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?