Terra Sigillata

Dichloroacetate or DCA is a small molecule that has been in the press over the last four years due to its potential to inhibit aerobic glycolysis in cancer cells. The cells from each of us usually produce energy in the form of ATP from a variety of nutrient sources plus oxygen using a very efficient process called oxidative phosphorylation. However, when oxygen is partly depleted, such as in skeletal muscle when exercising strenuously (“going anerobic”), energy is produced from glucose by a far less efficient process called glycolysis. Glycolysis is the most primitive form of cellular metabolism [Note added: This last sentence is not correct; see below for correction from Prof Larry Moran. – APB]

The glycolytic pathway has become of renewed interest in cancer. Why? Because some but not all cancer cells differ from normal cells by using the inefficient production of ATP by glycolysis regardless of the amount of oxygen that’s around. You’ll hear the term “Warburg effect” used to describe this phenomenon because biochemist Otto Warburg published a famous 1956 paper in the journal, Science, suggesting that the origin of cancer lies in the ability of cancer cells to shift metabolism to glycolysis.

In the intervening years, debate has ensued that accelerate glycolysis in cancer cells is just a by-product of the oncogenic process. But we now appreciate that in some cases, the accelerating of glycolysis encourages cancer. For example, the greater level of the enzyme lactate dehydrogenase (LDH) in some cancer cells is now known to be a direct effect of the oncogenic protein, c-Myc, which by itself can cause normal cells to become cancerous.

The unusual nature of some cancer cells to rely on glycolysis even in the presence of oxygen presents an opportunity to possibly target cancer more selectively while minimizing damage to normal cells as occurs with classical chemotherapy drugs or radiation therapy. Indeed, the promise of targeting the Warburg effect in cancer is intoxicating.

At present, there are a few chemicals known to inhibit glycolysis that resemble some of the intermediates in the process but require extremely high concentrations. One is called 3-bromopyruvate – as I wrote here in 2007, this chemical inhibits both glycolysis and oxidative phosphorylation so it would have to be injected directly into the artery that feeds the cancerous tumor. The other chemical is dichloroacetate (DCA).

DCA has been around for a long time and has been used in people with inherited diseases of mitochondrial metabolism. In 2007, a group at the University of Alberta led by cardiologist Evangelos Michelakis demonstrated that very high doses of DCA can slow the progression of human tumor cells grown in immunocompromised rats. The response to this story was unbelievable with internet marketers popping up to sell the simple chemical and conspiracy theorists saying that because DCA was cheap and not patentable, no drug company would ever develop it, it was being kept a secret, and so. In truth, the work was in very, very early stages.

This didn’t stop hopeful patients from seeking out DCA sellers even though DCA can be contaminated with other related substances that are far more toxic. And in the most egregious case among these DCA purveyors, an Edmonton man who purported to sell DCA online was recently arrested in Phoenix and pleaded guilty to five cases of wire fraud – not because he was selling DCA but rather a white powder comprised of some combination of sucrose, lactose, dextran, and starch.

Yes. Not even the unproven DCA. Fake DCA.

The best coverage of the DCA story was put forth by my blogging colleague, Orac at Respectful Insolence, who wrote over 20 posts on issues associated with the previous study and the internet marketing of DCA. At the bottom of this post where we wrote about this trial beginning, there is a list of links to Orac’s posts as well as eight or nine of our own.

This week, the Michelakis group has published a follow-up paper in Science Translational Research that includes laboratory experiments with cell lines isolated from cancer of 49 volunteers and a phase I trial of DCA in five patients with advanced glioblastoma who were also receiving a standard anticancer drug temozolomide (Temodar®) and radiation therapy. Keep in mind that the purpose of a phase I trial is not to determine a drug’s effectiveness but rather its dosing and side effect profile. This is important because DCA has never been systematically studied in patients with cancer. I have not seen the paper because my institution does not receive the journal or have electronic access. However, press reports are noting that of the four patients surviving out of the starting five, three experienced reductions in the size of their tumors.

However, we don’t know if these changes were due to DCA or the other treatments the patients were also receiving – this information is not included in most reports I have read.

In fact, I’ve seen some reports such as this one whose title suggests that the compound is effective against aggressive brain cancer. Others are less dramatic but still misleading, using words and phrases such as “cure,” “panacea,” “breakthrough,” and “clinical trials successful.” Words such as “preliminary,” “premature,” or “guarded” are in short supply.

Elsie Stolte of the Edmonton Journal has written perhaps the most widely distributed article that is reasonably measured and focuses more on the fact that half the costs of the $1.5 million study was funded by individual contributions across Canada. However, even that article fails to mention that the other drugs taken at the same time may have contributed to the effects observed and there are few other slightly misleading comments.

