He N Xu1,2,3, Min Feng4,5, Kavindra Nath4, David Nelson4, Jeff Roman4, Huaqing Zhao6, Zhenwu Lin4,5, Jerry Glickson4, Lin Z Li7,8,9,10. 1. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. hexu2@pennmedicine.upenn.edu. 2. Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. hexu2@pennmedicine.upenn.edu. 3. Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. hexu2@pennmedicine.upenn.edu. 4. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. 5. Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. 6. Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, PA, USA. 7. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA. linli@pennmedicine.upenn.edu. 8. Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA. linli@pennmedicine.upenn.edu. 9. Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. linli@pennmedicine.upenn.edu. 10. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. linli@pennmedicine.upenn.edu.
Abstract
PURPOSE: Fluorescence of co-enzyme reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) provides a sensitive measure of the mitochondrial redox state and cellular metabolism. By imaging NADH and Fp, we investigated the utility of optical redox imaging (ORI) to monitor cellular metabolism and detect early metabolic response to cancer drugs. PROCEDURES: We performed ORI of human melanoma DB-1 cells in culture and DB-1 mouse xenografts to detect the redox response to lonidamine (LND) treatment. RESULTS: For cultured cells, LND treatment for 45 min significantly lowered NADH levels with no significant change in Fp, resulting in a significant increase in the Fp redox ratio (Fp/(NADH+Fp)); 3-h prolonged treatment led to a decrease in NADH and an increase in Fp and a more oxidized redox state compared to control. Significant decrease in the mitochondrial redox capacity of LND-treated cells was observed for the first time. For xenografts, 45-min LND treatment resulted in a significant reduction of NADH content, no significant changes in Fp content, and a trend of increase in the Fp redox ratio. Intratumor redox heterogeneity was observed in both control and LND-treated groups. CONCLUSION: Our results support the utility of ORI for evaluating cellular metabolism and monitoring early metabolic response to cancer drugs.
PURPOSE: Fluorescence of co-enzyme reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) provides a sensitive measure of the mitochondrial redox state and cellular metabolism. By imaging NADH and Fp, we investigated the utility of optical redox imaging (ORI) to monitor cellular metabolism and detect early metabolic response to cancer drugs. PROCEDURES: We performed ORI of humanmelanomaDB-1 cells in culture and DB-1mouse xenografts to detect the redox response to lonidamine (LND) treatment. RESULTS: For cultured cells, LND treatment for 45 min significantly lowered NADH levels with no significant change in Fp, resulting in a significant increase in the Fp redox ratio (Fp/(NADH+Fp)); 3-h prolonged treatment led to a decrease in NADH and an increase in Fp and a more oxidized redox state compared to control. Significant decrease in the mitochondrial redox capacity of LND-treated cells was observed for the first time. For xenografts, 45-min LND treatment resulted in a significant reduction of NADH content, no significant changes in Fp content, and a trend of increase in the Fp redox ratio. Intratumor redox heterogeneity was observed in both control and LND-treated groups. CONCLUSION: Our results support the utility of ORI for evaluating cellular metabolism and monitoring early metabolic response to cancer drugs.
Entities:
Keywords:
DMSO; Early detection; FAD; Flavoproteins; Mitochondria; NADH; Optical imaging; Redox ratio
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