DCA: Cancer Breakthrough or Urban Legend?

[Guest guest]

Intriguing article about a possible cancer treatment breakthrough:

DCA: Cancer Breakthrough or Urban Legend?

Enthusiasm Outpacing Science in Possible Cancer Therapy Discovery

OPINION by LEN LICHTENFELD, M.D.

Feb. 5, 2007 — - There is the medical equivalent of a tsunami wave

building out there, only we don't know where this one is going to land.

It is called DCA, and we at the American Cancer Society are suddenly

receiving requests for information about something few if any of us

had heard about as a cancer treatment until this past week.

I suspect some of this rapid explosion is fueled in part by the

Internet and the rapid exchange of information, and some by advocates

who believe in the long-held conspiracy theory that someone is holding

back the single simple answer to curing all cancer.

We even received an urgent plea from one media outlet Thursday asking

us to help them out with understanding DCA, since its Web site was

being inundated with Internet traffic that was overwhelming its servers.

Before we replace rational discourse with irrational exuberance, it is

my personal opinion that a bit of caution is in order. The basic

reason for my conservative view is " been there, done that. "

Origin of DCA Hopes Unclear

I don't know the details of how this phenomenon got started, but I can

take a stab at an answer.

An article written by a researcher at the University of Alberta in

Canada appeared in the January 2007 issue of the journal Cancer Cell.

I do not know the researcher, but the institution is one that is a

recognized, established university.

The basic gist of the research report is that cancer cells rely on

certain energy pathways that are different from normal cells, similar

to the situation that occurs in what we medically call lactic acidosis.

Lactic acidosis, in very simple terms, occurs in our bodies when we

are very ill or may be suddenly severely traumatized. Our cells

basically become starved for energy and switch into other energy

pathways that rely less on oxygen, resulting in the production of

lactic acid.

As a result, large quantities of lactic acid circulate in our system,

which can contribute to a significantly increased risk of death.

What the Alberta researcher hypothesized was that cancer cells work

through similar metabolic pathways. If you could revert them to

normal, then the cells would switch back to the typical energy

pathway, and either die or convert to normal cells.

Where DCA, or dichloroacetic acid, fits into this theory is that it

can apparently convert the bad metabolic pathways into good ones.

As noted in the conclusions of the study, it can do so selectively --

affecting cancer cells and not harming normal cells.

According to the authors of the report, DCA is nontoxic and is

currently used in children who have a rare genetic condition where

they produce too much lactic acid.

They go on to point out that DCA is used in these children to reverse

the condition with minimal or no side effects.

No Simple Answer

Let me assure you that this is a gross oversimplification of a very

complicated discussion. Trying to explain this study in plain words is

not an easy task.

But the concepts are basic, and the theories of differential cancer

cell metabolism have been around for a long time. The paper itself

cites something called the Warburg theory, espoused in the 1930s as an

example of support for this principle.

In fact, for years we have been studying the possibility that

improving the microenvironment surrounding cancer cells by increasing

oxygen levels of tumors through various means will lead to improved

responses to treatments.

To demonstrate the concept, the authors in the current report did a

number of experiments that came to the conclusion that DCA was, in

fact, effective in meeting the goals of their expectations.

In these experiments in the laboratory, they found that DCA could

reverse the abnormal metabolism in several laboratory-based cancer

cell lines. DCA also reversed the " immortality " of these test tube

cancer cells by inducing apoptosis -- a process of natural cell death.

Finally, they injected some of these laboratory-based cancer cell

lines into rats who were genetically engineered to have no basic

immune system, and found that if they put DCA into their drinking

water, the tumor growth was significantly slower than in a comparison

group of rats that did not receive DCA.

In one group of rats where DCA was given after the injected tumors had

been allowed to grow, the tumors immediately (in the authors' words)

decreased in size.

So far, so good.

But here is where things begin to get a bit dicey.

These are quotes taken directly from the article. The first is from a

summary printed at the bottom of the first page of the report:

" The ease of delivery, selectivity, and effectiveness make DCA an

attractive candidate for proapoptotic cancer therapy which can be

rapidly translated into phase II-III clinical trials. "

In the discussion section of the paper, the authors conclude with the

following statement:

" Our work … offers a tantalizing suggestion that DCA may have

selective anticancer efficacy in patients. The very recent report of

the first randomized long-term clinical trial of oral DCA in children

with congenital lactic acidosis (at doses similar to those used in our

in vivo experiments) showing that DCA was well tolerated and safe

(Stacpoole et al., 2006) suggests a potentially easy translation of

our work to clinical oncology. " (Emphasis mine)

In other words, the authors are saying that in their opinion these

experiments in the lab and rats suggests that DCA may be a simple,

effective treatment for cancer and we should move forward with

clinical trials based solely on their theory and their results.

