Terra Sigillata

I’ve stood at the periphery of the dichloroacetate (DCA) story mostly because my attention has been needed elsewhere as of late. However, I was very interested in the blogosphere attention given to the Cancer Cell paper from a group led by Dr Evangelos Michelakis at the University of Alberta in Edmonton. The University of Alberta has now set up a website with links to all press coverage on this report as well as a donation page for those who want to support further clinical studies of DCA for cancer.

Long story made short, DCA is a mitochondrial respiratory modulator that reduces lactic acid production and has been used to treat rare mitochondrial diseases such as congenital lactic acidosis (CLA). Otto Warburg proposed in 1930 that cancer cells continue to use the process of glycolysis even in the abundance of oxygen and that targeting the glycolytic production of lactate might selectively kill cancer cells. Cancer researchers have long debated whether aerobic glycolysis is a cause of cancer, or simply an effect of cellular transformation. My cursory read of the Michelakis paper seems to suggest that DCA can kill cancer cells in culture and A549 lung carcinoma cells injected under the skin of athymic rats (immunocompromised animals that allow cancer cells from another species to be propagated).

The mechanism appears to be prevention of pyruvate from being converted to lactate; instead, pyruvate is shunted to acetyl-CoA where it can enter the Krebs cycle (see Fig 1 of the paper). This step is normally catalyzed by pyruvate dehydrogenase (PDH) but is inhibited by pyruvate dehydrogenase kinase (PDK). DCA appears to inhibit the inhibitor (PDK), with acetyl-CoA giving rise to higher levels of the electron donor, NADH. NADH enters the electron transport chain at Complex I and creates reactive oxygen species (ROS) that trigger the mitochondrial changes required for programmed cell death, or apoptosis.

Not discussed in other reports is that genetic evidence supports a role for this enzyme in that small-interfering RNA to a PDK isoform mimics this effect of DCA, at least in cultured cells, again by increasing mitochondrial production of ROS via Complex I. (An aside, if DCA ever becomes a cancer therapy, herein lies a reason why antioxidants should not be used with it, as is often cautioned with conventional anticancer therapies as well).

I have an unusual interest in mitochondrial respiration since my graduate department had a few mitochondrial experts and I interviewed for a rotation with a physician-scientist who has been studying DCA for metabolic diseases since the 1970s and has conducted clinical trials with the compound.

So, what I think is most exciting about the Michelakis paper is that it provides support for aerobic glycolysis as being a cause of cancer, or at least a process that is permissive for maintenance of the neoplastic phenotype. This is a major conceptual advance and accounts for why it is published in Cancer Cell.

But I’m sort of taken aback by how the blogosphere has jumped on DCA as the cure for cancer and how there appears to be paranoia that the pharmaceutical industry will view DCA as a threat since it cannot be patented and, presumably, would not be interested in developing the agent.

Where I would caution too much overinterpretation is upstream from these development concerns: many, many compounds that show anticancer activity in animals turn out to fail in human trials. For example, as my colleague Orac cautioned similarly, his points #1 and #2 in his much-discussed post should be kept in mind. Orac notes his hero, Judah Folkman, pioneer of the concept of antiangiogenic therapies for cancer – Folkman has been working on this idea since 1971 and Gina Kolata of the New York Times apparently misquoted Nobel laureate, Jim Watson, as saying in 1998 that Judah Folkman would cure cancer in two years. Antiangiogenic therapies are finally making advances in the clinic almost ten years later, but still remain far from “cures” and still often require combination with conventional cytotoxic agents to have a significant clinical effect.

So, I fear that the DCA story is being blown out of proportion, no matter how promising the animal experiments appear to be. Note in Figure 8A of the Michelakis paper that DCA does not completely cure the animals, but reduces tumor growth by about 60 or 70%. It is impressive that DCA does cause reduction in tumor bulk after tumors are allowed to form, but we are many, many steps away from a human treatment.

Also, no one really seems to be paying attention to the fact the DCA is known liver carcinogen in rats and mice, possibly in the ballpark of concentrations necessary for effects in the Michelakis paper. (EPA and NIEHS have been interested in negative health effects of DCA since it is a by-product of municipal water chlorination where it ends up being at concentrations far too low to be either beneficial or dangerous).

