Researchers at the University of Maryland School of Medicine have discovered a novel interaction between two proteins involved in regulating cell growth that could provide possible new drug targets for treating diffuse large B-cell lymphoma, the most common type of non-Hodgkin's lymphoma.
In a study published online in Nature Communications, the scientists report that they have found a complex molecular and functional relationship between ERK (extracellular signal-regulated kinase), a protein that helps to regulate cell proliferation and survival, and CHK2 (checkpoint kinase 2), a protein that is involved in the cellular DNA damage response. They also demonstrated, for the first time, elevated levels of both proteins in diffuse large B-cell lymphoma cells, compared to non-cancerous cells.
Ronald B. Gartenhaus, M.D., associate professor of medicine at the University of Maryland School of Medicine and the senior author, says researchers found that CHK2 appears to regulate the activity of ERK, although the exact mechanism is not clear. "The two proteins physically interact, which was not known before, and we may be able to use this interaction for therapeutic advantage. We found that treating human B-cell lymphoma cells with both an ERK inhibitor inhibitor and a CHK2 inhibitor killed substantially more cancer cells than treating the cells with either drug alone," he says.
"Based on our findings, we believe that a combination therapy targeting both ERK and CHK2 could offer a potential new approach to treating diffuse large B-cell lymphoma," says Dr. Gartenhaus, who is co-leader of the Program in Molecular and Structural Biology at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.
The drugs used to inhibit ERK and CHK2 caused the cancer cells to die through a process called apoptosis, or programmed cell death. Human cells normally self-destruct in a controlled manner, but cancer cells lose this ability and consequently grow uncontrollably.
E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, "This is a very important discovery that may ultimately benefit patients with diffuse large B-cell lymphoma, a common hematological malignancy that can be difficult to treat. These findings provide valuable new insight into the molecular make-up of this cancer that may lead to new targeted drug therapies."
Lymphoma is a cancer that originates in the lymphocytes (a type of white blood cell) of the immune system. Diffuse large B-cell lymphoma is a fast-growing, aggressive form of non-Hodgkin's lymphoma. It accounts for about 30 to 35 percent of all non-Hodgkin's lymphomas, and about 25,000 new cases are diagnosed each year. Non-Hodgkin's lymphomas usually are treated with several types of chemotherapy – cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) – and a biological therapy, such as the monoclonal antibody rituximab (Rituxan). Radiation therapy may be used on occasion, and bone marrow or stem cell transplantation may also be a treatment option.
Dr. Gartenhaus says researchers hope the study findings will help to develop new therapies that will be effective and well-tolerated by patients. "We believe it is important to identify drugs that can improve the efficacy and reduce the toxicity of standard anti-lymphoma therapy," he says.
The new research showed that using compounds to inhibit ERK and CHK2 did not cause any significant damage to normal cells or tissue examined in the lab, according to Bojie Dai, Ph.D., a postdoctoral fellow at the University of Maryland School of Medicine and the lead author. "We hope that new therapies directed at these two proteins would have modest side effects because they would target only the lymphoma cells," Dr. Dai says.
Dr. Gartenhaus says that researchers don't know yet whether the interaction between ERK and CHK2 occurs in other types of lymphoma.
The study was funded by a grant from the National Institutes of Health and a Merit Review Award from the U.S. Department of Veterans Affairs.
Bojie Dai, X. Frank Zhao, Krystyna Mazan-Mamczarz, Patrick Hagner, Sharon Corl, El Mustapha Bahassi, Song Lu, Peter J. Stambrook, Paul Shapiro and Ronald B. Gartenhaus. "Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma." Published online in Nature Communications on July 19, 2011. http://dx.doi.org/10.1038/ncomms1404.
Karen E. Warmkessel | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
19.07.2018 | Earth Sciences
19.07.2018 | Power and Electrical Engineering
19.07.2018 | Materials Sciences