Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells.
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Oncology, Biology, and Genetics Department (DOBiG), University of Genoa, Genoa-Italy.Abstract
The small, water soluble molecule Dichloroacetate (DCA) is recently arousing lively interests in the field of cancer therapy for it has been shown to be able to inhibit the growth of human tumors acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells. Neuroblastoma was one of the tumor types on which DCA was considered ineffective as it is composed of cells with few recognized mitochondrial anomalies. Neuroblastoma, however, is composed of different cell types in terms of metabolism, phenotype and malignant potential. Despite the above prediction, in this work, we show that (i) DCA exhibits an unexpected anticancer effect on NB tumor cells and (ii) this effect is selectively directed to very malignant NB cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. This result supports the need of a detailed investigation of DCA anticancer properties against this tumor type with the final aim of its possible use as therapeutic agent.Copyright © 2011 UICC.
http://www.ncbi.nlm.nih.gov/pubmed/21557214
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From New Scientist
Article originally published online 17 January 2007:
http://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers.html
http://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers.html
It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe.
It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.
It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.
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.
DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.
Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).
Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don't get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.
Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.
"The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.
The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.
DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can't make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.
Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. "The question is: which comes first?" he says.
Comments by Dr. Matteo Conti. I contacted Dr. Conti, one of the authors of the paper. Here is a summary of their work, in his words: (September 2011)
"The work shows that DCA is active in Neuroblastoma.
In neuroblastoma, Dr. Pagano differentiates three cell types at various degree of malignancy. The less differentiated type is more malignant.
DCA acts principally against those cells that are more malignant, and less differentiated.
DCA's action is mainly anti-proliferative, it slows growth and multiplication of malignant stem cells. Alone, it does not kill them.
The effect is very marked.
In mice bearing the tumor, all three cell types being present, DCA exhibist a tumor inhibiting effect, however it is not able to eradicate the tumor.
Alone, DCA despite being effective, is probably not enough for a complete cure.
We are now looking for synergizers, however the idea is that they could be tumor of even cell type specific.
Cocktails for specific type of tumors could possibly be a way to improve DCA efficacy.
These results prompt us many questions. A few of them:
1. Why is that DCA is more active against more malignant cells? An answer is that probably the metabolism and the mitochondrial status of malignant cells is very different from that of slow turning cells. DCA can decrease malignancy of a tumor mass, slowing malignant cells at the expense of other cells in the same mass.
2. Can metabolism be manipulated, in addition to DCA, in order to switch malignancy of tumors?
3. Are there ways of boosting DCA effect to promote killing of cells sensitized by DCA? Apparently yes.
Comments by Dr. Matteo Conti. I contacted Dr. Conti, one of the authors of the paper. Here is a summary of their work, in his words: (September 2011)
"The work shows that DCA is active in Neuroblastoma.
In neuroblastoma, Dr. Pagano differentiates three cell types at various degree of malignancy. The less differentiated type is more malignant.
DCA acts principally against those cells that are more malignant, and less differentiated.
DCA's action is mainly anti-proliferative, it slows growth and multiplication of malignant stem cells. Alone, it does not kill them.
The effect is very marked.
In mice bearing the tumor, all three cell types being present, DCA exhibist a tumor inhibiting effect, however it is not able to eradicate the tumor.
Alone, DCA despite being effective, is probably not enough for a complete cure.
We are now looking for synergizers, however the idea is that they could be tumor of even cell type specific.
Cocktails for specific type of tumors could possibly be a way to improve DCA efficacy.
These results prompt us many questions. A few of them:
1. Why is that DCA is more active against more malignant cells? An answer is that probably the metabolism and the mitochondrial status of malignant cells is very different from that of slow turning cells. DCA can decrease malignancy of a tumor mass, slowing malignant cells at the expense of other cells in the same mass.
2. Can metabolism be manipulated, in addition to DCA, in order to switch malignancy of tumors?
3. Are there ways of boosting DCA effect to promote killing of cells sensitized by DCA? Apparently yes.
