Recent Medical Research at a Canadian University has confirmed that scientists do understand the cause of cancer. The dying off of old cells to be replaced by new cells is a normal part of our cellular life-cycle and keeps us well. It seems that in cancerous cells, our body has forgotten how to tell the aged cells how to die off and be replaced by healthy new cells.
This process is governed by the mitochondria and is known as "cell death" or "apoptosis". In a cancer cell, the mitochondria has lost the ability to direct the cell to die off - the sick cell becomes "immortal", spreading and making the person increasingly unwell.
Recent Medical trials using DCA have proven this compound can reactivate the mitochondria restoring the cell's original function of "apoptosis" enabling shrinkage in tumor size and mass. Testimonials have shown reversal in illness, remission, clean health tests, increased health and vitality. Favourable results (scientifically measurable) have been accomplished within days (less than a week) of starting treatment with DCA.
"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."
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.
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, Michelakiss experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell).
Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump dont 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 tumors.
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 cant make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.
Canadian researchers find a simple cure for cancer, but major pharmaceutical companies are not interested. Researchers at the University of Alberta, in Edmonton, Canada have recently cured cancer, yet there is but little ripple in the news or on TV. It is a simple technique using a very basic drug. The method employs dichloroacetate, which is currently used to treat metabolic disorders, so there is no concern of side effects or other long term effects.
The drug doesn’t require a patent, so anyone can employ it widely and cheaply compared to the costly cancer drugs produced by major pharmaceutical companies.
Canadian scientists tested dichloroacetate (DCA) on human cells; it killed lung, breast and brain cancer cells and left the healthy cells alone. It was tested on rats inflicted with severe tumors; their cells shrank when they were fed with water supplemented with DCA. The drug is widely available and the technique is easy to use, but why are the major drug companies not involved, or the media not interested in this find?
In human cells there is a natural cancer fighting organelle, the mitochondria, but it needs to be triggered in order to be effective. Scientists used to think that the mitochondria of cancerous cells were damaged and thus ineffective. They used to focus on glycolysis, which is less effective in fighting cancer and wasteful. The drug manufacturers focused on the glycolysis method to fight cancer. DCA treatment on the other hand doesn’t rely on glycolysis but instead on reactivating the mitochondria; which allows the cell to die and prevents the cancer from spreading.
This reactivation is a process called apoptosis. You see, mitochondria contain an all-too-important self-destruct button that cannot 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 be allowed to 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.
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Cheap, 'safe' drug kills most cancers
- Updated 13:31 17 May 2011 by Andy Coghlan
- For similar stories, visit the Cancer Topic Guide
New Scientist has received an unprecedented amount of interest in this story from readers. If you would like up-to-date information on any plans for clinical trials of DCA in patients with cancer, or would like to donate towards a fund for such trials, please visit the site set up by the University of Alberta and the Alberta Cancer Board. We will also follow events closely and will report any progress as it happens.
Update, 16 May 2011: If you've just heard about this story, please read this recent update too.
Article originally published online 17 January 2007:
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.
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.
Cancer - Learn more about one of the world's biggest killers in our comprehensive special report.
Cancer cells change the way they metabolize oxygen in a way that promotes their survival. In laboratory studies of isolated cancer cells grown in tissue culture, DCA restores the original metabolism, and promotes their self-destruction. This has led to the use of DCA for treating cancer, by individuals experimenting with it themselves, by doctors administering it to patients as a non-approved drug, by scientists testing it in cancer tissue cultures in cell culture and in mice, and in human Phase II studies. DCA has improved certain biochemical parameters, but it has not demonstrated improved survival.[citation needed]
Contents[hide] |
[edit] Chemistry and occurrence
The chemistry of dichloroacetic acid is typical for halogenated organic acids. It is a member of the chloroacetic acids family. The dichloroacetate ion is produced when the acid is mixed with water. As an acid with a pKa of 1.35,[1] pure dichloroacetic acid is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract.[2]DCA does not occur in nature. It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals.[3] DCA is typically prepared by the reduction of trichloroacetic acid.
