SHARKS RX Spring 2017 Magazine

NOVA SOUTHEASTERN UNIVERSITY College of Pharmacy 20 21 Deth and Trivedi are exploring how the environment, nutrition, and diet and exercise regulate genes in the body and how epigenetic changes turn genes off and on— a modification of the DNA called methylation. Trivedi, assistant professor of pharmaceutical sciences, focuses on the epigenetics while Deth, professor of pharmaceutical sciences, examines metabolism, redox, and the methylation process. The redox/methylation hypothesis is the focal point of their work. Both researchers are studying autism and the age-related diseases, among other conditions. “We found that the metabolic capacity of autistic children to have antioxidants in their body was shut down in an epigenetic manner,” Trivedi explained. “We have shown that in kids with autism—where genes are important in metabolism, social skills, or verbal skills— those genes are shut down, and that the shutdown of gene expression is done by epigenetic changes.” Deth has found that children with autism have about one-third fewer antioxidants in their blood than other children. “When you have low levels of antioxidants like that, it inhibits some methylation,” he said. “We’ve made a connection here between this biochemical problem—oxidative stress—and metabolic problems common in autism. Oxidative stress leads to impaired DNA and interrupts development.” In addition, Deth discovered that vitamin B12 is a key cofactor for methylation. By measuring the total B12 in the brain, he found that an individual’s vitamin B12 level normally decreases with age, especially over 40. He also discovered that vitamin B12 normally goes down more than tenfold in normal individuals; that autistic children had only about one third the B12 they should have had compared to their age-match group; and that middle-age, schizophrenic subjects had similarly lower B12 compared to the 35–45-year-old comparison group. In studying conditions such as addiction, autism, and Alzheimer’s disease, Trivedi and Deth recommend nutrition supplement-based therapy to correct metabolic problems, such as oxidative stress and impaired methylation. “There are a lot of different conditions in which epigenetic changes make a contribution,” Trivedi said. “And, they can be treated based on nutritional and supplementation therapy.” Latimer’s team is working on “turning down” DNA repair, killing cancer cells more easily with chemotherapy, and with a smaller, more targeted dose of it. “Being able to modulate or control the level of DNA repair, we think, will be a central way of making tumor cells vulnerable,” said Latimer, associate professor of pharmaceutical sciences and director of the NSU AutoNation Breast and Solid Tumor Cancer Research Institute. Latimer’s lab examines tumors just a few days after being removed and discovered that when those tumors evolved into drug-resistant varieties, they have high DNA repair. “If we’re really effective in rheostating that repair level down, and then we hit with the traditional chemotherapy, we should have a much higher kill rate,” she said. Ph.D. candidate Homood As Sobeai found a biologic drug—micro RNA—that controls DNA repair. The proof? When the drug is put into stage 4 tumor cells, their repair capacity drops. The next question is whether or not chemotherapy is more effective in the presence of micro RNA. “The last part of this is how to bring it to humans,” Latimer said. “Delivery probably is through nanotechnology. You would put it into a microscopic nanoparticle that would go only into the tumor cells and ignore everything else.” As director of the NSU Rumbaugh-Goodwin Institute for Cancer Research since 2007, Rathinavelu, professor of pharmaceutical sciences and associate dean of institutional planning and development, and his research team are developing new therapeutics, specifically targeting oncogenic proteins. He has developed and patented two anticancer drugs—code-named JFD and F16—that already are in preclinical testing. Rathinavelu’s team wants to eliminate typical drawbacks found in cancer drugs discovered from the 1970s and 1980s. “We want to develop therapeutics that are going to be safer and more specific for attacking cancer and not producing serious side effects,” he said. In addition, Rathinavelu is collaborating with a researcher from Florida International University to study the use of phycocyanin, which is found in blue-green algae that is growing in Florida’s Everglades, to enhance the effects of existing chemotherapy agents. Using that combination, his team has been able to obtain the same therapeutic benefit, with less toxicity. “In any kind of drug-discovery process, use of genomics and bioinformatics will be very important,” Rathinavelu said. “And we use those very effectively to determine what kind of cancer-causing genes and cancer-causing proteins are going to be good for targeting.” Richard Deth Malav Trivedi A number of College of Pharmacy faculty members are working in the state-of-the art labs at the Center for Collaborative Research . The following is a look at their research. Jean Latimer Appu Rathinavelu Groundbreaking Researchers Make a Difference (cont.) Richard Deth, Ph.D. Malav Trivedi, Ph.D. Jean Latimer, Ph.D. Appu Rathinavelu, Ph.D. (continued on next page)

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