APRIL/MAY
TAXOL STRANGLES PROTEIN, CANCER CELLS SELF-DESTRUCT
By Katrina Miles
Florida State Biophysicist Lee Makowski calls it "programmed cell death." It will give scientists new insights on exactly how the anti-cancer drug, Taxol, kills tumor cells. What it may do ultimately is aid researchers in developing more advanced cancer-fighting drugs.
Makowski and his research group had been studying the structure of microtubules - the molecular cables that pull two cells apart during cell division - when they discovered how Taxol triggers apoptosis - cells dying on purpose.
"Think of it this way," said Makowski. "When an embryo is developing it has webbed feet and hands. But, by the time the baby is born those cells between the digits have died, separating the fingers and toes. Why? Because eventually these cells die off by way of a process known as apoptosis."
Apoptosis also protects the body from cancer. If a cell becomes transformed and starts uncontrolled growth, there are proteins within the cell that react to that transformation and trigger apoptosis, killing the cell to protect the body.
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"It's a programmed cell death - a cellular method - by which the cell, on purpose, decides to commit suicide," Makowski said.
Knowing this, and knowing that Taxol targets microtubules to prevent cells from dividing, which triggers apoptosis - the next question for Makowski and his group was "why is this important?"
"Ah, that was the $64,000 question," said Makowski. "But, what we discovered is that Taxol also attacks a second target in cancer cells."
And it's a question whose answer may make it easier for researchers to develop more efficient anti-cancer drugs. However, first they had to find which other parts of a cell Taxol could bind to.
To do this, the FSU researchers created a huge library of bacterial viruses genetically engineered to act like cellular proteins. Then, they screened the library to find which of the viruses bind to Taxol.
Again they happened upon another neat discovery. In addition to Taxol binding to microtubules, it also binds to a protein called Bcl-2, a molecule first discovered in human leukemias.
"Again you ask 'so what?' But, let me tell you. Bcl-2 is a critical component in the mechanism that causes apoptosis," Makowski said. "Simply, it blocks the cell from completing the process of cell death. So, when there's lots of it, cells can't kill themselves and a tumor can proliferate."
Makowski's research team discovered that Taxol binds very tightly to Bcl-2 - strangling the protein, thus allowing apoptosis to continue.
"This discovery shows that Taxol mounts a two-pronged attack against cancer cells, perhaps explaining why it is so effective," said Makowski, who is now 15 months into a two-year sabbatical from his duties at the FSU Institute. His findings were published in the January issue of the Journal of Molecular Biology. He is currently working as a program manager in the division of biological infrastructure at the National Science Foundation - where he received a grant for his study.
"Knowing that Taxol binds to Bcl-2 gives us better assays for figuring out which Taxols might be better cancer-fighting agents," Makowski said.