Scientists Find Second Way
to Kill Cancer Cells: Discovery Opens Possibilities
for New Therapies
New study shows aklylating DNA
damage stimulates regulated necrotic cell death
(Philadelphia, PA) – Researchers
at the Leonard and Madlyn Abramson Family
Cancer Research Institute at the University
of Pennsylvania have found a second way by which chemotherapeutic
agents can kill cancer cells. The finding –
which will appear online and ahead of print in the
June 1st edition of the journal Genes & Development
– represents an important advance in understanding
how and why some cancer cells die and others do not
in response to existing chemotherapy. The results
suggest the possibility that targeted therapies can
be developed which will force cancer cells to die
before they can grow into tumors.
"This finding shows, for the first
time, that cancer cells are unusually sensitive to
dying by necrosis, when their ability to metabolize
glucose is blocked," said Craig Thompson,
MD, Principal Investigator of the study and
Scientific Director of the Abramson Family Cancer
Research Institute (AFCRI). "Up until now, research
has focused on finding ways to program cancer cells
to die through apoptosis – a very regulated,
orderly form of cell death that does not trigger an
immune response. Now, we know that cancer cells can
be forced to die, suddenly, through necrosis. If we
can harness this method, which does trigger an immune
response, then, the door will be opened to a whole
new and less toxic way to treat cancer."
Despite long-term use, the action of
chemotherapeutic agents – to kill and stop the
growth of cancer cells – is not well understood.
The agents have proven to be effective treatments
even for tumors lacking the genes considered essential
for apoptosis, but the precise cellular mechanism
for this has remained unexplained up until now.
To study this issue, the researchers
created mouse cells that were unable to die by apoptosis.
The cells were engineered to be deficient in either
the tumor suppressor gene p53, the most commonly
mutated gene in human cancer, or two key proteins
essential for the execution of apoptotic cell death,
Bax and Bak. The researchers then determined whether
any standard chemotherapeutic drugs could kill these
cells. They discovered that some commonly used chemotherapeutic
drugs – alkylating agents such as mechlorethamine
hydrochloride (nitrogen mustard) – retained
the ability to kill the cells engineered to be resistant
to apoptosis. When exposed to alkylating agents, the
cancer cells died by necrosis, a form of cell death
that results from energy depletion.
Of equal importance, the researchers
found that the induced necrotic cell death was specific
to proliferating cancer cells. The rapid energy depletion
was triggered by activation of a DNA repair protein,
called PARP. Its activation leads to an inhibition
of the cancer cell's ability to break down glucose
to produce the cellular fuel ATP, a process termed
glycolysis. In contrast, non-proliferating or non-cancerous
cells did not exhibit energy depletion, as they produce
most of their ATP by metabolizing a mixture of fats,
proteins, and carbohydrates in a process termed oxidative
phosphorylation. This explains why necrotic cell death,
induced by the chemotherapeutic agents, was specific
to cancer cells and did not affect healthy, non-proliferating
cells. When PARP activation was blocked, necrotic
cell death failed to occur despite exposure to the
chemotherapeutic agents.
Chemotherapeutic drugs activate PARP
by damaging DNA. While this is effective at killing
tumor cells, it comes at the price of damaging many
normal cells, creating mutations that might lead to
new cancers. In contrast, the new work suggests that
drugs directly activating PARP might prove effective
at treating cancer without many of the serious side
effects of existing chemotherapy.
"Our next step is to try to safely
manipulate necrotic cell death in cancerous tumors,
" said Wei-Xing Zong, PhD, study
author and Post-Doctoral Fellow at the AFCRI. "Ultimately,
the hope is that this could lead to new, safer targeted
therapies to kill cancer cells before they turn into
deadly tumors that can spread elsewhere in the body."
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