January 16, 2007 - Edmonton - 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.
One qualifier to the above statement: Whether dichloroacetate (DCA) would really be non-toxic when used in therapeutic doses against cancer remains to be seen. When used to treat a genetic disorder involving high lactic acid DCA caused peripheral neuropathy. DCA inhibits a kinase enzyme that deactivates an enzyme called pyruvate dehydrogenase (PDH) which is involved in mitochondrial metabolism (i.e, it is involved in sugar breakdown to make energy).
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. Sebastian Bonnet, have published the results of their research in the journal Cancer Cell.
Many cancer cells do not break sugar down completely. They just do a step called glycolysis. They do not do a step called the Krebs cycle (aka the citric acid cycle or tricarboxylic acid cycle or TCA cycle) which extracts all the energy out of sugar molecules to make energy carrier molecules called NADH and ATP. This was first observed about cancer all the way back in the 1930s. Up until now the assumption to explain this was that cancer cells lost that ability. But this result suggests that not only do cancer cells suppress that ability but that suppression helps them grow uncontrollably.
Pyruvate dehydrogenase (PDH) synthesizes acetyl-CoA which is used in the first step of the TCA cycle in mitochondria. If DCA has either toxicity problems or problems with achieving sufficient doses that does not defeat this approach to anti-cancer drug development. The kinase that DCA blocks could become a target for drug development. A drug that would disable that kinase would likely activate mitochondria in cancer cells just like DCA does.
I remember a scientist telling me decades ago that classic intermediary metabolism doesn't get the attention it deserves because everyone was rushing into genetics. Many scientists decided that there was little of interest left to learn from studying the main pathways of energy metabolism. This result argues for his view. How can we get all the way to the year 2007 without noticing sooner the powerful results from a simple long known molecule?
Michelakis decided the conventional wisdom on cancer and mitochondria might be wrong and decided to test it.
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.
No one single molecule is going to cure all cancers by itself. But combinations of compounds where all have toxicity highly specific to cancer cells will certainly end up curing a great many cancers. Monoclonal antibodies targetted at cancers, anti-angiogenesis compounds that block blood vessel growth in cancers, gene therapies that activate in cancer cells and assorted other compounds such as DCA are going to cure many cancers when used in combination.
"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. "Cancer cells actively suppress their mitochondria, which alters their metabolism, and this appears to offer cancer cells a significant advantage in growth compared to normal cells, as well as protection from many standard chemotherapies. Because mitochondria regulate cell death - or apoptosis - cancer cells can thus achieve resistance to apoptosis, and this appears to be reversed by DCA."
The suppression of mitochondria might be a way for cancer cells to divide in low oxygen environments found deep in tumors lacking in sufficient vasculature. By turning on mitochondria in these cells their need for oygen is probably increased and that likely contributes to their death. This suggests that DCA might work well in combination with anti-angiogenesis drugs since the ability of anti-angiogenesis drugs to block blood vessel growth will decrease the amount of oxygen available to tumors and therefore make more cells in tumors susceptible to the effects of DCA.
DCA (aka Ceresine) has a big problem: It is not patentable and hence provides little incentive for commercial companies to raise money to fund clinical studies to develop it as an anti-cancer drug. People who are philosophically opposed to patents ought to take note of this.
Furthermore, the DCA compound is not patented or owned by any pharmaceutical company, and, therefore, would likely be an inexpensive drug to administer, Michelakis added.
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.
If DCA is on the market in less regulated countries then maybe it'll get tried out in human cancer patients under less restrictive regulatory regimes.
Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.
People who have fatal diseases should be allowed to try anything as a treatment.
|Share |||Randall Parker, 2007 January 21 09:06 PM Biotech Cancer|