Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer.

[Rich66]

Br J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Links

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer.

Michelakis ED, Webster L, Mackey JR.
Department of Medicine, University of Alberta, Edmonton, Canada. evangelos.michelakis@capitalhealth.ca
The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.

University of Alberta DCA website:

http://www.depmed.ualberta.ca/dca/

[Rich66]

Scientists cure cancer, but no one takes notice

By: David McRaney

Posted: 1/23/07

EDITORS NOTE:
Since the original publication of this article we have been inundated with responses from the public at all walks of life. It is important to note that research is ongoing with DCA, and not everyone is convinced it will turn out to be a miracle drug. There have been many therapies that were promising in vitro and in animal models that did not work for one reason or another in humans. To provide false hope is not our intention. There is a lot of information on DCA available on the web, and this column is but one opinion on the topic. We hope you will do your own research into the situation. So, we have added links to resources at the end of this column. If you are arriving here form a linking website like Fark, then those links will not appear because they tend to grab only the text. For those visitors, here is a link to the original research: www.depmed.ualberta.ca/dca
END NOTE
Scientists may have cured cancer last week.
Yep.
So, why haven't the media picked up on it?
Here's the deal. Researchers at the University of Alberta in Edmonton, Canada found a cheap and easy to produce drug that kills almost all cancers. The drug is dichloroacetate, and since it is already used to treat metabolic disorders, we know it should be no problem to use it for other purposes.
Doesn't this sound like the kind of news you see on the front page of every paper?
The drug also has no patent, which means it could be produced for bargain basement prices in comparison to what drug companies research and develop.
Scientists tested DCA on human cells cultured outside the body where it killed lung, breast and brain cancer cells, but left healthy cells alone. Rats plump with tumors shrank when they were fed water supplemented with DCA.
Again, this seems like it should be at the top of the nightly news, right?
Cancer cells don't use the little power stations found in most human cells - the mitochondria. Instead, they use glycolysis, which is less effective and more wasteful.
Doctors have long believed the reason for this is because the mitochondria were damaged somehow. But, it turns out the mitochondria were just dormant, and DCA starts them back up again.
The side effect of this is it also reactivates a process called apoptosis. You see, mitochondria contain an all-too-important self-destruct button that can't be pressed in cancer cells. Without it, tumors grow larger as cells refuse to be extinguished. Fully functioning mitochondria, thanks to DCA, can once again die.
With glycolysis turned off, the body produces less lactic acid, so the bad tissue around cancer cells doesn't break down and seed new tumors.
Here's the big catch. Pharmaceutical companies probably won't invest in research into DCA because they won't profit from it. It's easy to make, unpatented and could be added to drinking water. Imagine, Gatorade with cancer control.
So, the groundwork will have to be done at universities and independently funded laboratories. But, how are they supposed to drum up support if the media aren't even talking about it?
All I can do is write this and hope Google News picks it up. In the meantime, tell everyone you know and do your own research.
PLEASE READ THE EDITOR'S NOTE AT THE TOP OF THIS COLUMN, AND PLEASE CLICK ON THE LINKS TO OTHER DCA RESOURCES LISTED DIRECTLY UNDER THIS COLUMN.
This is a column of opinion written by Printz Executive Editor David McRaney. Comments can be sent to printz@usm.edu

[Rich66]

Letter from Dr. Evangelos Michelakis
October 2008

Dear Friends,

This is a short update on our DCA project at the University of Alberta.

We would like to express our gratitude and appreciation for your support in our fund raising efforts. Through donations on this web page and philanthropic foundations we have been able to expand our basic science efforts as well as initiated and run two clinical trials in Edmonton. In collaboration with the Cross Cancer Institute and the Alberta Cancer Board, we are running clinical trials in patients with solid tumours that have failed standard therapies as well as in patients with malignant brain tumours. The objectives of these trials is to determine the safety of DCA as a novel therapy for cancer. We are trying to determine the optimal dose and to monitor potential adverse effects, such as drug interactions and toxicities. This is necessary to do before embarking on more definitive trials to test the effectiveness of this drug in the treatment of cancer. We have enrolled more than half of our target numbers of patients in these trials and we are gaining invaluable experience. Both the progress and the preliminary results are promising, although the detailed outcomes of these trials will be published in medical journals, after their completion.

We are very encouraged by these early results, and are now preparing to initiate additional clinical trials, in Edmonton and in collaboration with other Universities in around the world.

We are gratified to see that other researchers have begun to share our excitement with DCA. Several recent studies have reported findings similar to ours. These include some work suggesting that DCA has anti-cancer effects in endometrial and prostate cancer (see the references at the end of this letter). However a word of caution, these experiments were not done in patients, but rather in animals and test tubes, and so the applicability of these results to human disease has not been determined. They make however, the need for clinical trials even more pressing. We also reiterate that in the absence of knowledge about the safety and effectiveness of this drug in people it is unwise to be taking this agent unsupervised and outside of a clinical trial.

