"PITs cause cells to self-destruct by interfering with the signaling pathways that regulate cell survival. As compounds that promote cell death, PITs show promise in halting the harmful, unwanted growth characteristic of cancer," said senior author Alexei Degterev, PhD, assistant professor in the biochemistry department at Tufts University School of Medicine (TUSM) and member of the biochemistry program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.
Degterev teamed up with colleagues at TUSM, Northeastern University, Massachusetts General Hospital, Harvard Medical School, and the National Chemical Laboratory in Pune, India, to identify compounds that could disrupt a cell signaling molecule called PIP3. Out of 50,000 small molecules screened, the team identified two that inhibited PIP3.
"We tested the more stable of these two molecules in mice and found that it inhibited tumor growth and induced cancer cell death," said co-first author Benchun Miao, PhD, formerly a postdoctoral associate in the biochemistry department at TUSM and fellow in Degterev's lab and now a postdoctoral associate in the Nutrition and Cancer Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.
"We also found that PITs showed an even stronger anti-tumor effect in cells with high PIP3 levels. In humans, these high-PIP3 cells are responsible for aggressive forms of cancer such as glioblastoma," said co-first author Igor Skidan, PhD, formerly a postdoctoral fellow in the department of pharmaceutical sciences at Northeastern University and now a senior scientist at Morphotek, Inc.
According to Degterev, PITs are a promising and relatively unexplored approach to cancer treatment. He says that PITs are a new class of compounds that inhibit PIP3, positioned at an early point in a cell signaling pathway over-activated in many human tumors. The study also presents a methodology for identifying other molecules similar to PITs. Degterev hopes that this approach will help researchers isolate other new compounds that halt cancer growth.
"We are not yet at the stage of considering PITS as leads for therapeutics. Our next focus, with our collaborators at National Chemical Laboratory, will be to develop PITS to be more effective," says Degterev.
This study was supported by the Smith Family Awards for Excellence in Biomedical Research, a National Institute on Aging Mentored Research Scientist Career Development Award, a US Army Innovator Award; as well as the National Cancer Institute and the National Institute on Aging, both parts of the National Institutes of Health. Patent applications related to the discoveries described in this paper have been filed by Tufts University, Harvard University, and the National Chemical Laboratory, India.
Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T,Durugkar KA, Maki J, Ramana CV, Schaffhausen B, Wagner G, Torchilin V, Yuan J, Degterev A. PNAS Early Edition (November 1, 2010). "Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains." Published online November 1, 2010, doi: 10.1073/pnas.1004522107
About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science.
If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.
Siobhan E. Gallagher | EurekAlert!
Discovery of a Key Regulatory Gene in Cardiac Valve Formation
24.05.2017 | Universität Basel
Carcinogenic soot particles from GDI engines
24.05.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt
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....
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...
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...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
24.05.2017 | Physics and Astronomy
24.05.2017 | Physics and Astronomy
24.05.2017 | Event News