"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!
At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History
New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy