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Dr. St. Clair's research focuses on investigating the fundamental mechanisms by which reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to normal tissue injury and cancer formation. Her laboratory is the first to clone the human gene for the primary superoxide removal enzyme in the mitochondria, manganese superoxide dismutase (MnSOD), and this initial study has been expanded into several separate but related projects. These projects involve evaluating genetic abnormalities of antioxidant enzymes, the mechanisms regulating gene expression, and the impact these alterations have on the ability of humans to cope with oxidative stress. She has made the seminal observation that expression of MnSOD suppresses neoplastic transformation and promotes differentiation of cancer cells, leading to a reduction in the tumorigenicity and metastatic capability of cancer cells. Her work has led to a paradigm shift in the thinking about the role of antioxidants in cancer therapy.
Chemotherapy-induced side effects to normal tissues are a major problem limiting the success of cancer therapy. The ability of normal tissues to tolerate these side effects frequently imposes a limit on the dose of the anticancer agent that can be given safely to the patient, which in turn limits the probability of a cure. Over the past several years, Dr. St. Clair has led a team of investigators in a series of studies that move between bench and bedside, leading to a novel model of ROS-induced cognitive and cardiac dysfunction. This model proposes that, in addition to the direct ROS-mediated mitochondrial injury in cardiac tissue, there is an indirect mechanism for drug-induced injury common to both cardiac and CNS tissues that results from a cytokine-mediated chain of events triggered by drug-induced oxidative modification of proteins. This team project is designed to identify practice-changing therapy through an integrated program of carefully coordinated mechanistic, interventional, and translational studies with the potential to limit currently devastating tissue injury including chemotherapy-induced cognitive impairment.
Generation of ROS is a major mechanism responsible for the therapeutic effect of ionizing radiation and nearly 50% of chemotherapeutic drugs. Currently, these therapeutic strategies are being used to kill cancer cells without the benefit of a rational design that exploits the intrinsic differences in the cellular redox status of normal cells and cancer cells. Cancer cells are usually under higher oxidative stress than normal cells and it is known that an additional increase in prooxidant level can trigger cell death. Thus, therapeutic approaches that use redox active antioxidants that push tumor cells into oxidative stress overload but stimulate adaptive responses in normal cells can be developed to selectively enhance the efficient killing of cancer cells by radiation/chemotherapy. Dr. St. Clair is developing a novel dual-purpose drug approach that would not only improve the efficacy of cancer therapy but could also improve quality of life for cancer survivors by protecting normal tissue from ROS-generating therapeutics.
Lexington Kentucky 40536
1095 VA Drive
University of Kentucky
- Yen HC, Oberley TD, Vichitbanda S, Ho YS, St. Clair DK. The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice. J Clin Invest 98:1253-1260, 1996.
- Zhao Y, Chaiswing L, Oberley TD, Batinic-Haberle I, St. Clair WH, Epstein CJ, St. Clair DK. A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res 65:1401-1405, 2005.
- Lien YC, Noel T, Liu H, Stromberg AJ, Chen KC, St. Clair DK. Phospholipase C-delta1 is a critical target for TNF receptor-mediated protection against adriamycin-induced cardiac injury. Cancer Res 66:4329-4338, 2006.
- Dhar SK, Tangpong J, Chaiswing L, Oberley TD, St. Clair DK. Manganese superoxide dismutase is a p53-regulated gene that switches cancers between early and advanced stages. Cancer Res. 71:6684-6695, 2011.
- Xu Y, Fang F, Miriyala S, Crooks PA, Oberley TD, Chaiswing L, Noel T, Holley AK, Zhao Y, Kiningham KK, St Clair DK, St Clair WH: KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Effects of Parthenolide in Normal and Cancer Cells. Cancer Res. 73:4406-17, 2013.
(five most recent publications via an automated list from PubMed, based on researcher’s ID and the University of Kentucky)
- Majima HJ, Indo HP, Nakanishi I, Suenaga S, Matsumoto K, Matsui H, Minamiyama Y, Ichikawa H, Yen HC, Hawkins CL, Davies MJ, Ozawa T, St Clair DK.
Chasing great paths of Helmut Sies "Oxidative Stress".
Arch Biochem Biophys. 2016 Apr 1;595:54-60.
- Miriyala S, Thippakorn C, Chaiswing L, Xu Y, Noel T, Tovmasyan A, Batinic-Haberle I, Vander Kooi CW, Chi W, Latif AA, Panchatcharam M, Prachayasittikul V, Allan Butterfield D, Vore M, Moscow J, St Clair DK.
Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling.
Free Radic Biol Med. 2016 Feb;91:68-80.
- Miriyala S, Chandra M, Maxey B, Day A, St Clair DK, Panchatcharam M.
Arjunolic acid ameliorates reactive oxygen species via inhibition of p47(phox)-serine phosphorylation and mitochondrial dysfunction.
Int J Biochem Cell Biol. 2015 Nov;68:70-7.
- Barone E, Cenini G, Di Domenico F, Noel T, Wang C, Perluigi M, St Clair DK, Butterfield DA.
Basal brain oxidative and nitrative stress levels are finely regulated by the interplay between superoxide dismutase 2 and p53.
J Neurosci Res. 2015 Nov;93(11):1728-39.
- Keeney JT, Miriyala S, Noel T, Moscow JA, St Clair DK, Butterfield DA.
Superoxide induces protein oxidation in plasma and TNF-α elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy.
Cancer Lett. 2015 Oct 28;367(2):157-61.