living organisms from plants, viruses, fungi to people and one of their roles involves tumor suppressor genes (maspin) - I think this includes p53?

Billn


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Mack
Member since Jan-9-09
12 posts
Jan-28-09, 01:35 AM (PST)
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25. "RE: DCA and acetyl l carnitine"
In response to message #23
 
   Thanks Sandra and Didier. Seems DHA should definitely be added to the arsenal. Aside from its ability to increase oxidation within the cardiolipin and trigger apoptosis, it may also have something to do with Ca2+ storage within the mitochondria, the release of which drives cell death. Not too sure whether EPA adds anything to triggering apoptosis though.

Interestingly I came across a study that indicated that Ca2+ release from the lysosomes is what drives the extrusion of phosphatidylserine from the cell and causes the subsequent engulfment of the dying cell by the immune system, a separate mechanism from ca2+ release from the mitochondria and cell death. Might look into the mechanism. Having the immune system get up close and personal to bunches of tumour cells can only be a good thing

I was also interested to note in Tim's Lymphoma story his blood pressure appears to increase with DCA use. Is this a noted common side effect of DCA at the dosages used? If so this will need to be watched and possible fixes considered especially if calcium channel blockers are used to lower it which may interfere with apoptosis. While tumours are the primary concern, we don't want any side effects of high blood pressure detracting from dca's successful action. Perhaps there is a management dose of DCA after remission that is lower than treatment and does not cause this high blood pressure?

antony


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Sandra
Member since Feb-27-07
604 posts
Jan-28-09, 05:03 AM (PST)
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26. "RE: DCA and acetyl l carnitine"
In response to message #25
 
Mack,

Could you please post a link to the study you refer to? Sounds fascinating!

Calcium channel blockers are often used to circumvent drug resistance. See this link on Verapami: http://www.thedcasite.com/Resistance/Resistance.html#verapamil

Magnesium is also a calcium channel blocker http://hyper.ahajournals.org/cgi/content/full/44/6/897

Take care,
Sandra


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Mack
Member since Jan-9-09
12 posts
Jan-28-09, 05:46 AM (PST)
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27. "RE: DCA and acetyl l carnitine"
In response to message #26
 
   Sorry Sandra, I will be more ordered in future

I think this is the Jan 09 study:

http://www.ncbi.nlm.nih.gov/pubmed/19126538?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"A hallmark of apoptotic cells is the Ca2+-dependent appearance of phosphatidylserine (PS) at the cell surface as a result of its redistribution from the inner-to-outer plasma membrane leaflet. While endoplasmatic reticulum (ER) and mitochondrial Ca2+ are known to participate in apoptosis, their role in PS externalization has not been established. In this study, several organelle-specific fluorescent markers and Ca2+-sensitive probes were used to identify the source of Ca2+ critical to PS externalization. By employing Rhod-2AM, fluorescein-labeled high molecular weight dextran and Calcium Green 1, we provide evidence that lysosomes respond to apoptotic stimuli by releasing their luminal Ca2+ to the cytosol. Cells treated with the cytosolic phospholipase A2 inhibitor, cPLA2a, had no effect on caspase activation but exhibited a significant decrease in lysosomal Ca2+ release and externalization of PS in response to apoptotic stimuli. Similarly, cells depleted of lysosomal Ca2+ underwent programmed cell death, yet failed to externalize PS. These data indicate that while Ca2+ release from other intracellular organelles to the cytosol is adequate for apoptosis, the release of Ca2+ from lysosomes is critical for PS externalization."

Essentially, cell death is still triggered by Ca2+ release from the mitochondria but attracting an immune response to engulf the cancer cell appears to require Ca2+ release from the lysosomes forcing PS through the outer membrane, kind of like a mini driver giving the finger to a pack of Hells' Angels.

Re the calcium channel blocker verapamil preventing chemo resistence, I guess that's another reaction that appears to me counter intuitive. For instance in this study

http://www.ncbi.nlm.nih.gov/pubmed/10334460?ordinalpos=69&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

"Apoptosis has been shown in the literature to be the form of cell death occurring in renal tubular epithelial cells during the reperfusion phase after brief periods of renal ischaemia. In the present study apoptosis was examined in the rat kidney in the first 24 hours after 30 min ischaemia and apoptosis was influenced by administration of the Ca channel blockers Verapamil, Bepridil, Nifedipin and Sensit. Apoptosis was observed in the renal tubular cells two hours after the start of reperfusion and reached in maximum at hour 6. All above mentioned Ca channel blockers decreased the occurrence and degree of apoptosis."

Of course this was in the kidney and occured after ischemia. Perhaps apoptosis triggered by reperfusion after oxygen deprivation follows a different pathway from mitochondrial triggerd apoptosis after activation by dca. As always evidence rules over theory.

regards

Mack


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