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The newspaper of The Johns Hopkins University March 24, 2008 | Vol. 37 No. 27
Study: Protein Class Displays Strong Anticancer Action

By Audrey Huang Johns Hopkins Medicine

Johns Hopkins researchers have discovered a previously unsuspected mechanism of cell death that may afford a new way to find and develop stronger yet less-harmful anticancer drugs. Specifically, they have found that a cellular stress-response protein prevents cells from dying by interacting with a particular signaling protein and mediating its response to some conventional anticancer drugs. The results appear in the Jan. 14 Early Edition of the Proceedings of the National Academy of Sciences.

"A major hang-up in cancer chemotherapy is the toxicity caused by DNA disruption of cell division throughout the body. Our research suggests that drugs like cisplatin and novobiocin kill cells as much from this newly discovered mechanism as any other mechanism of cell death," said Solomon H. Snyder, Distinguished Service Professor of Neuroscience, Pharmacology and Psychiatry at Johns Hopkins. "Targeting this new mechanism in drug design might make for therapies with fewer side effects."

Snyder and colleagues previously had discovered that cell stressors, including anticancer drugs, rapidly activate the protein IP6K2, which promotes cell death. The team searched for proteins that bind to and potentially control IP6K2 and found a heat shock protein, HSP90.

"This was really interesting because HSP90 is a survival protein," Snyder said. "On the one hand, we have IP6K2, which is pro-death, and on the other, we have the pro-life HSP90, so we thought maybe they might be duking it out in a cell."

When the researchers looked more closely at the interactions between HSP90 and IP6K2, they found that when the two are bound to each other, IP6K2 stops working. When the researchers altered IP6K2 so that it couldn't bind to HSP90, they were able to restore IP6K2 function. And presumably, according to Snyder, the cell would die.

The team then asked whether the anticancer drugs cisplatin and novobiocin, which cause cell death, somehow interfered with HSP90-IP6K2 interactions. The scientists found that at normal, therapeutic doses, both drugs did block the two proteins from binding, enabling IP6K2 to function uninhibited.

According to Snyder, HSP90 normally binds to IP6K2 and prevents cell death. But the drugs cisplatin and novobiocin can bind to HSP90 and cause it to let go of IP6K2, freeing IP6K2 to promote cell death.

"Our findings could be applied to design new anticancer drugs that specifically block this HSP90-IP6K2 interaction. These drugs may be more selective and therefore have fewer side effects than classical chemotherapeutic agents, which can cause all sorts of DNA damage," Snyder said.

The research was funded by a U.S. Public Health Service grant and research scientist award.

Authors on the paper are Anutosh Chakraborty, Michael Koldobskiy, Katherine Sixt, Krishna Juluri, Asif Mustafa, Adele Snowman, Damian van Rossum, Randen Patterson and Snyder, all of Johns Hopkins.


Related Web sites

Solomon Snyder
'Proceedings of the National Academy of Sciences'


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