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To: CactusCarlos
Dichloroacetate and cancer

Category: Science
Posted on: May 16, 2011 10:02 AM, by PZ Myers

So many people have sent me this sensationalistic article, "Scientists cure cancer, but no one takes notice", that I guess I have to respond. I sure wish it were true, but you should be able to tell from how poorly it is written and the ridiculous inaccuracies (mitochondria are cells that fight cancers?) that you should be suspicious. The radical, exaggerated claims make the truth of the story highly unlikely.

Researchers at the University of Alberta, in Edmonton, Canada have cured cancer last week, yet there is a little ripple in the news or in TV. It is a simple technique using very basic drug. The method employs dichloroacetate, which is currently used to treat metabolic disorders. So, there is no concern of side effects or about their long term effects.

The simple summary is this: that claim is a lie. There have been no clinical trials of dichloroacetate (DCA) in cancer patients, so there is no basis for claiming they have a cure; some, but not all, cancers might respond in promising ways to the drug, while others are likely to be resistant (cancer is not one disease!); and there are potential neurotoxic side effects, especially when used in conjunction with other chemotherapies.

So we have one popular account that is badly written and makes exaggerated claims. There is also a university press release, the source for the sloppy popular account, that doesn't contain the egregious stupidities but does tend to inflate basic research studies into an unwarranted clinical significance. And then, of course, there are the actual peer reviewed papers that describe the research and rationale, and also the reservations, on DCA. It's like a game of telephone: you can actually trace the account from the sober science paper to the enthusiastic press release to the web account with its extravagant claims of a simple, cheap cure for cancer, and see how the story is gradually corrupted. It would be funny if the final result wasn't going to dupe a lot of desperate people.

But there is a germ of truth to the story, in that DCA does have potential. Here's how it works.

There are two major pathways that we use to extract energy from sugar. One is glycolysis, which extracts two ATP molecules from each molecule of sugar, and doesn't require oxygen. Then there is glucose oxidation, which as you might guess from the name, does require oxygen, but which takes the byproducts of glycolysis and burns them completely to produce 36 ATP. So there's the tradeoff: if your cells are oxygen-starved, or hypoxic, they can still get energy from sugar, but it's relatively inefficient, but if they do have access to oxygen, they can extract much more. This is why you breathe, and why your heart beats, and why you have an elaborate circulatory system to deliver oxygenated blood to your tissues: without oxygen, you suffer a catastrophic hit to the efficiency of energy production.


Another feature of these two energy-producing pathways is that they are in different cellular compartments. Glycolysis takes place in the cytoplasm, while glucose oxidation occurs in the mitochondria. There is a gate-keeping enzyme, pyruvate dehydrogenase kinase (PDK), that regulates the flow of pyruvate, a product of the glycolysis pathway, into the mitochondria for oxidation. If PDK is active, it suppresses the transport of pyruvate into the mitochondria, and the cell is forced to rely on glycolysis, even if oxygen is available. If PDK is inactivated, pyruvate is shuttled into the mitochondria, even if oxygen is low.

This is where DCA comes in. DCA inhibits PDK, forcing cells to use the more efficient form of energy production. That sounds like a strange way to make a cancer cell uncomfortable, but the other factor here is that mitochondria are primary regulators of apoptosis, or cell suicide. They are loaded with sensors and enzymes that react to abnormalities in the cell (like being cancerous!) by activating a self-destruct mechanism. Shut down the mitochondra, you shut down the self-destruct mechanism that polices the cell. So the idea is a little indirect: by goosing the mitochondria, we also wake up the safety switch that, if all goes well, will cause the cell to spontaneously kill itself.

There are good reasons to think this might work. Many cancer cells arise in hypoxic environments; a poorly vascularized tumor, for instance, is going to be oxygen starved in the absence of blood flow, and the inhibition of mitochondria may be a factor in their survival. There is a well-known phenomenon called the Warburg effect, in which cancer cells will rely on glycolysis even when oxygen is available, suggesting that they have suppressed their mitochondria.

DCA also seems like a relatively safe drug. It's been used for a long time in patients with metabolic disorders, or with metabolic side effects from other problems.

A large number of children and adults have been exposed to DCA over the past 40 years, including healthy volunteers and subjects with diverse disease states. Since its first description in 1969, DCA has been studied to alleviate the symptoms or the haemodynamic consequences of the lactic acidosis complicating severe malaria, sepsis, congestive heart failure, burns, cirrhosis, liver transplantation and congenital mitochondrial diseases. Single-arm and randomised trials of DCA used doses ranging from 12.5 to 100 mg kg-1 day-1 orally or intravenously). Although DCA was universally effective in lowering lactate levels, it did not alter the course of the primary disease (for example sepsis).

This is encouraging. It means there is a body of work already published on the effects of DCA, which should simplify the process of moving it into clinical trials. The authors, however, very clearly indicate that it won't be a magic bullet affecting all cancers, but that some are likely candidates.