Since I cannot yet access the paper, I wish to direct you to a superb and approachable review of the latest findings written by Dr Kat Arney at the Cancer Research UK blog, Science Update. The four closing paragraphs of her article include modified verbiage that Cancer Research UK has been using in patient information content about DCA since 2007:

It is clear that DCA is an intriguing drug – one of many currently being investigated by scientists around the world. It will be interesting to see the results of more extensive lab-based experiments and larger clinical trials of DCA. And cancer cell metabolism is certainly a productive area of research that we’re actively funding.

The fact that DCA is off-patent is no barrier to its development as a treatment for cancer. For example, Cancer Research UK has secured a licence for an off-patent drug called fenretinide, which could be used to treat rare childhood cancers. And there is certainly no “conspiracy” by pharmaceutical companies to prevent research into DCA – there is just not enough evidence at the moment to support its widespread use to treat patients.

While these results are intriguing, it is unlikely that this one compound represents “the cure” for cancer – and it is also unlikely that DCA is the “wonder drug” that the headlines portray. Cancer is a complex and multi-faceted disease, and it can be caused by a range of different faults within the cell. It is unlikely that any single drug could ever treat all forms of the disease.

There are many promising new treatments for cancer currently in development, funded by organisations across the globe – including Cancer Research UK. If anything, these new results show why research is so important in bringing safe and effective treatments to people with cancer – they don’t provide definitive answers, but they support further investigations which may yield benefits for patients in the future.

Pharmaceutical chemist Dr Derek Lowe who blogs at In The Pipeline also has a nice post on his perspective.

I look forward to reading the complete report and following up when I have more information.

Of course, you should also expect Orac to fire off a few thousand words about the paper as well.

Comments

  1. #1 Rob
    May 14, 2010

    I don’t think that DCA is a cure for cancer and am actively looking for clinical trials that are promising. In the meantime, over the last year since May 21st of 2009 I have been taking DCA, no other chemo, for my metastatic colon cancer (large Hylar and lung tumors). I have had six CT scans the first two showing significant reductions in tumor size and the last four no change in size. I have just upped my dose back to the original dose I tried in hopes of another reduction. As it is I have no symptoms and feel fine a year in and credit it to DCA as does one of my oncologist. The other two are mum on the subject but agree with my decision to stay doing just what I am.

  2. #2 Galen
    May 14, 2010

    The writer of this garbage fails to mention one very important point. To wit: The participants in the study had basically run out of options and, in the absence of DCA, would have been told to go home and die. With DCA, their disease is in remission and they are living normal lives. To say that DCA is “not an effect treatment” is blatantly false. I smell a nefarious agenda for which someone should be deeply ashamed.

  3. #3 Abel Pharmboy
    May 14, 2010

    Galen, I don’t blame you but your comment reflects why we must have clinical trials before we fool ourselves into making premature conclusions. I understand that these patients were end-stage but they would not have been told to go home to die; on the contrary, they would have received similar standard-of-care and temozolomide. But remember, this trial did not compare temozolomide alone vs. temozolomide plus DCA. So, there’s no way for us to know if the patients would have done equally well without the DCA. If you give treatments A, B, and C and see an effect, you cannot conclude that B is responsible for the effect. Why not A? Why not C? Why not nothing at all? We really don’t know until we do the comparison correctly with a large enough number of patients – and that is what the Edmonton group is doing.

    If you were a regular reader, you would know that I am open to the study of all treatments for cancer but I also try to be objective so as not to create false hope – unfortunately, this happens all the time in the media, whether it is DCA or the next $40,000/year drug that only extends life by a month.

    In fact, I am deeply intrigued by the potential to target tumor cell glycolysis, particularly in combination with other drugs. So I am very excited by this work but wish to caution that the current report not be overinterpreted.

    Rob, you are certainly going about it the right way, pursuing promising clinical trials and making your oncologist aware that you are using DCA. I truly hope that your good luck is indeed due to DCA and I wish you good health.

  4. #4 Larry Moran
    May 15, 2010

    Sorry to nitpick but ….

    Glycolysis is the most primitive form of cellular metabolism.

    is not correct. There are many pathways that are certainly more primitive than glycolysis and one of the most important is gluconeogenesis. Most of the enzymes in this pathway are the same ones used in glycolysis but the flux runs in the opposite direction. Glucose is synthesized.

    Every organism has a gluconeogenesis pathway but some don’t have the enzymes required to make it run backwards (glycolysis). Thus, gluconeogenesis is the primitive pathway and glycolysis is a latecomer to the party.

