Katrina M Miranda
Associate Professor, BIO5 Institute
Associate Professor, Chemistry and Biochemistry-Sci
Primary Department
(520) 626-3655
Work Summary
We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.
Research Interest
Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Publications

Boitano, S., Omsland, A., Miranda, K. M., Friedman, R. L., & Boitano, S. A. (2008). Bordetella bronchiseptica responses to physiological reactive nitrogen and oxygen stresses. FEMS microbiology letters, 284(1).
BIO5 Collaborators
Scott A Boitano, Katrina M Miranda

Bordetella bronchiseptica can establish prolonged airway infection consistent with a highly developed ability to evade mammalian host immune responses. Upon initial interaction with the host upper respiratory tract mucosa, B. bronchiseptica are subjected to antimicrobial reactive nitrogen species (RNS) and reactive oxygen species (ROS), effector molecules of the innate immune system. However, the responses of B. bronchiseptica to redox species at physiologically relevant concentrations (nM-microM) have not been investigated. Using predicted physiological concentrations of nitric oxide (NO), superoxide and hydrogen peroxide (H2O2) on low numbers of CFU of B. bronchiseptica, all redox active species displayed dose-dependent antimicrobial activity. Susceptibility to individual redox active species was significantly increased upon introduction of a second species at subantimicrobial concentrations. An increased bacteriostatic activity of NO was observed relative to H2O2. The understanding of Bordetella responses to physiologically relevant levels of exogenous RNS and ROS will aid in defining the role of endogenous production of these molecules in host innate immunity against Bordetella and other respiratory pathogens.

Ford, P. C., Bourassa, J., Miranda, K., Lee, B., Lorkovic, I., Boggs, S., Kudo, S., & Laverman, L. (1998). Photochemistry of metal nitrosyl complexes. Delivery of nitric oxide to biological targets. Coordination Chemistry Reviews, 171(1), 185-202.

Abstract:

The discoveries that nitric oxide serves important roles in mammalian bioregulation and immunology have stimulated intense interest in the chemistry and biochemistry of NO and derivatives such as metal nitrosyl complexes. Also of interest are strategies to deliver NO to biological targets on demand. One such strategy would be to employ a precursor which displays relatively low thermal reactivity but is photochemically active to give NO. This proposition led the authors to investigate photochemical properties of metal nitrosyl complexes such as the iron-sulfur-nitrosyl Roussin cluster anions Fe2S2(NO)2-4 and Fe4S3(NO)-7 as well as metalloporphyrin nitrosyls including ferriheme complexes (with M. Hoshino of the Institute of Physical and Chemical Research, Japan) and nitrosyl nitrito complexes of ruthenium porphyrins Ru(P)(ONO)(NO). Continuous and flash photolysis studies of these compounds are reviewed here as are studies (with D.A. Wink and J.B. Mitchell of the Radiation Biology Branch of the US National Cancer Institute) using metal nitrosyl photochemistry as a vehicle for delivering NO to hypoxic cell cultures in order to sensitize γ-radiation damage. © 1998 Elsevier Science S.A.

Miranda, K. M., Espey, M. G., Yamada, K., Krishna, M., Ludwick, N., Kim, S., Jourd'heuil, D., Grisham, M. B., Feelisch, M., Fukuto, J. M., & Wink, D. A. (2001). Unique oxidative mechanisms for the reactive nitrogen oxide species, nitroxyl anion. Journal of Biological Chemistry, 276(3), 1720-1727.

PMID: 11042174;Abstract:

The nitroxyl anion (NO-) is a highly reactive molecule that may be involved in pathophysiological actions associated with increased formation of reactive nitrogen oxide species. Angeli's salt (Na2N2O3; AS) is a NO- donor that has been shown to exert marked cytotoxicity. However, its decomposition intermediates have not been well characterized. In this study, the chemical reactivity of AS was examined and compared with that of peroxynitrite (ONOO-) and NO/N2O3. Under aerobic conditions, AS and ONOO- exhibited similar and considerably higher affinities for dihydrorhodamine (DHR) than NO/N2O3. Quenching of DHR oxidation by azide and nitrosation of diaminonaphthalene were exclusively observed with NO/N2O3. Additional comparison of ONOO- and AS chemistry demonstrated that ONOO- was a far more potent one-electron oxidant and nitrating agent of hydroxyphenylacetic acid than was AS. However, AS was more effective at hydroxylating benzoic acid than was ONOO-. Taken together, these data indicate that neither NO/N2O3 nor ONOO- is an intermediate of AS decomposition. Evaluation of the stoichiometry of AS decomposition and O2 consumption revealed a 1:1 molar ratio. Indeed, oxidation of DHR mediated by AS proved to be oxygen-dependent. Analysis of the end products of AS decomposition demonstrated formation of NO2/- and NO3/- in approximately stoichiometric ratios. Several mechanisms are proposed for O2 adduct formation followed by decomposition to NO3/- or by oxidation of an HN2O3/- molecule to form NO2/-. Given that the cytotoxicity of AS is far greater than that of either NO/N2O3 or NO + O2/-, this study provides important new insights into the implications of the potential endogenous formation of NO- under inflammatory conditions in vivo.

Johnson, G., Chozinski, T., Salmon, D., Moghaddam, A., Chen, H., & Miranda, K. (2013). Quantitative detection of nitroxyl upon trapping with glutathione and labeling with a specific fluorogenic reagent. Free Radical Biology and Medicine, 63, 476-484.
Basudhar, D., Cheng, R. C., Bharadwaj, G., Ridnour, L. A., Wink, D. A., & Miranda, K. M. (2015). Chemotherapeutic potential of diazeniumdiolate-based aspirin prodrugs in breast Cancer. Free radical biology & medicine.

Diazeniumdiolate-based aspirin prodrugs have previously been shown to retain the anti-inflammatory properties of aspirin while protecting against the common side effect of stomach ulceration. Initial analysis of two new prodrugs of aspirin that also release either nitroxyl (HNO) or nitric oxide (NO) demonstrated increased cytotoxicity toward human lung carcinoma cells compared to either aspirin or the parent nitrogen oxide donor. In addition, cytotoxicity was significantly lower in endothelial cells, suggesting cancer-specific sensitivity. To assess the chemotherapeutic potential of these new prodrugs in breast cancer, we studied their effect both in cultured cells and in a nude mouse model. Both prodrugs reduced growth of breast adenocarcinoma cells more effectively than the parent compounds while not being appreciably cytotoxic in a related non-tumorigenic cell line (MCF-10A). The HNO donor also was more cytotoxic than the related NO donor. The basis for the observed specificity was investigated in terms of impact on metabolism, DNA damage and repair, apoptosis, angiogenesis and metastasis. The results suggest a significant pharmacological potential for treatment of breast cancer.