They tested pyrvinium in cultured cells and in multiple animal models of early development (frogs, nematode worms, fruit flies) and demonstrated that in each case, pyrvinium blocked Wnt signaling. They also found that in cultured colon cancer cells, pyrvinium inhibited both Wnt signaling and cell proliferation.
To identify the target of pyrvinium, Lee and his colleagues combined four isolated proteins, all with known roles in the Wnt pathway. They found that pyrvinium increased the activity of one of the proteins, an enzyme called casein kinase 1alpha (CK1alpha).
The activation of a kinase as a way to inhibit the Wnt signaling pathway was unexpected, Lee said.
"The targeted cancer therapies that are being intensively studied right now are mostly kinase inhibitors," he said. "It's intriguing to think that maybe there are certain kinases like CK1alpha that we can activate as targets for treating cancer."
Pyrvinium stays in the gastrointestinal tract (to treat pinworms), so Lee is working with collaborators in the Vanderbilt Institute of Chemical Biology to develop new CK1alpha inhibitors. He is also collaborating with Pampee Young, M.D., Ph.D., associate professor of Pathology and Medicine, to study the Wnt pathway's role and pyrvinium's effects on cardiac repair after myocardial infarction.
"Our original goal in developing the screening strategy was to find compounds that would tell us something about the biology of the Wnt pathway," Lee said. "It's an added bonus that these compounds could be useful therapeutic agents in heart disease or cancer."
The frog embryo extract and screening strategy may also be applied to identifying compounds that modify other developmentally important signaling pathways, Lee added.
|Contact: Leigh MacMillan|
Vanderbilt University Medical Center