Di-Chloro-Acetate
by Andy Coghlan, January 17, 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. Tumors 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 tumor 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 payoff
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.
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