University of Wisconsin-Milwaukee scientists can now uncover mechanisms that assist the spread of cancer or map the location of drug action in a human brain, and do so without leaving campus. It’s all made possible by cutting-edge equipment housed in the new Shimadzu Laboratory for Advanced and Applied Analytical Chemistry.
The lab is helping accelerate the variety of research at the Milwaukee Institute of Drug Discovery. It represents initiatives in neuroscience, cancer and infectious diseases, and hosts collaborations among UWM departments, other academic centers and medical product companies.
Here are five drug development projects currently underway at UWM.
Taking depression out of treating alcoholism
Alcoholism is the third-leading cause of death in United States, but existing drugs used to treat this addiction come with severe and debilitating side effects.
Current drugs block the euphoric effects of alcohol by curtailing the flow of dopamine, a chemical messenger that activates the brain’s pleasure center through opioid receptors.
But when dopamine levels plunge, patients often are left with depression – dashing not only the pleasurable feeling of “reward” from alcohol, but pleasure gained from other stimuli, too.
Researchers in James Cook’s lab are working on drugs that target dopamine through a different receptor. These GABAA receptors control alcohol cravings by ensuring that dopamine is blocked only in response to alcohol triggers, and they also play a role in calming anxiety and depression, said doctoral student researcher V.V.N. Phani Babu Tiruveedhula.
Tests on rats confirm that the compound is successful at both aims and indicate it could also be used in a model to address binge drinking. More testing is needed, but new methods of synthesis created by Tiruveedhula could lead to a drug on the market within five or six years.
A two-for-one medication
What if there were a drug available that was just as effective as a potent anti-cancer drug already on the market, but it inflicted fewer side effects? And what if that same compound also showed promise for treating memory loss?
A team of current and former UWM researchers has created compounds that fill both bills.
The reason the same compound can treat diseases that are so different, said UWM psychology Professor Karyn Frick, is the compounds the team is developing accomplish multiple jobs in the body.
The compounds were designed and patented by UWM chemistry Professor Mahmun Hossain and his student, Joseph Ulicki. Also on the project were former UWM faculty member Yi-Qiang Cheng, who is now at the University of North Texas, and former UWM scientist Steve Clark.
Like the highly toxic drug vorinostat, the UWM-developed compounds are HDAC inhibitors – drugs that kill cancer cells by blocking enzymes responsible for unchecked growth.
Cells can turn cancerous when their DNA is physically constricted, making it difficult for the cells to “read” genetic instructions correctly. HDAC inhibitors “unbundle” DNA that’s packaged too tightly.
It turns out the female hormone estrogen, important for maintaining memory, also “loosens” DNA. In studies with mice, Frick’s lab found that HDAC inhibitors can make up for memory loss when estrogen levels drop, as happens in menopause, for example.
Now the team, which also includes Doug Steeber, associate professor of biological sciences, is looking for more funding to continue the research for both uses.
Calming asthma without side effects
A team of UWM chemists is testing an unusual strategy to improve the treatment of asthma, which is the most common chronic disease affecting U.S. children and highly prevalent in communities of color.
Current drugs to combat asthma symptoms are not always effective and can cause side effects with long-term use.
The compound being developed targets receptors in the central nervous system that calm anxiety, but those receptors have never been used therapeutically for lung diseases. Could targeting these receptors also alleviate asthma’s two main symptoms by relaxing the smooth muscles lining the lungs and taming inflammation?
The research team, which includes UWM chemists James Cook and Alexander “Leggy” Arnold, and Douglas Stafford, director of UWM’s Milwaukee Institute for Drug Discovery, has funding from the National Institutes of Health to find out.
They hope to replace corticosteroids inhalers, which are often used improperly, with an oral medication that is more effective and has fewer side effects.
A link between cancer and the vitamin D receptor
Although calcium and vitamin D are associated with bone health, they are also very important for the proper functioning of nearly every cell in the human body.
Metabolic products of vitamin D activate calcium’s “master regulator” in the body – the vitamin D receptor, or VDR – which gives instructions to genes for proper cell growth and differentiation. That’s why scientists are working on using VDR to slow the growth of cancer cells.
“Many women know the drug tamoxifen as a savior in the fight against breast cancer. The drug’s action is mediated by the estrogen receptor, a close relative of VDR,” said Alexander “Leggy” Arnold, associate professor of biochemistry. “Initial studies suggest that new drug candidates that bind the VDR can help to fight other cancers.”
In fact, numerous new anti-cancer drugs in clinical trials are based on vitamin D, but they might disrupt calcium levels in the body long-term.
Arnold has found new chemical compounds that alter the VDR’s action selectively, so the drugs can work and not interfere with the calcium regulation needed for normal health.
He has also tested his compounds’ efficacy in animal models of ovarian cancer and leukemia – two cancers that are likely to become resistant to leading chemotherapy drugs. Arnold holds a patent on the work through the UWM Research Foundation.
A search-and-destroy cancer treatment
Even as they save lives, conventional cancer drugs don’t discriminate between malignant cells and healthy ones. In order to destroy tumors, they target all cells in the body.
“A common problem is the side effects, so the patients suffer a lot during the treatment,” UWM bio-organic chemist Xiaohua Peng said.
Peng is developing compounds that kill only the cancer cells, using a novel approach: The drug is activated by a condition unique to cancer cells – increased oxidative stress.
Oxidative stress occurs naturally in the body during processes like metabolism, and it creates byproducts, including free radicals, involved in aging. But oxidative stress skyrockets in cancer cells. Because they grow and divide so quickly, they’re literally engaged in a metabolic marathon.
Peng’s compounds become toxic only in the exact location of increased oxidative stress. Early tests at the National Cancer Institute and University of Texas MD Anderson Cancer Center showed promising results.