I am not being critical of the authors' comments, except for

describing this as a " potentially easy " process. Nothing in

translation from the bench to the bedside is easy.

This is not the first time such suggestive statements have been made.

In fact, these types of comments are not unusual in papers of this type.

What I am critical of is the lack of discrimination in judgment of

other folks -- not the researchers -- who have picked up on these

lines and rapidly circulated the thought that we have a cure for

cancer at hand, and that we must stop doing everything else and get

this simple, safe and effective treatment to cancer patients immediately.

Even my own blog was " hit " with such a suggestion this past week.

Well, as they say, if I had a nickel for every time I heard such a

proposition based on this type of evidence, I would be a rich man.

The Facts About DCA

Please try to understand that I am not saying this is a theory that

won't work. It may, and if it does prove valuable, that would be terrific.

It is just that I have been around a while and have seen this type of

hope and hype just a few times too many.

I have seen cancer patients' hopes lifted and dashed so often that I

can't help but be cautious and conservative in my thinking.

Let's take a look at what we can say.

First, I did a literature search on PubMed looking for articles with

the terms dichloroacetic acid and cancer.

Although I didn't have access to all of the articles, one underlying

theme stood out: DCA is an organic chemical that causes liver cancer

in laboratory mice when put in their drinking water.

It is not nontoxic. It is a byproduct of another chemical called

trichloroethylene (TCE), which has been a source of concern as a

cancer-causing agent for some time.

Here is what the Agency for Toxic Substances and Disease Registry has

to say about TCE:

" HIGHLIGHTS: Trichloroethylene is a colorless liquid which is used as

a solvent for cleaning metal parts. Drinking or breathing high levels

of trichloroethylene may cause nervous system effects, liver and lung

damage, abnormal heartbeat, coma, and possibly death. "

So before you start going out and adding DCA to your drinking water to

prevent cancer, a degree of caution would be very prudent at this point.

Another item that came up in the Google search was a 1983 article from

the New England Journal of Medicine.

Here is a quote from that article:

" Despite improvement in their lactic acidemia, all patients but one

died of their underlying disease. No serious drug-related toxicity

occurred. We conclude that dichloroacetate is a safe and effective

adjunct in the treatment of patients with lactic acidosis, although

the ultimate prognosis may depend on the underlying disease. "

In other words, the treatment was a success, but the patient died.

New Developments Not Out of the Question

But experience is the best teacher in my opinion.

For example, even in the short time my blog has been in " production, "

I have written articles on other relatively nontoxic substances and

their potential role in either preventing or reducing the burden of

cancer.

New discoveries about vitamin C and vitamin D come to mind.

We haven't seen the hue and cry about getting these vitamins into

cancer clinical trials, yet based on evidence similar to the DCA

paper, there is equal reason to believe that either or both of these

vitamins may have a role in cancer prevention and/or cancer treatment.

It is indeed a long, difficult road that must be traveled to

demonstrate that an exciting new idea actually works in the treatment

of cancer.

So, pardon me if I am a skeptic. As Rabbit said, " I am just

drawn that way. "

But I am also an optimist, as I have said many times in these pages. I

do believe that there are exciting new developments in cancer

treatment emerging from laboratories around the world. Maybe DCA is

one of them.

It's just that I believe in patience, prudence and caution, because my

experience has taught me that those are the best guidelines to follow

in assessing reports such as the one in Cancer Cell.

It is way too soon to know whether this is a cancer treatment

breakthrough or an urban legend or something in between.

I am acutely aware that there are cancer patients out there who are

fighting every day for their survival, hoping that there is one last

chance to get a treatment that may prolong or save their lives.

For some of you out there to inappropriately make them feel that DCA

is the answer to their prayers based on this single early-stage report

in a medical research journal is, in my opinion, not acceptable at

best -- and despicable at worst.

