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!
Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.
Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...
Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.
Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
29.09.2016 | Event News
28.09.2016 | Event News
27.09.2016 | Event News
29.09.2016 | Materials Sciences
29.09.2016 | Materials Sciences
29.09.2016 | Interdisciplinary Research