Genome-Scale Modeling of NADPH-Driven β-Lapachone Sensitization in Head and Neck Squamous Cell Carcinoma

Abstract

Our modeling approach suggests differences in metabolism and β-lapachone redox cycling that underlie phenotypic differences in radiation-sensitive and -resistant cancer cells. This approach can be extended to investigate the synergistic action of NAD(P)H: quinone oxidoreductase 1 bioactivatable drugs and radiation therapy. Antioxid. Redox Signal. 29, 937-952.

[18F]DCP, First Generation PET Radiotracer for Diagnosis of Radiation Resistant Head and Neck Cancer

“…Our published studies using a matched model of radiation response for HNSCC found significantly decreased levels of ROS and increased levels of antioxidant proteins in the radiation resistant rSCC-61 cells compared with the radiation sensitive SCC-61 (10,11). The enzymatic activity of antioxidant proteins was supported in rSCC-61 cells by increased production of NADPH, which is critical to sustain the cycling of cellular peroxiredoxins, major antioxidant enzymes upregulated in radiation resistant cells and involved in degradation of H2O2 and lipid peroxides (23). Overall, differences in redox metabolism are reflected in the DNA damage and protein oxidation profiles, with the radiation resistant rSCC-61 cells displaying lower level of single and double-strand DNA breaks and lower protein sulfenylation, a finding validated using ex vivo analysis of human HNSCC tumor specimens (10).…”

“…The serum stability of (Figure 2A). Having demonstrated the compatibility with in vivo applications from the perspective of serum stability, the next studies focused on the cellular binding efficiency and selectivity of [ 18 F]DCP using the matched SCC-61 and rSCC-61 HNSCC cells, which have been thoroughly characterized and reported in previous publications (10,11,22,23).…”

“…Compared with the radiation sensitive SCC-61, the radiation resistant rSCC-61 cells display increased using single exponential kinetics and the second order rate constants were calculated by dividing the rate with the respective concentration of probes (5 mM). 7 resistance to ionizing radiation (SCC-61: SF2 0.35, rSCC-61 SF2 0.66; SF2 -survival factor at 2 Gy), decreased ROS including cytosolic, mitochondrial and nuclear H2O2, upregulation of antioxidant proteins (e.g., Prx 1-3, GST-pi, NQO1) (10), increased mitochondrial MTHFD2 contributing to higher NADPH levels (23), and increased glucose uptake with glucose metabolism being funneled into the Pentose Phosphate Pathway and leading overall to increased NADPH/NADP + ratio in these cells (SCC-61: 11.1; rSCC-61: 17.5) (11). The rSCC-61 cells were also characterized by decreased mitochondrial respiration measured by the oxygen consumption rates (SCC-61: 169 pmoles/min; rSCC-61: 96 pmoles/min) and ATP synthesis (SCC-61: 155 pmoles/min; rSCC-61: 83 pmoles/min) (11).…”

“…Human HNSCC SCC-61 and rSCC-61 cells extensively characterized in previous publications (10,11,22,23) were utilized for the majority of the studies here. The SCC-61 cells were obtained from Dr. Ralph Weichselbaum, University of Chicago), and the rSCC-61 cells were generated in vitro by repeated irradiation and selection of a radiation resistant clone (10).…”

A pH/ROS Cascade‐Responsive Charge‐Reversal Nanosystem with Self‐Amplified Drug Release for Synergistic Oxidation‐Chemotherapy

“…[13,30] The ATP-dependent P-gp-mediated drug efflux is critical to the development of MDR; [31,32] thus, PPDC@β-Lap might provide extra benefit for overcoming MDR and enhancing antitumor efficiency. [13,30] The ATP-dependent P-gp-mediated drug efflux is critical to the development of MDR; [31,32] thus, PPDC@β-Lap might provide extra benefit for overcoming MDR and enhancing antitumor efficiency.…”