Dr. Len Lichtenfeld is deputy chief medical officer for the American

Cancer Society. You can view the full blog by clicking here.

http://abcnews.go.com/Health/CancerPreventionAndTreatment/story?id=2848454 & page=\

1

The actual study that triggered the controversy:

A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its

Normalization Promotes Apoptosis and Inhibits Cancer Growth

Sébastien Bonnet,1 L. Archer,1,2 Joan Allalunis-,3 Alois

Haromy,1 Christian Beaulieu,4 ,4 T. Lee,5

D. Lopaschuk,5,6 Lakshmi Puttagunta,7 Bonnet,1 Gwyneth

Harry,1 Kyoko Hashimoto,1 J. Porter,8 A. Andrade,8

Bernard Thebaud,1,6 and Evangelos D. Michelakis1,

1 Pulmonary Hypertension Program and Vascular Biology Group,

University of Alberta, Edmonton, AB T6G 2B7, Canada

2 Department of Physiology, University of Alberta, Edmonton, AB T6G

2B7, Canada

3 Department of Oncology, University of Alberta, Edmonton, AB T6G 2B7,

Canada

4 Department of Biomedical Engineering, University of Alberta,

Edmonton, AB T6G 2B7, Canada

5 Department of Pharmacology, University of Alberta, Edmonton, AB T6G

2B7, Canada

6 Department of Pediatrics, University of Alberta, Edmonton, AB T6G

2B7, Canada

7 Department of Laboratory Medicine and Pathology, University of

Alberta, Edmonton, AB T6G 2B7, Canada

8 Ontario Genomics Innovation Centre, Ottawa Health Research

Institute, and Department of Cellular and Molecular Medicine,

University of Ottawa, Ottawa, ON K1N 6N5, Canada

Corresponding author

Evangelos D. Michelakis

emichela@...

Summary

The unique metabolic profile of cancer (aerobic glycolysis) might

confer apoptosis resistance and be therapeutically targeted. Compared

to normal cells, several human cancers have high mitochondrial

membrane potential ( & #916; & #936;m) and low expression of the K+ channel Kv1.5,

both contributing to apoptosis resistance. Dichloroacetate (DCA)

inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts

metabolism from glycolysis to glucose oxidation, decreases & #916; & #936;m,

increases mitochondrial H2O2, and activates Kv channels in all cancer,

but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent

mechanism. DCA induces apoptosis, decreases proliferation, and

inhibits tumor growth, without apparent toxicity. Molecular inhibition

of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are

important therapeutic targets in cancer; the orally available DCA is a

promising selective anticancer agent.

http://www.cancercell.org/content/article/abstract?uid=PIIS1535610806003722

Al Pater, do you have access to this study in its entirety? Thanks.

bill4cr

[Guest guest]

Hi All, No, I do not have the access to the paper, but see the adverse effects and the free full-text paper below. http://en.wikipedia.org/wiki/Dichloroacetic_acid#Adverse_effects Caldwell JC, Keshava N.Key issues in the modes of action and effects of trichloroethylene metabolites for liver and kidney tumorigenesis.Environ Health Perspect. 2006 Sep;114(9):1457-63. Review. PMID: 16966105 http://tinyurl.com/2j7x4c Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is

difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs) , and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA) , trichloroacetic acid (TCA) , and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl) -l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol

exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans. bill4cr <bill4cr@...> wrote: Intriguing article about a

possible cancer treatment breakthrough:DCA: Cancer Breakthrough or Urban Legend?Enthusiasm Outpacing Science in Possible Cancer Therapy DiscoveryOPINION by LEN LICHTENFELD, M.D.Feb. 5, 2007 — - There is the medical equivalent of a tsunami wavebuilding out there, only we don't know where this one is going to land.It is called DCA, and we at the American Cancer Society are suddenlyreceiving requests for information about something few if any of ushad heard about as a cancer treatment until this past week.I suspect some of this rapid explosion is fueled in part by theInternet and the rapid exchange of information, and some by advocateswho believe in the long-held conspiracy theory that someone is holdingback the single simple answer to curing all cancer.We even received an urgent plea from one media outlet Thursday askingus to help them out with understanding DCA, since its Web site wasbeing

inundated with Internet traffic that was overwhelming its servers.Before we replace rational discourse with irrational exuberance, it ismy personal opinion that a bit of caution is in order. The basicreason for my conservative view is "been there, done that."Origin of DCA Hopes UnclearI don't know the details of how this phenomenon got started, but I cantake a stab at an answer.An article written by a researcher at the University of Alberta inCanada appeared in the January 2007 issue of the journal Cancer Cell.I do not know the researcher, but the institution is one that is arecognized, established university.The basic gist of the research report is that cancer cells rely oncertain energy pathways that are different from normal cells, similarto the situation that occurs in what we medically call lactic acidosis.Lactic acidosis, in very simple terms, occurs in our bodies when weare very ill

