Researchers at UC Davis, University of Massachusetts and Harvard Medical School have created a combination drug that controls both tumor growth and metastasis.
By combining a COX-2 inhibitor, similar to Celebrex, and an epoxide hydrolase (sEH) inhibitor, the drug controls angiogenesis (blood vessel formation), limiting a tumor’s ability to grow and spread. The study appears today in the journal Proceedings of the National Academy of Sciences.
“We’ve been studying the effects of COX and sEH inhibitors, both by themselves and in combination, for several years,” said senior author and UC Davis Distinguished Professor Bruce Hammock.
“We were surprised to find that the dual inhibitor was more active than higher doses of each compound, either individually or together. By combining the two molecules into one we got much greater potency against several diseases and completely unique effects in terms of blocking tumor growth and metastasis.”
Both COX and sEH enzymes control lipid signaling, which has long been associated with inflammation, cell migration, proliferation, hypertension and other processes. COX inhibitors block production of inflammatory and pain-inducing lipids, while sEH inhibitors preserve anti-hypertensive, anti-inflammatory and analgesic compounds. Separate COX and sEH inhibitors were previously found to work together in reducing inflammation and neuropathic pain.
After testing individual COX-2 and sEH inhibitors, the team synthesized the drug (PTUTB), the first combined COX-2/sEH inhibitor. They then tested the dual inhibitor against human lung and breast tumors, both in vitro and in mice. They found that PTUTB blocked angiogenesis, inhibiting the proliferation of endothelial cells, which are critical to blood vessel formation. This in turn limited tumor growth and metastasis, reducing lung and breast tumor growth by 70 to 83 percent.
In breast and lung cancers, the dual inhibitor blocked angiogenesis, which blocked the growth of solid tumors,” said Hammock. “This represents a new mechanism to control blood vessel and tumor growth.”
Robert Weiss, a co-author and professor of nephrology at UC Davis, added that the combination drug achieved the results with minimal side effects and no cardiovascular or gastrointestinal effects.
“This is particularly important when administering COX-2 inhibitors, which have well-known cardiovascular risks,” he said. “However, the added sEH inhibitor appears to block COX-2’s side effects.”
The research was initiated by first author Guodong Zhang when he was a postdoctoral fellow in the Hammock laboratory. Zhang previously demonstrated that sEH inhibitors improve the power of omega-3 fatty acid (fish oil) diets to reduce tumor growth and metastasis, and implicated epoxides of the dietary supplement DHA as the causative agent.
By advancing a new anti-angiogenic compound, the study extends the work of renowned Harvard Medical School physician and researcher Judah Folkman, who illuminated the importance of angiogenesis to tumor growth, inspiring a new class of anti-cancer drugs. Two of the study’s authors, Dipak Panigrahy and Mark Kieran, previously worked with Folkman at Harvard Medical School.
Though the research was focused exclusively on cancer, researchers said the dual compound could benefit other conditions, such as macular degeneration.
“If we move beyond cancer, this drug combination could block a number of pathologies, ranging from cardiac hypertrophy to neuropathic pain,” said Hammock. “The compound looks quite powerful for a number of conditions.”
The research teams are continuing their work on several fronts.
“One member of our research team already has made more potent inhibitors with more drug-like properties,” Hammock said. “We are looking at the molecules for a variety of indications alone and in combination, including for kidney disease, fibrotic diseases, pancreatic and colon cancer and other problems.” The molecules are patented by the University of California and are available for license and testing.
Co-author Jun-Yan Liu, who performed the analytical chemistry for the study while a postgraduate researcher at UC Davis, is now examining the efficacy of the compounds in kidney disease and gout at a laboratory in the Shanghai Tenth Peoples Hospital.
“One of the most exciting things about this project was the ability to work with experts in multiple fields to find new drug class and new mechanism that promises to actually help people with cancer,” Liu said.
Other researchers included: Sung Hee Hwang, Jun Yang, Lisa M. Mahakian, Yanru Wang, Elizabeth S. Ingham, Sarah Tam, Robert H. Weiss and Katherine W. Ferrara, all of UC Davis, and Hiromi I. Wettersten, formerly of UC Davis and now at UC San Diego.
The research was supported by NIEHS R01 ES02710, Superfund P42 ES04699, NIH/NIOSH U54 OH07550, R01 CA134659, R01 CA112356, R01 CA103828, NIH contract HHSN268201000043C, Research Investments in the Sciences and Engineering (RISE) Program of UC Davis, R01 CA148633, R01 CA135401, R01 DK082690, the Stop and Shop Pediatric Brain Tumor Fund, the C.J. Buckley Pediatric Brain Tumor Fund, the Medical Service of the US Department of Veterans Affairs and the American Asthma Society.
Dorsey Griffith | Eurek Alert!
One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center
The gut microbiota plays a key role in treatment with classic diabetes medication
01.06.2017 | University of Gothenburg
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology