Protein Class Displays Strong Anticancer Action

“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,” says Solomon H. Snyder, M.D., a professor of neuroscience at 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,” says Snyder. “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 team looked closer 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 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. They 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,” says Snyder.

The results appear in the Early Edition of the Proceedings of the National Academy of Sciences. 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 Hopkins. The research was funded by a U.S. Public Heath Service grant and research scientist award.