or may be suddenly severely traumatized. Our cellsbasically become starved for energy and switch into other energypathways that rely less on oxygen, resulting in the production oflactic acid.As a result, large quantities of lactic acid circulate in our system,which can contribute to a significantly increased risk of death.What the Alberta researcher hypothesized was that cancer cells workthrough similar metabolic pathways. If you could revert them tonormal, then the cells would switch back to the typical energypathway, and either die or convert to normal cells.Where DCA, or dichloroacetic acid, fits into this theory is that itcan apparently convert the bad metabolic pathways into good ones.As noted in the conclusions of the study, it can do so selectively --affecting cancer cells and not harming normal cells.According to the authors of the report, DCA is nontoxic and iscurrently used in

children who have a rare genetic condition wherethey produce too much lactic acid.They go on to point out that DCA is used in these children to reversethe condition with minimal or no side effects.No Simple AnswerLet me assure you that this is a gross oversimplification of a verycomplicated discussion. Trying to explain this study in plain words isnot an easy task.But the concepts are basic, and the theories of differential cancercell metabolism have been around for a long time. The paper itselfcites something called the Warburg theory, espoused in the 1930s as anexample of support for this principle.In fact, for years we have been studying the possibility thatimproving the microenvironment surrounding cancer cells by increasingoxygen levels of tumors through various means will lead to improvedresponses to treatments.To demonstrate the concept, the authors in the current report did

anumber of experiments that came to the conclusion that DCA was, infact, effective in meeting the goals of their expectations.In these experiments in the laboratory, they found that DCA couldreverse the abnormal metabolism in several laboratory-based cancercell lines. DCA also reversed the "immortality" of these test tubecancer cells by inducing apoptosis -- a process of natural cell death.Finally, they injected some of these laboratory-based cancer celllines into rats who were genetically engineered to have no basicimmune system, and found that if they put DCA into their drinkingwater, the tumor growth was significantly slower than in a comparisongroup of rats that did not receive DCA.In one group of rats where DCA was given after the injected tumors hadbeen allowed to grow, the tumors immediately (in the authors' words)decreased in size.So far, so good.But here is where things begin to

get a bit dicey.These are quotes taken directly from the article. The first is from asummary printed at the bottom of the first page of the report:"The ease of delivery, selectivity, and effectiveness make DCA anattractive candidate for proapoptotic cancer therapy which can berapidly translated into phase II-III clinical trials."In the discussion section of the paper, the authors conclude with thefollowing statement:"Our work … offers a tantalizing suggestion that DCA may haveselective anticancer efficacy in patients. The very recent report ofthe first randomized long-term clinical trial of oral DCA in childrenwith congenital lactic acidosis (at doses similar to those used in ourin vivo experiments) showing that DCA was well tolerated and safe(Stacpoole et al., 2006) suggests a potentially easy translation ofour work to clinical oncology." (Emphasis mine)In other words, the authors are saying

that in their opinion theseexperiments in the lab and rats suggests that DCA may be a simple,effective treatment for cancer and we should move forward withclinical trials based solely on their theory and their results.I am not being critical of the authors' comments, except fordescribing this as a "potentially easy" process. Nothing intranslation from the bench to the bedside is easy.This is not the first time such suggestive statements have been made.In fact, these types of comments are not unusual in papers of this type.What I am critical of is the lack of discrimination in judgment ofother folks -- not the researchers -- who have picked up on theselines and rapidly circulated the thought that we have a cure forcancer at hand, and that we must stop doing everything else and getthis simple, safe and effective treatment to cancer patients immediately.Even my own blog was "hit" with such a suggestion

this past week.Well, as they say, if I had a nickel for every time I heard such aproposition based on this type of evidence, I would be a rich man.The Facts About DCAPlease try to understand that I am not saying this is a theory thatwon't work. It may, and if it does prove valuable, that would be terrific.It is just that I have been around a while and have seen this type ofhope and hype just a few times too many.I have seen cancer patients' hopes lifted and dashed so often that Ican't help but be cautious and conservative in my thinking.Let's take a look at what we can say.First, I did a literature search on PubMed looking for articles withthe terms dichloroacetic acid and cancer.Although I didn't have access to all of the articles, one underlyingtheme stood out: DCA is an organic chemical that causes liver cancerin laboratory mice when put in their drinking water.It is not

nontoxic. It is a byproduct of another chemical calledtrichloroethylene (TCE), which has been a source of concern as acancer-causing agent for some time.Here is what the Agency for Toxic Substances and Disease Registry hasto say about TCE:"HIGHLIGHTS: Trichloroethylene is a colorless liquid which is used asa solvent for cleaning metal parts. Drinking or breathing high levelsof trichloroethylene may cause nervous system effects, liver and lungdamage, abnormal heartbeat, coma, and possibly death."So before you start going out and adding DCA to your drinking water toprevent cancer, a degree of caution would be very prudent at this point.Another item that came up in the Google search was a 1983 article fromthe New England Journal of Medicine.Here is a quote from that article:"Despite improvement in their lactic acidemia, all patients but onedied of their underlying disease. No serious