It is also misleading to say that no drug company will be interested in DCA – although it cannot be patented as a molecule, its use and ultimate formulation can be, and it could even be developed under the Orphan Drug Act in the US, where companies are given substantive tax breaks and marketing incentives to develop low-profit-potential agents. For example, this is how the non-patentable sodium phenylbutyrate was developed to treat childhood urea cycle disorders. Many human cancers meet orphan disease criteria (less than 200,000 US patients per year) and some of the biggest “blockbuster” drugs today (i.e., erythropoietin) were developed originally as orphan drugs.

Sharon Begley of the Wall Street Journal also had an article on 26 January that suggests another way that such trials for DCA might be funded: non-profits foundations that fund small pharma companies (reprinted free here in the Pittsburgh Post-Gazette). This is an interesting article worth reading for its own virtues, independently of the DCA discussion.

So, if DCA can successfully treat human cancers, I predict 1) a drug company will sponsor the agent for the FDA approval process and 2) they will find a way to make a good profit with it.

The question, however, is will DCA successfully treat human cancers?

Comments

  1. #1 boojieboy
    February 4, 2007

    Thank you Thank you Thank you.

    You have done us a great service.

    This is exactly what I had hoped someone could supply us with. It makes my job much easier: from now on, whenever DCA comes up, send ‘em to this post.

  2. #2 Bull Shite
    February 6, 2007

    The tox data you quote are not translated in human treatments that I have seen. The experiment only lasted 3 weeks because of funding, now imagine, if it had lasted 8 weeks. DCA has been given to humans at 25mg/Kg/day for years and the worst thing they saw was some reversible peripheral neuropathy. Had the experiment lasted 8 weeks, then what would we have seen of tumor shrinkage?

  3. #3 Abel Pharmboy
    February 6, 2007

    boojie: many thanks for reading. I like to remain as optimistic as possible about any potential new cancer breakthrough but after twenty years in this business, I’ve seen a lot of hype raise false hopes of patients then fall by the wayside.

    Bull: yours is indeed a good question and why further study of this agent is required. Would the tumors have shrunk completely with longer treatment or would a resistant subpopulation have grown out? That’s why we do research and that’s why I’ll be watching further developments with this agent. Thanks for reading.

  4. #4 GordonM
    February 18, 2007

    I like to comment on boojie`s statement about a potential cancer breakthrough-hype raising false hopes of cancer sufferers.
    Undoubtedly this is true. However, when a legitimate anti-
    cancer protocol has been proven to be effective against many different types of cancer, it is, to me, astonishing to learn that world wide this news generates little or no interest. I am referring to the John Holt UHF therapy.
    John Holt MD, now retired, has on numerous occasions tried to make this particular modality available to a wide spectrum of the medical community. To no avail, scorn and rebuttal was his share.
    So is the world waiting for a cure? Apparently not.

    Gordon

  5. #5 Daim
    February 18, 2007

    John Holt’s UHF therapy had extensive clinical trials in Australia. They failed.

    Now it’s DCA’s turn for trials. I hope the trials fair better than UHF did.

    Daim

  6. #6 betsy
    February 22, 2007

    WHy is no one talking about testing the lactate to pyruvate ratio? It seems that would give you an idea if that was an issue. Or what about taking high doses of thiamin?

  7. #7 MCAW
    February 25, 2007

    As the web/blog buzz about the effects of DCA on cancer continues, we have no idea if it really works on humans as it does in mice/rats. My question is this: If a drug is so effective in killing cancer cells in rats, why does it act so differently in humans?

    As in DCA, we know it’s effects on the cancer cells but what makes it act different between us and them (the rats)? Do the rats allow more of the chemical to enter the blood stream than ours by ingestion, making it more effective for them then us? If this is so, then would it not just need a more direct way to enter the blood stream such as IV or direct skin absorbs like the nicotine patch. It just wonders me that so many cancer free mice coming out of the labs and so few humans.

    Why can we not mimic the cures in humans as we do mice.

