Posted by 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.
May 14, 2010
May 14, 2010
May 14, 2010
May 15, 2010
May 18, 2010
May 22, 2010