Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Inhibiting key enzymes kills difficult tumor cells in mice

16.08.2011
Tumors that do not respond to chemotherapy are the target of a cancer therapy that prevents the function of two enzymes in mouse tumor cells, according to Pennsylvania medical researchers.

"We've known for well over a decade that when tumors become hypoxic they become resistant to chemotherapy and radiotherapy," said Wafik S. El-Deiry, M.D. Ph.D., American Cancer Society Research Professor, Rose Dunlap Professor and chief of hematology/oncology, Penn State College of Medicine. "This is a huge problem in the treatment of patients with cancer. As tumors progress, they have regions that are not well perfused with blood vessels and tumors become hypoxic."

A hypoxic tumor lacks oxygen because there are not enough blood vessels within the tumor to allow red blood cells to transport oxygen throughout the tumor.

El-Deiry and his team report in a recent issue of Cancer Research that the drug sangivamycin-like molecule 3 (SLM3) helps keep tumor cells from multiplying in lab mice.

Treating a tumor with SLM3 inhibits two kinase, or enzymes: GSK-3ß, which regulates cell growth and cell death, and CDK1, which regulates cell division and blood vessel growth. Tumor cells treated with SLM3 become more sensitive to chemotherapy and die, according to El-Deiry and his colleagues.

"If you just inhibit GSK-3ß, that may not be enough and not necessarily desirable," said El-Deiry, who is also the associate director for translational research, Cancer Institute. "But there's something fortuitous about the dual targeting of these two kinases, (GSK-3ß and CDK-1), with respect to cancer therapy. If you inhibit these two kinases, the dual inhibition works together to kill hypoxic tumor cells.

"While pure inhibition of GSK-3ß can promote cell proliferation, the combination of GSK-3ß and CDK-1 inhibition not only inhibits cell proliferation but also promotes cell death," El-Deiry added.

To find SLM3, the researchers screened a chemical library looking for molecules that induce apoptosis -- cell death -- in hypoxic tumor cells. SLM3 does that, and the researchers found eight molecules whose structures were similar.

SLM3 was the version that induced the most cell death in concert with TRAIL, a naturally occurring molecule in the body that tells a cell it is time to die. TRAIL sets a process in motion that targets and shuts down tumor cells and keeps them from spreading.

SLM3, a nucleoside analog, helps keep tumor cells from multiplying by stopping cells before they duplicate their DNA. Nucleosides are the building blocks of nucleic acids and molecules like ATP -- the energy source for the body. A nucleoside analog competes with ATP and inhibits kinases, like GSK-3ß and CDK1.

GSK-3ß helps regulate cell growth and cell death. CDK1 decreases the tumor's ability to divide and generate more blood vessels. SLM3 inhibits both these kinases.

"The bottom line is the molecules actually work to shrink tumors when these molecules are combined with chemo or TRAIL therapy," El-Deiry said. "We think that these are important observations that need to be tested further in the clinic."

Other Penn State College of Medicine researchers include Nathan G. Dolloff, assistant professor of hematology/oncology; Joshua E. Allen, graduate student, hematology/oncology; Yingqiu Y. Liu, research specialist; and David T. Dicker, technical specialist.

Also working on this research were Patrick A. Mayes, former graduate student, now at GlaxoSmithKline; Colin J. Daniel, graduate student, and Rosalie C. Sears, associate professor, molecular and medical genetics, Oregon Health Science University; J. Judy Liu and David I. H. Jee, graduate students, Harvard University; Lori S. Hart, research associate, and Jay F. Dorsey, assistant professor, radiation oncology, Emma E. Furth, professor of pathology and laboratory medicine and Peter S. Klein, associate professor of hematology/oncology, University of Pennsylvania; Kageaki Kuribayashi, Sapporo Medical University, Japan; and J. Martin Brown, professor of radiation oncology, Stanford University.

The National Institutes of Health supported this research.

Victoria M. Indivero | EurekAlert!
Further information:
http://www.psu.edu

More articles from Life Sciences:

nachricht A room with a view - or how cultural differences matter in room size perception
25.04.2017 | Max-Planck-Institut für biologische Kybernetik

nachricht Studying a catalyst for blood cancers
25.04.2017 | University of Miami Miller School of Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Early organic carbon got deep burial in mantle

25.04.2017 | Earth Sciences

A room with a view - or how cultural differences matter in room size perception

25.04.2017 | Life Sciences

Warm winds: New insight into what weakens Antarctic ice shelves

25.04.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>