[edit] Therapeutic use
Owing to the highly corrosive action of the acid, only the salts of dichloroacetic acid are used therapeutically, including its sodium and potassium salts, sodium dichloroacetate and potassium dichloroacetate.[edit] Lactic acidosis
The dichloroacetate ion stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting the enzyme pyruvate dehydrogenase kinase.[4] Thus, it decreases lactate production by shifting the metabolism of pyruvate from fermentation towards oxidation in the mitochondria. This property has led to trials of DCA for the treatment of lactic acidosis in humans.[5][6][7][8]A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[6] A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication.[7] A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival.[8]
Thus, while early case reports and pre-clinical data suggested that DCA might be effective for lactic acidosis, subsequent controlled trials have found no clinical benefit of DCA in this setting. In addition, clinical trial subjects were incapable of continuing on DCA as a study medication owing to progressive toxicities.
[edit] Potential cancer applications
Cancer cells generally express increased glycolysis, because they rely on anaerobic respiration that occurs in the cytosol (lactic acid fermentation) rather than oxidative phosphorylation in the mitochondria for energy (the Warburg effect), as a result of hypoxia that exists in tumors and malfunctioning mitochondria. [9] [10] Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells.A phase I study published in January 2007 by researchers at the University of Alberta, who had tested DCA on human[11] cancer cells grown in mice, found that DCA restored mitochondrial function, thus restoring apoptosis, allowing cancer cells to self-destruct and shrink the tumor.[12]
These results received extensive media attention, beginning with an article in New Scientist titled "Cheap, ‘safe’ drug kills most cancers".[11] Subsequently, the American Cancer Society and other medical organizations have received a large volume of public interest and questions regarding DCA.[13] Clinical trials in humans with cancer have not been conducted in the USA and are not yet final in Canada, emphasizing the need for caution in interpreting the preliminary results.[13][14]
[edit] Results of phase II clinical trials
In in vitro studies, Evangelos Michelakis of University of Alberta found that in tissue samples from 49 patients, DCA caused depolarization of mitochondria in GBM tissue but not in normal brain tissue.[15]Five palliative patients with primary GBM were entered into a phase II trial. Three had not responded to several chemotherapies; two were newly diagnosed. After surgical removal of tumor mass, they were treated with DCA and chemotherapy.[15]
Of the five patients tested, one died after three months. The surviving four were followed for 15 months. Their Karnofsky scores were unchanged in two cases, and decreased by 10 points in two patients.[15]
DCA was associated with tumor regression and had a good safety profile. DCA side effects were minimal.[15]
Michelakis is proceeding with phase three human studies with private funding from philanthropic groups and individuals. DCA's legal status as a discovery is public domain because it was made or discovered as far back as 1864[16] and has been used in the treatment of canine and human lactic acidosis, some who presented at the beginning of treatment with cancer.
[edit] Concerns about pre-trial use
Following its initial publication, The New Scientist later editorialized, "The drug may yet live up to its promise as an anti-cancer agent – clinical trials are expected to start soon. It may even spawn an entirely new class of anti-cancer drugs. For now, however, it remains experimental, never yet properly tested in a person with cancer. People who self-administer the drug are taking a very long shot and, unlikely as it may sound, could even make their health worse."[17]In 2010, it was found that for human colorectal tumours grown in mice, under hypoxic conditions, DCA decreased rather than increased apoptosis, resulting in enhanced growth of the tumours.[18] These findings suggest that at least in some cancer types DCA treatment could be detrimental to patient health, highlighting the need for further testing before it can be considered a safe and effective cancer treatment.[18]
[edit] Planned and ongoing clinical trials
DCA is non-patentable as a compound, though a patent has been filed for its use in cancer treatment.[19] Research by Evangelos Michelakis has received no support from the pharmaceutical industry.[citation needed] Concerns have been raised that without strong intellectual property protection, the financial incentive for drug development is reduced, and therefore obtaining sufficient funds to conduct clinical trials presents difficulty.[11][13][14][20] However, other sources of funding exist; previous studies of DCA have been funded by government organizations such as the National Institutes of Health, the Food and Drug Administration, the Canadian Institutes of Health Research and by private charities (e.g. the Muscular Dystrophy Association). Recognizing anticipated funding challenges, Michelakis's lab took the unorthodox step of directly soliciting online donations to fund the research.[21] After 6 months, his lab had raised over $800,000, enough to fund a small Clinical Phase 2 study. Michelakis and Archer have applied for a patent on the use of DCA in the treatment of cancer.[19][22]On 24 September 2007, the Department of Medicine of Alberta University reported that after the trial funding was secured, both the Alberta local ethics committee and Health Canada approved the first DCA clinical trial for cancer.[23] This initial trial was relatively small with enrollment of up to 50 patients. The trial was completed in August 2009.[24] In May 2010 the team published a press release[25] stating no conclusions could be drawn as a result of the trial. A paper describing the results was published[26] but not linked from the press release. Only five patients had been treated with the drug during the trial.
