Khramtsov VV. and Gillies RJ. 2014, "Janus-faced tumor micronvironment and redox, Antiox". Redox Signaling, 21, 723–729.
Bobko AA; Dhimitruka I; Zweier JL; Khramtsov VV., "Fourier Transform EPR of Trityl Radicals for Multifunctional Assessment of Chemical Microenvironment". Angew. Chem. Int. Edit. 2014, 53, 2735-2738.
Chen D, Bobko AA, Gross AC, Evans R, Marsh CB, Khramtsov VV, Eubank TD, Friedman A. 2014, "Involvement of Tumor Macrophage HIFs in Chemotherapy Effectiveness: Mathematical Modeling of Oxygen, pH, and Glutathione", PLoS One, e107511. DOI: 10.1371/journal.pone.0107511.
Samouilov A; Efimova OV; Bobko AA; Sun Z; Petryakov S; Eubank TD; Trofimov DG; Kirilyuk IA; Grigor’ev IA; Takahashi W; Zweier JL; Khramtsov VV, 2014, "In Vivo Proton-Electron Double-Resonance Imaging of Extracellular Tumor pH Using an Advanced Nitroxide Probe", Analyt. Chem., 86 (2), 1045–1052.
Goodwin, J., Yachi, K., Nagane, M., Yasui, H., Miyake, Y., Inanami, O., Bobko, A.A., Khramtsov, V.V., Hirata, H. 2014, "In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation", NMR Biomedicine, 27 (4), 453-458;
Dhimitruka I; Bobko AA; Eubank TD; Komarov DA; Khramtsov VV. "Phosphonated Trityl Probe for Concurrent In Vivo Tissue Oxygen and pH Monitoring Using EPR-based Techniques". J Am Chem Soc 2013, 135, 5904−5910.
Magnetic Resonance Approaches to Biomedicine
Supported by NIH R01EB014542 (04.2012-03.2016), R01CA194013 (04.2015-03.2020), R01CA192064 (08.2015-07.2020)
Most of my research is devoted to the development and application of new magnetic resonance approaches to biomedicine, including electron paramagnetic resonance (EPR) spectroscopy and imaging and Overhauser-enhanced magnetic resonance imaging (OMRI or proton-electron double-resonance imaging, PEDRI). Our current projects develop the unique paramagnetic probes allowing noninvasive simultaneous detection of tissue oxygenation, acidity (pH), redox status, intracellular glutathione (GSH) and interstitial inorganic phosphate in living subjects. Based on thorough examination of recent literature and experimental data accumulated in our laboratories, we published a new hypothesis of a Janus-faced tumor microenvironment (TME) and its role in tumorigenesis.
Janus-faced tumor microenvironment. The key components of the chemical TME, oxygen, pH, redox and GSH, are shown in red. Hypoxia-induced acidosis potentiates accumulation of free metal ions such as Fe3+ and Cu2+. In its turn, a high reducing capacity of TME promotes metal ion reduction to Fenton-active state, e.g. via γ‐glutamyltransferase (GGT)/GSH-dependent generation of reducing cysteinyl-glycine dipeptide, GlyCysS¯. A cycling local hypoxia in TME facilitates further electron transfer to oxygen with formation of O2•- radical, triggering radical reaction cascade of O2•- dismutation to H2O2 followed by OH-radical formation via Fenton reaction. Low-reactive ROS, H2O2 and O2•-, penetrate into tumor cells by diffusion or via anion channels, latter contributing to increase of intracellular pH (pHi) with corresponding decrease in oxidizing potential of ROS. In a contrary, low acidic pHe in TME enhances ROS oxidizing potential towards surrounding cells that may result in oxidative damage and mutagenesis as well as adaptive response (e.g., increase of GSH) and changing cellular phenotype. Increase in H2O2, O2•-, GSH and pH has been shown contribute into the triggering cells in proliferation stage. Compared to normal cells, cancer cells are well protected against oxidative stress, in part by elevated GSH content and activities of GSH-dependent antioxidant enzymes, including glutathione peroxidases (GPx1 and GPx4 denote peroxidases that target hydrogen peroxide and lipid peroxide, correspondingly) and glutathione reductase, GSSG-Rx (Khramtsov & Gillies, 2014, ARS, 21, 723–729).
The focus of the current NIH-supported research is application of multifunctional in vivo TME analysis using in vivo magnetic resonance spectroscopy and imaging to investigate TME role in tumor progression and therapy.