    This makes sense because you couldn’t evolve a pathway to degrade glucose before you had a pathway to synthesize it! Unless, of course, you imagine an ancient environment that was awash in glucose that magically appeared from somewhere.

    The most primitive energy-producing metabolic pathway was probably some form of proton pump coupled to synthesis of phosphoenolpyruvate or 1,3-bisphosphoglycerate.

    The rest of your posting was excellent!

  5. #5 Abel Pharmboy
    May 16, 2010

    Professor Moran: not a nitpick at all – my statement was wrong and I greatly appreciate the correction. Thank you very much for the lesson – I should really get a copy of your Biochemistry text.

    The most primitive energy-producing metabolic pathway was probably some form of proton pump coupled to synthesis of phosphoenolpyruvate or 1,3-bisphosphoglycerate.

    That is a great hypothesis – quite fun to imagine what steps came first.

    Thanks for the nice comment on the rest of the post. I see that this study is being covered particularly heavily in the Canadian press.

  6. #6 jre
    May 18, 2010

    Abel, your forbearance with Galen is not much short of saintly.
    When you take the time and trouble to write a balanced, information-rich post on a complex technical subject, and a commenter dismisses it as “garbage”, that commenter is lucky not to be dismissed as noise.

    I found Prof. Moran’s comment to be both enlightening and wonderfully appropriate to the discussion, touching as it did on the evolution of metabolic pathways. The DCA booster who prompted Orac’s post on this subject first gained notoriety as a denier of evolution, so we’re pushing all the crank buttons here!

  7. #7 Dave Springer
    May 22, 2010

    You need another correction to your article, Abel.

    In early 2007 anyone could purchase pharmaceutical grade sodium dichloroacetate from a big chemical supply house on the west coast. On 2/7/2007 I identified 18 suppliers of sodium dichloroacetate, the compound described in Michelakis’ process patent and blogged a link to them here:

    http://www.uncommondescent.com/biology/dca-the-patent-pending-treatment-protocol/

    One of those sources was a US supplier, it was pharmaceutical grade, unrestricted, and about $1/gram in bulk (1 kilogram).

    Very soon after that time the FDA somehow (not sure how) forced the sole US supplier to refuse sales to individuals not specifically authorized by the FDA to receive it.

    In other words in 2006 Joe the Plumber could buy all the pharmaceutical grade DCA he wanted for anything he wanted to use it for. In 2007, after Michelakis published and people started buying DCA to self-medicate, Joe found that he could no longer purchase DCA in the United States.

    By April 2007, Jim Tassano had teamed up with a UC Berkeley chemist who had developed manufacturing processes for a number of synthetic FDA-approved chemo-therapy drugs and reworked one of his (Tassano’s) pesticide synthesis lines in California to produce pharmaceutical grade DCA and marketed it, with rather obvious disclaimer that it was being sold only for use in treating cancer in pets, which ostensibly the FDA could not block. It was called PetDCA with recommended dosages for dogs up to 150 pounds in weight which just so happened to exactly match the dosages published in milligrams/kilograms that appeared in Michelakis’ patent.

    I blogged that chapter of the saga on 10 April 2007 here:

    http://www.uncommondescent.com/biology/dca-update/

    So you see, the FDA actually created the demand for Tassano’s product by restricting sales of sodium dichloroacetate from the extant, large well established US chemical supply house offering a pharmaceutical grade product. It took a little longer but Tassano was shut down too and then someone in Canada started marketing milk sugar and claiming it was DCA. He was just recently convicted of fraud.

    The FDA should never have imposed restrictions on the established US supplier. It was rash and caused more problems than it solved.

  8. #8 Dave Springer
    May 22, 2010

    @Rob

    You may already be aware that many DCA self-medicants reported almost immediate effects of regaining normal appetite and energy levels. Whether or not tumors were reduced or growth arrested it appeared to improve their quality of life in the meantime and they were grateful for that alone. Quite a contrast with conventional chemotherapy where the side-effects are often so unpleasant that the cure feels worse than the disease.

  9. #9 rob
    May 23, 2010

    This study was just released in the UK relating to colon cancer and DCA.

    http://www.nature.com/bjc/journal/vaop/ncurrent/abs/6605701a.html

    I never had symptoms having my metastatic colon cancer discovered in an unrelated X-ray thinking I had been cured by resection in 2006.

    I ride my bike over a bridge everyday. Measure my health at 65 by the effort it takes. Today was as good as I remember. I think DCA helps with the lactic acid, a good side affect.

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