Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New path found for colon cancer drug discovery

22.11.2010
An old pinworm medicine is a new lead in the search for compounds that block a signaling pathway implicated in colon cancer.

The findings, reported by Vanderbilt University Medical Center researchers in the November issue of Nature Chemical Biology, suggest a fresh approach for developing therapeutics that target the pathway.

More than 90 percent of sporadic (non-inherited) colon cancers — the second deadliest type of cancer in the developed world — are caused by mutations that result in inappropriate activation of the Wnt (pronounced “wint”) signaling pathway. Blocking this pathway has been a desirable therapeutic target, but its complexity has made it difficult to determine which molecular participants to inhibit.

“There's no obvious target in the pathway where we could say, 'OK, if we inhibit the activity of this protein, that will inhibit Wnt signaling,'” said Ethan Lee, M.D., Ph.D., associate professor of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center researcher, and senior investigator of the current study.

Lee and his colleagues were interested in understanding the details of the Wnt pathway, which also plays an important role in early development. In frogs, loss of early Wnt signaling results in headless embryos; too much early Wnt signaling causes two heads to form.

“To me, that's really quite remarkable and says this pathway is biologically important,” Lee said.

To explore Wnt signaling at a biochemical level, Lee and his team developed frog embryo extracts and showed that this cell-free system retained many events of the Wnt signaling pathway. Using this system, they established a screening strategy to search for chemicals that modify Wnt signaling — with the goal of learning more about the biology of the pathway.

The investigators screened several thousand chemical compounds, from a “library” of FDA-approved drugs and other bioactive compounds.

They found that pyrvinium, an FDA-approved anti-parasite drug, blocked Wnt signaling in the frog extracts.

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.

Curtis Thorne, Ph.D., is the first author of the Nature Chemical Biology paper. The Gastrointestinal Specialized Program of Research Excellence (GI SPORE) at Vanderbilt-Ingram, the American Cancer Society, and the National Institutes of Health supported the research.

Leigh MacMillan | EurekAlert!
Further information:
http://www.vanderbilt.edu

More articles from Life Sciences:

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>