July 16, 2002
Drug Wrecks the Power Plants of Cancer Cells
Researchers have identified a compound that selectively kills tumor
cells by destroying their metabolic power plants. The researchers
believe that the compound, code-named F16, could serve as a model for a
targeted chemotherapy with low toxicity.
In an article published in the July 2002 issue of the journal
Cancer Cell, researchers led by Howard Hughes Medical Institute
senior investigator Philip
Leder at Harvard Medical School reported that they screened 16,000
small molecules to look for compounds that would have a favorable
effect on transgenic mouse cells engineered to overexpress the
cancer-causing gene neu. The human counterpart of neu,
which is called HER-2, has been implicated in 20-30 percent of
human breast cancers, and is linked with a poor prognosis for breast
cancer treatment.
“This study also illustrates how basic investigations designed to answer fundamental questions about the mechanism of cancer can, at the same time, provide very interesting and practical leads such as this one.”
Philip Leder
“Because neu or its human analog are such important
elements in breast cancer, we decided to carry out these experiments to
identify metabolic pathways that might collaborate with HER-2 or
neu in the development of malignancy,” said Leder.
In the experiments, the paper’s lead author, HHMI associate
Valeria R. Fantin, introduced the neu gene into mouse mammary
epithelial cells. Mouse mammary epithelial cells that overexpress
neu bear some of the characteristics of human breast tumors.
Fantin then tested each of the 16,000 molecules to see how it affected
the growth of the transgenic and normal mouse cells. These studies
showed that F16 selectively inhibited the growth of the
neu-overexpressing cells, but not the normal cells.
Additional studies indicated that F16 also inhibited the
proliferation of a number of mouse cancer-cell lines that were derived
in Leder’s laboratory and a panel of human breast cancer cell
lines. The researchers found that F16 prevented the formation of tumors
that would normally occur when neu-overexpressing cells are
injected into otherwise healthy mice.
In investigating how F16 selectively killed the cells in which
neu was overexpressed, the physical properties of the molecule
yielded an approach to solving the mystery, Leder said. “It
turned out that when one of our co-authors, Marcelo Berardi, looked at
the structure of the molecule, he recognized the possibility that it
might be fluorescent. So, when we looked at the pattern of fluorescence
within a cell when it took up F16, it resembled the pattern that would
be given by using dyes that selectively stain mitochondria,” he
said.
Mitochondria are organelles that supply cells with energy. It has
long been known that cancer cells undergo complex metabolic changes,
which affect the mitochondria. In particular, damaged mitochondria can
trigger programmed cell death, called apoptosis, by releasing the
chemical cytochrome c.
Leder and Fantin collaborated with HHMI investigator Stanley
J. Korsmeyer and Luca Scorrano at the Dana-Farber Cancer Institute
to characterize how F16 interacted with the mitochondria. According to
Fantin, the F16 molecule possesses a widely distributed positive charge
on a lipophilic core that attracts it to the negatively charged
membranes of mitochondria of cancer cells and allows the molecule to
traverse them. The higher negative charge is a property that seems to
be characteristic of mitochondria in many cancer cells. “Because
these mitochondria have a higher negative transmembrane potential, we
believe that this compound is selectively concentrated by them,”
said Fantin.
The effects of high F16 concentrations on cancer cells’
mitochondria are dramatic, Fantin said. “Electron microscopy
studies showed that when the mitochondria take up F16, they become
swollen, and eventually the outer mitochondrial membrane
ruptures,” she said. “And when we looked at markers of
apoptosis like cytochrome c release, we could see clear evidence of
such release in F16-affected cells.”
According to Leder, F16 and perhaps other related compounds have
properties that may make them promising anti-cancer drugs.
“First, F16 inhibits growth and induces cell death of tumor cells
while apparently sparing normal cells,” said Leder. “And it
does so by virtue of a property of tumor cells that can be exploited by
this drug – namely, the high charge of the tumor mitochondria, as
compared to that in normal cells.
“Secondly, this compound seems to be active at relatively low
concentrations, which will be important in reducing any toxicity that
this class of compounds may have as an anti-tumor agent,” said
Leder.
Leder and his colleagues are now exploring the metabolic and genetic
basis for the difference in membrane potential between normal cells and
tumor cells. They are also beginning studies to understand the
effectiveness of F16 and related compounds on tumors.
“We believe that this study also illustrates how basic
investigations designed to answer fundamental questions about the
mechanism of cancer can, at the same time, provide very interesting and
practical leads such as this one, which may turn out to be of value in
the future,” said Leder.
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