drug-related toxicityoccurred. We conclude that dichloroacetate is a safe and effectiveadjunct in the treatment of patients with lactic acidosis, althoughthe ultimate prognosis may depend on the underlying disease."In other words, the treatment was a success, but the patient died.New Developments Not Out of the QuestionBut experience is the best teacher in my opinion.For example, even in the short time my blog has been in "production,"I have written articles on other relatively nontoxic substances andtheir potential role in either preventing or reducing the burden ofcancer.New discoveries about vitamin C and vitamin D come to mind.We haven't seen the hue and cry about getting these vitamins intocancer clinical trials, yet based on evidence similar to the DCApaper, there is equal reason to believe that either or both of thesevitamins may have a role in cancer prevention and/or cancer

treatment.It is indeed a long, difficult road that must be traveled todemonstrate that an exciting new idea actually works in the treatmentof cancer.So, pardon me if I am a skeptic. As Rabbit said, "I am justdrawn that way."But I am also an optimist, as I have said many times in these pages. Ido believe that there are exciting new developments in cancertreatment emerging from laboratories around the world. Maybe DCA isone of them.It's just that I believe in patience, prudence and caution, because myexperience has taught me that those are the best guidelines to followin assessing reports such as the one in Cancer Cell.It is way too soon to know whether this is a cancer treatmentbreakthrough or an urban legend or something in between.I am acutely aware that there are cancer patients out there who arefighting every day for their survival, hoping that there is one lastchance to

get a treatment that may prolong or save their lives.For some of you out there to inappropriately make them feel that DCAis the answer to their prayers based on this single early-stage reportin a medical research journal is, in my opinion, not acceptable atbest -- and despicable at worst.Dr. Len Lichtenfeld is deputy chief medical officer for the AmericanCancer Society. You can view the full blog by clicking here.http://abcnews.go.com/Health/CancerPreventionAndTreatment/story?id=2848454 & page=1The actual study that triggered the controversy:A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and ItsNormalization Promotes Apoptosis and Inhibits Cancer GrowthSébastien Bonnet,1 L. Archer,1,2 Joan Allalunis-,3 AloisHaromy,1 Christian Beaulieu,4

,4 T. Lee,5 D. Lopaschuk,5,6 Lakshmi Puttagunta,7 Bonnet,1 GwynethHarry,1 Kyoko Hashimoto,1 J. Porter,8 A. Andrade,8Bernard Thebaud,1,6 and Evangelos D. Michelakis1,1 Pulmonary Hypertension Program and Vascular Biology Group,University of Alberta, Edmonton, AB T6G 2B7, Canada2 Department of Physiology, University of Alberta, Edmonton, AB T6G2B7, Canada3 Department of Oncology, University of Alberta, Edmonton, AB T6G 2B7,Canada4 Department of Biomedical Engineering, University of Alberta,Edmonton, AB T6G 2B7, Canada5 Department of Pharmacology, University of Alberta, Edmonton, AB T6G2B7, Canada6 Department of Pediatrics, University of Alberta, Edmonton, AB T6G2B7, Canada7 Department of Laboratory Medicine and Pathology, University ofAlberta, Edmonton, AB T6G 2B7, Canada8 Ontario Genomics Innovation Centre, Ottawa Health

ResearchInstitute, and Department of Cellular and Molecular Medicine,University of Ottawa, Ottawa, ON K1N 6N5, CanadaCorresponding authorEvangelos D. Michelakisemichelacha (DOT) ab.caSummaryThe unique metabolic profile of cancer (aerobic glycolysis) mightconfer apoptosis resistance and be therapeutically targeted. Comparedto normal cells, several human cancers have high mitochondrialmembrane potential ( & #916; & #936;m) and low expression of the K+ channel Kv1.5,both contributing to apoptosis resistance. Dichloroacetate (DCA)inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shiftsmetabolism from glycolysis to glucose oxidation, decreases & #916; & #936;m,increases mitochondrial H2O2, and activates Kv channels in all cancer,but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependentmechanism. DCA induces apoptosis,

decreases proliferation, andinhibits tumor growth, without apparent toxicity. Molecular inhibitionof PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK areimportant therapeutic targets in cancer; the orally available DCA is apromising selective anticancer agent.http://www.cancercell.org/content/article/abstract?uid=PIIS1535610806003722Al Pater, do you have access to this study in its entirety? Thanks.bill4cr-- Al Pater, PhD; email: Alpater@...

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