On behalf of the many people here at the University of Alberta that continue to work on DCA,

Thank you very much!

Recent medical reports on DCA:

Journal: Gynecol Oncol. 2008 Jun;109(3):394-402
Title: Dichloroacetate induces apoptosis in endometrial cancer cells.
Authors: Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

Journal : Prostate. 2008 Aug 1;68(11):1223-3
Title: Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation.
Authors: Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S, Urbanek C, Rosser CJ. Department of Urology, University of Florida, Gainesville, Florida, USA

Journal: Proceedings of the National Academy of Sciences, PNAS 2007 104:9445-9450
Title: Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy
Authors: Rob A. Cairns, Ioanna Papandreou, Patrick D. Sutphin, and Nicholas C. Denko Stanford University, Palo Alto, CA, USA



UPDATE March 15, 2007
The University of Alberta Discovery
DCA is an odourless, colourless, inexpensive, relatively non-toxic, small molecule. And researchers at the University of Alberta believe it may soon be used as an effective treatment for many forms of cancer.
Dr. Evangelos Michelakis, a professor at the U of A Department of Medicine, has shown that dichloroacetate (DCA) causes regression in several cancers, including lung, breast, and brain tumors.
Michelakis and his colleagues, including post-doctoral fellow Dr. Sebastien Bonnet, have published the results of their research in the journal Cancer Cell.
Scientists and doctors have used DCA for decades to treat children with inborn errors of metabolism due to mitochondrial diseases. Mitochondria, the energy producing units in cells, have been connected with cancer since the 1930s, when researchers first noticed that these organelles dysfunction when cancer is present.
Until recently, researchers believed that cancer-affected mitochondria are permanently damaged and that this damage is the result, not the cause, of the cancer. But Michelakis, a cardiologist, questioned this belief and began testing DCA, which activates a critical mitochondrial enzyme, as a way to "revive" cancer-affected mitochondria.
The results astounded him.
Michelakis and his colleagues found that DCA normalized the mitochondrial function in many cancers, showing that their function was actively suppressed by the cancer but was not permanently damaged by it.
More importantly, they found that the normalization of mitochondrial function resulted in a significant decrease in tumor growth both in test tubes and in animal models. Also, they noted that DCA, unlike most currently used chemotherapies, did not have any effects on normal, non-cancerous tissues.
"I think DCA can be selective for cancer because it attacks a fundamental process in cancer development that is unique to cancer cells," Michelakis said. "One of the really exciting things about this compound is that it might be able to treat many different forms of cancer”.
Another encouraging thing about DCA is that, being so small, it is easily absorbed in the body, and, after oral intake, it can reach areas in the body that other drugs cannot, making it possible to treat brain cancers, for example.
Also, because DCA has been used in both healthy people and sick patients with mitochondrial diseases, researchers already know that it is a relatively non-toxic molecule that can be immediately tested patients with cancer.

”The results are intriguing because they point to the critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy”
Dario Alteri
Director University of Massachusetts Cancer Center

Investing in Research
The DCA compound is not patented and not owned by any pharmaceutical company, and, therefore, would likely be an inexpensive drug to administer, says Michelakis, the Canada Research Chair in Pulmonary Hypertension and Director of the Pulmonary Hypertension Program with Capital Health, one of Canada’s largest health authorities.
However, as DCA is not patented, Michelakis is concerned that it may be difficult to find funding from private investors to test DCA in clinical trials. He is grateful for the support he has already received from publicly funded agencies, such as the Canadian Institutes for Health Research (CIHR), and he is hopeful such support will continue and allow him to conduct clinical trials of DCA on cancer patients.
Michelakis’ research is currently funded by the CIHR, the Canada Foundation for Innovation, the Canada Research Chairs program, and the Alberta Heritage Foundation for Medical Research.
"This preliminary research is encouraging and offers hope to thousands of Canadians and all others around the world who are afflicted by cancer, as it accelerates our understanding of and action around targeted cancer treatments," said Dr. Philip Branton, Scientific Director of the CIHR Institute of Cancer.
DCA and Cancer Patients
The University of Alberta’s DCA Research Team is set to launch clinical trials on humans in the spring of 2007 pending government approval. Knowing that thousands of cancer patients die weekly while waiting for a cure, Dr. Michelakis and his team are working at accelerated speed, condensing research that usually takes years into months. Fundraisers at the University of Alberta are determined to raise the money to allow this next phase of research to begin. Once Health Canada grants formal approval, the University of Alberta’s Research Team will begin testing DCA on patients living with cancer. Results with regards to the safety and efficacy of treatment should be known late this year.

“If there were a magic bullet, though, it might be something like dichloroacetate, or DCA…”
Newsweek, January 23, 2007