Building on newly discovered genetic threads in the
rich tapestry of biochemical signals that cause cancer, a
Johns
Hopkins Kimmel Cancer Center team has dramatically
killed brain cancer cells by blocking those signals with a
statin and an experimental anti-tumor drug.
The unlikely pairing of cholesterol-lowering
lovastatin and cyclopamine killed 63 percent of
medulloblastoma cells grown in the laboratory. By contrast,
using either agent alone wiped out fewer than 20 percent of
cells. The Johns Hopkins researchers published their
findings in the January issue of The American Journal of
Pathology.
The researchers caution that the
cyclopamine-lovastatin combination has yet to be tested in
animals, much less people, but they conclude that the tumor
cell killing by the combo is tantalizing. Cyclopamine works
by blocking the so-called "hedgehog" pathway, long known to
promote and guide cell and organ growth. Excessive growth
is the chief characteristic of cancer. The investigators
believe that blocking hedgehog with cyclopamine makes
cancer cells more susceptible to lovastatin.
Along with its cholesterol-clogging effects,
lovastatin, sold under the trade name Mevacor, is known to
curb destruction of proteins that put the brakes on cell
growth, causing cancer cells to self-destruct through a
process called apoptosis. The effects of the statin already
are being studied in people at high risk for the deadly
skin cancer melanoma.
First extracted from corn lilies in the 1950s,
cyclopamine is a powerful toxin known to stunt fetal
development and cause birth defects in humans and animals.
Its connection to anti-cancer efforts grew out of later
insights into its blockage of hedgehog, which gets its name
from spiky hairs that develop on fruit flies lacking the
signal.
"We already knew from earlier research that hedgehog
controls brain cell survival and growth, and that blocking
signals in this pathway may stop uncontrolled growth of
cancer cells," said Charles Eberhart, associate professor
of pathology, ophthalmology and oncology. "But the new work
shows the hedgehog blockade may halt another powerful
cell-survival signal, and lovastatin could provide the
added boost necessary to kill more cancer cells."
Specifically, Eberhart found links between the
expression of key hedgehog-related genes in medulloblastoma
cells and another cell signal already tied to cancer,
Bcl-2. Eberhart and his team believed that a combination of
a hedgehog blockade and a pro-apoptosis drug like
lovastatin would kill more cancer cells.
"Our experiments suggest that hedgehog's action is
woven together with Bcl-2, best known for its role in
causing B-cell lymphomas," he said. "Cancer cells thwart
suicide by overproducing Bcl-2, assuring them a long
life."
When the Johns Hopkins researchers noticed that Bcl-2
and hedgehog expression increased in tandem in
medulloblastoma cells, they tried adding hedgehog-blocking
cyclopamine to the cells and found that Bcl-2 production
dwindled and tumor cells died off.
Lead author Eli E. Bar, a pathology fellow, said he
was "surprised by the degree to which the drug combination
was so effective."
According to Eberhart, only half of children with
medulloblastoma survive. "And those who do survive can
suffer debilitating side effects caused by current toxic
therapies," he said.
The study was supported by the National Institute of
Neurological Disorders and Stroke. Co-authors were Aneeka
Chaudhry and Mohamed H. Farah.
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