Dichloroacetate could be tested in a variety of cancer types. The realisation that (i) a diverse group of signalling pathways and oncogenes result in resistance to apoptosis and a glycolytic phenotype, (ii) the majority of carcinomas have hyperpolarised/ remodeled mitochondria, and (iii) most solid tumours have increased glucose uptake on PET imaging, suggest that DCA might be effective in a large number of diverse tumours. However, direct preclinical evidence of anticancer effects of DCA has been published only with non-small cell lung cancer, glioblastoma and breast, endometrial and prostate cancer. In addition, the lack of mitochondrial hyperpolarisation in certain types of cancer, including oat cell lung cancer, lymphomas, neuroblastomas and sarcomas, suggest that DCA might not be effective in such cases. Cancers with limited or no meaningful therapeutic options like recurrent glioblastoma or advanced lung cancer should be on top of the list of cancers to be studied.

Notice that the only work done so far is preclinical: that means it has been tested in mouse models, tissue culture, but hasn't really been tried in cancer patients yet. The authors come right out and say that, express some possible reservations about its effectiveness, and suggest what needs to be done next.

No patient with cancer has received DCA within a clinical trial. It is unknown whether previously studied dose ranges will achieve cytotoxic intra-tumoral concentrations of DCA. In addition, the overall nutritional and metabolic profile of patients with advanced cancer differs from those in the published DCA studies. Furthermore, pre-exposure to neurotoxic chemotherapy may predispose to DCA neurotoxicity. Carefully performed phase I dose escalation and phase II trials with serial tissue biopsies are required to define the maximally tolerated, and biologically active dose. Clinical trials with DCA will need to carefully monitor neurotoxicity and establish clear dose-reduction strategies to manage toxicities. Furthermore, the pharmacokinetics in the cancer population will need to be defined.

Do not rush out and buy DCA and gurgle it down as a cancer preventative. We don't know that it works — the safe concentrations for you may not be sufficient to kill any cancer cells, and the concentrations needed to kill cancer cells may be so high that it will do horrible, unpredicted, and dangerous things to you (some work with patients with congenital mitochondrial disorders also revealed some degree of peripheral neuropathy, for instance). This is why we have clinical trials: to work out safe and effective doses, look for dangerous interactions with other drugs — and if you have cancer, you're already on a complicated cocktail of drugs — and detect unexpected side effects.

We should be urging further investigation of this promising drug with the beginning of clinical trials, but it's far too early to be babbling about "cancer cures". There have been lots of drugs that look great in the lab and have excellent rationales for why they should work, but the reality of cancer is that it is complicated and diverse and there are many more pitfalls between a drug that poisons cancer cells in a petri dish and a drug that actually works well in the more complex environment of a human being.

One other factor that inflames the conspiracy nuts over this drug is that DCA is simple, dirt-cheap, and completely unpatentable — there is no economic incentive for a pharmaceutical company to invest a gigantic bucket of money in clinical trials, because there is no hope for a return on the investment.

This is why an independent academic community with research funded for knowledge rather than profit is so important, and really emphasizes why we cannot afford to privatize all biomedical research. The authors propose a plan for progressing without the involvement of the pharmaceutical industry.

Funding for such trials would be a challenge for the academic community as DCA is a generic drug and early industry support might be limited. Fundraising from philanthropies might be possible to support early phase I - II or small phase III trials. However, if these trials suggest a favourable efficacy and toxicity, the public will be further motivated to directly fund these efforts and national cancer organisations like the NCI, might be inspired to directly contribute to the design and structure of larger trials. It is important to note that even if DCA does not prove to be the 'dawn of a new era', initiation and completion of clinical trials with a generic compound will be a task of tremendous symbolic and practical significance. At this point the 'dogma' that trials of systemic anticancer therapy cannot happen without industry support, suppresses the potential of many promising drugs that might not be financially attractive for pharmaceutical manufacturers. In that sense, the clinical evaluation of DCA, in addition to its scientific rationale, will be by itself another paradigm shift.

I can't blame the industry for not following up on this: a clinical trial costs millions of dollars, and even if DCA pans out, there is no profit at all to be gained from it. For this research, we have to turn to public support (they have an interest in better cancer treatments!) and to scientists and doctors themselves, who of course have a great personal interest in seeing their patients get better.

22 posted on 03/20/2012 7:01:28 PM PDT by E. Pluribus Unum (Government is the religion of the sociopath.)
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To: E. Pluribus Unum

If there is a huge jump in sales for DCA, we’ll know it is true!

23 posted on 03/20/2012 7:07:00 PM PDT by Randy Larsen (No Romney vote from my family!)
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To: E. Pluribus Unum

A true cure for cancer lies with and the Be Still excercise. Many have already been cured...this is because cancer is a spiritual disease, one that is caused by an out of control but suppressed irritable state. Scientist, as often is the case, are barking up the wrong tree.

46 posted on 03/20/2012 8:13:04 PM PDT by fabian (" And a new day will dawn for those who stand long, and the forests will echo with laughter")
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To: E. Pluribus Unum

Very nice reply. What do you in your day job?

49 posted on 03/20/2012 8:17:47 PM PDT by kruss3 (
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To: E. Pluribus Unum

Studies find an aspirin a day can keep cancer at bay

And today we get this about aspirins. Interesting.

53 posted on 03/20/2012 8:24:31 PM PDT by Orange1998
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