BreakThrough Digest Medical News |
| New compound holds high promise in battling kidney cancer Posted: 18 Feb 2013 09:00 PM PST Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (kidney) cancer. Named TIR-199, the compound targets the “proteasome,” a cellular complex in kidney cancer cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple myeloma cells, a cancer coming from bone marrow.
Michael Pirrung, a distinguished professor of chemistry at UC Riverside, announced the development of TIR-199 in a lecture he gave on Feb. 19 at the 5th International Conference on Drug Discovery and Therapy, held in Dubai, UAE. Operating like the garbage dump of a cell, the proteasome breaks down proteins. Drugs that block the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a variety of cancer cell lines, albeit with mixed results. For example, bortezomib, though effective against multiple myeloma, has many side effects because cells other than bone marrow cells are affected. “The novel feature of our new proteasome inhibitor, TIR-199, is that it is nearly as potent as bortezomib, but is selective in inhibiting the growth of only renal cancer cell lines,” Pirrung said. “It’s what makes TIR-199 attractive.” The TIR-199 research project at UC Riverside began about four years ago after a multidisciplinary, international team reported on a class of compounds that act on the proteasome. These compounds are the “syringolin” natural products ? such as a compound produced naturally by the wheat-infecting bacterium Pseudomonas syringae. TIR-199 is a synthetic relative of syringolin. “At UCR we began to work on, and completed the synthesis of, two compounds from this class of compounds,” Pirrung said. “Of the two, TIR-199 showed most promise.” Pirrung’s lab first shipped TIR-199 samples to the University of Hawaii, Hilo, where André Bachmann, an associate professor of pharmaceutical sciences and Pirrung’s collaborator, studied TIR-199 in test-tube assays for how it worked against the proteasome. Bachmann then tested the compound against a limited number of cancer cell lines that showed that TIR-199 was effective against the cancer cells. What remained unclear, however, was if TIR-199 was toxic to normal cells. Encouraged by these results, Pirrung submitted TIR-199 samples to the National Cancer Institute at the National Institutes of Health, where the compound was subjected to a rigorous 60-cell screening used routinely to test compounds for their effectiveness in battling 60 kinds of cancer, including leukemia, lung, colon, brain, breast, ovarian prostate and renal cancers. “We were very excited when the NCI informed us that TIR-199 has excellent potential to be moved to drug development because of its selective activity against renal cancer,” Pirrung said. “This is good news also because the NCI scientists told us there really are no good drugs out there to fight renal cancer.” Next, the NCI will test TIR-199 on cells grown in a hollow fiber that partially mimics the body by offering a three-dimensional environment. If the test results are positive, TIR-199 will be tested on mice. The UCR Office of Technology Commercialization has filed a patent application on TIR-199 and is currently seeking partners in industry interested in developing the compound commercially. Several biotechnology companies have already shown interest. “We still have to fine-tune TIR-199 in the lab because some aspects ? certain structural elements within it ? make it easily metabolized,” Pirrung said. “But now that we have a good handle on how structural changes in the compound affect anticancer activity and how the parent drug binds to the proteasome, we are pretty confident of making a better version ? the second generation ? of TIR-199.” ### The project was funded by a grant from the University of California Institute for Mexico and the United States (UC MEXUS), to Tannya Ibarra-Rivera, a former postdoctoral researcher in Pirrung’s lab who helped discover TIR-199 and after whose initials the compound is named; and to Pirrung from the UC Cancer Research Coordinating Committee. The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking exploration of issues critical to Inland Southern California, the state and communities around the world. Reflecting California’s diverse culture, UCR’s enrollment has exceeded 21,000 students. The campus will open a medical school in 2013 and has reached the heart of the Coachella Valley by way of the UCR Palm Desert Center. The campus has an annual statewide economic impact of more than $1 billion. A broadcast studio with fiber cable to the AT&T Hollywood hub is available for live or taped interviews. UCR also has ISDN for radio interviews. To learn more, call (951) UCR-NEWS. Contact: Iqbal Pittalwala |
| New discoveries linking gut bacteria with cholesterol metabolism give hope for the future Posted: 17 Feb 2013 09:00 PM PST Researchers at the Sahlgrenska Academy, University of Gothenburg, Sweden, show that cholesterol metabolism is regulated by bacteria in the small intestine. These findings may be important for the development of new drugs for cardiovascular disease.
It is well established that cholesterol is the major risk factor for cardiovascular disease. Cholesterol ? which is mainly synthesized in the body but also obtained from dietary sources ? is converted to bile acids in the liver, which are then secreted into the intestine and either removed from the body or recycled back to the liver. The influence of gut bacteria on human health and disease is a rapidly expanding research area. Fredrick Bäckhed’s research group is a leader in this field and is investigating how gut bacteria are linked to lifestyle diseases such as obesity, diabetes and cardiovascular disease. In a study published in the prestigious journal Cell Metabolism, they show that gut bacteria reduce bile acid synthesis in the liver by signaling through a specific protein, known as the FXR receptor, in the small intestine. ‘Drugs that reduce cholesterol levels have, in recent years, greatly reduced deaths from cardiovascular disease. Our study is a step forward because we have shown how gut bacteria regulate the formation of bile acids from cholesterol’, says Sama Sayin, medical doctor and PhD student at the Sahlgrenska Academy, University of Gothenburg, and the study’s first author. The FXR receptor not only affects cholesterol metabolism but is also involved in the body’s sugar and fat metabolism. ‘If future research can identify the specific bacteria that affect FXR signaling in the gut, this could lead to new ways to treat diabetes and cardiovascular disease’, says Fredrik Bäckhed, professor at the Sahlgrenska Academy, , University of Gothenburg, who led the study. ### The article ‘Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-betamuricholic acid, a naturally occurring FXR antagonist’ is published in Cell Metabolism on February 5. The study is a collaboration with researchers from VTT in Finland, the Karolinska Institute and AstraZeneca in Mölndal. The Wallenberg Laboratory: http://www.wlab.gu.se/ Contact: Contact: Fredrick Bäckhed |
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