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 Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory

nachricht ‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

Im Focus: Virtual Reality for Bacteria

An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications

Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...

Im Focus: A space-time sensor for light-matter interactions

Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.

The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

PhoxTroT: Optical Interconnect Technologies Revolutionized Data Centers and HPC Systems

11.12.2017 | Information Technology

Large-scale battery storage system in field trial

11.12.2017 | Power and Electrical Engineering

See, understand and experience the work of the future

11.12.2017 | Event News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>