  8. #8 Dr Gavin Lobo
    January 12, 2008

    very interesting

  9. #9 Bettawrekonize
    November 9, 2008

    “So, if DCA can successfully treat human cancers, I predict 1) a drug company will sponsor the agent for the FDA approval process and 2) they will find a way to make a good profit with it.”

    Wow, you have no idea how economics works. Read post eleven about monopoly (something that has been known by economists for a long time now) and how I relate them to patents (which are monopolies).

    http://forums.christianity.com/The_FDA_and_health/m_3795161/mpage_1/tm.htm#1 (post 11). Speaking of oncologists, “In 2002, the Journal of the American Medical Association reported that in the previous year, the average oncologist had made $253,000 of which 75% was profit on chemotherapy drugs administered in his/her office. Yet, surveys of oncologists by the Los Angeles Times and the McGill Cancer Center in Montreal show that from 75% to 91% of ongologists would refuse chemotherapy as a treatment for themselves or their families. Why? Too toxic and not effective. Yet, 75% of cancer patients are urged to take chemo by their oncologists.” (post 21). I suspect this is the real reason why special interest groups want open information closed.

  10. #10 Bettawrekonize
    November 9, 2008

    (or rather, I suspect that things like this are the real reasons … )

  11. #11 Bettawrekonize
    November 9, 2008

    I have little doubt that all of my posts won’t make it through because special interest groups will resort to doing what they always do when they can’t address a problem, censor it.

  12. #12 Bettawrekonize
    November 9, 2008

    Oh, my posts did make it through. Awesome.

  13. #13 Bettawrekonize
    November 9, 2008

    “However, when DaveScot and the sycophants on Uncommon Descent join in with the “cure for cancer” hype and conspiracy-mongering (with apparently only one voice of reason trying to counter DaveScot’s cluelessness), it’s really, really hard for me to resist the urge to introduce the mutual admiration society over at UD to a heapin’ helpin’ of Orac’s cluestick, too.”

    http://scienceblogs.com/insolence/2007/02/laying_the_cluestick_on_davescot_over_di_1.php

    “Population control for money is the easiest way to describe the new Codex which is run by the U.S. and controlled by Big Pharma and the like to reduce the population to a sustainable 500 million – a reduction of approximately 93 percent. The FAO and WHO have the audacity to estimate that by the introduction of just the vitamin and mineral guideline alone, at a minimum 3 billion deaths (1 billion from starvation and another 2 billion from preventable and degenerative diseases of under nutrition, e.g., cancer, cardiovascular disease, and diabetes) will result.”

    http://www.naturalnews.com/024128.html

    If this isn’t a conspiracy, I don’t know what is. Yet, the government/FDA tries to deny terminal cancer patients the right to try and get better from DCA (but the government is fine to submit a program that will result in billions many deaths). The hypocrisy. People need to stop believing the myth that our government wants what’s best for us. If they wanted what’s best for us, they would ban cigarettes instead of trying to deny terminal cancer patients the right to try to get better with DCA.

  14. #14 Bettawrekonize
    November 9, 2008

    “Children Exposed to Substances for Experimentation”

    “This is not the first time he has shown bad faith. When his appointment was held up by Senator Barbara Boxer and Senator Bill Nelson.until he suspended the notorious Children’s Environmental Exposure Research Study (CHEERS)–that was designed to expose toddlers to pesticide and record their reactions, Johnson agreed only to invite pesticide producers to submit their own study.”

    http://forums.christianity.com/Children_Exposed_to_Substances_for_Experimentation/m_3967882/mpage_1/tm.htm#1

    When will people realize that our government and these corporations are ran by a bunch of evil criminals who belong in jail. They can’t be trusted.

  15. #15 Bettawrekonize
    November 11, 2008

    “However, when DaveScot and the sycophants …join in with the … conspiracy-mongering…”

    Oh no, conspiracies never happen in the U.S.A, especially not within the secular (tax funded) community.

    http://www.naturalnews.com/024737.html

    This conspiracy has been going on from 2000 – 2007. But we have to remember, the U.S is somehow immune to conspiracies, they can’t happen here, not ever.

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