In May 2011, online reports[27] suggested that the Alberta group had released new data which the media "had not reported". However, this appeared to be caused by confusion between dates (the previous update was May 2010[28]) and cancer charities moved quickly to counter these rumours,[29][30] which were subsequently covered in New Scientist magazine.[31]
The use of this compound as an anti-cancer agent has been patented.[32]
[edit] Side effects
Reports in the lay press after the 2007 University of Alberta announcement claim that dichloroacetate "has actually been used safely in humans for decades",[33] DCA is generally well-tolerated, even in children.[34] Short-term, infused, bolus doses of DCA at 50 mg/kg/day have been well-tolerated.[35] The Medicor Cancer Centre reports on its website the use of 20–25 mg/kg/day on a two-week on, one week off cycle. This cycling helps determine which side effects are due to DCA, which are due to cancer, and if treatment should be discontinued.[36]At sustained, higher doses(generally 25 mg/kg/day taken orally, or greater), there is increased risk of several reversible toxicities, especially peripheral neuropathy, neurotoxicity, and gait disturbance.[4][33] Studies have also shown that it can be carcinogenic at high doses.[37]
[edit] Neuropathy
A clinical trial where DCA was given to patients of MELAS (a form of genetically inherited lactic acidosis) at 25 mg/kg/day was ended prematurely due to excessive peripheral nerve toxicity.[38] Dichloroacetate can also have anxiolytic or sedative effects.[3]Animal studies suggest that the neuropathy and neurotoxicity during chronic dichloroacetate treatment may be partly due to depletion of thiamine, and thiamine supplementation in rats reduced these effects.[39] However, more recent studies in humans suggest that peripheral neuropathy is a common side effect during chronic DCA treatment, even with coadministration of oral thiamine.[40][41] An additional study reported that 50 mg/kg/day DCA treatment resulted in unsteady gait and lethargy in two patients, with symptoms occurring after one month for one patient and two months for the second. Gait disturbance and consciousness were recovered with cessation of DCA, however sensory nerve action potentials did not recover in one month.[42]
It has been reported that animals and patients treated with DCA have elevated levels of delta-aminolevulinic acid (delta-ALA) in the urine. A study published in 2008 suggests that this product may be the cause of the neurotoxic side effect of DCA by blocking peripheral myelin formation.[43]
[edit] Carcinogenicity
Long term use (three years or more) of high doses (> 77 mg/kg/day) of DCA has been shown to increase risk of liver cancer in mice.[37] Studies of the trichloroethylene (TCE) metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans.[44][edit] Self-medication
The promise of DCA as a cheap, effective and safe treatment for cancer generated a great deal of public interest. Many people turned to self-medication.[45][46]Doctors warned of potential problems if people attempt to try DCA outside a controlled clinical trial. "If it starts going badly, who is following you before it gets out of control? By the time you realize your liver is failing, you're in big trouble", said Laura Shanner, Associate Professor of Health Ethics at the University of Alberta.[47]
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