Gayle M Gordillo1, Ayan Biswas1, Kanhaiya Singh1, Abhishek Sen1, Poornachander R Guda1, Caroline Miller2, Xueliang Pan3, Savita Khanna1, Enrique Cadenas4, Chandan K Sen1,5. 1. Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana, USA. 2. Electron Microscopy Core, Indiana University School of Medicine, Indianapolis, Indiana, USA. 3. Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA. 4. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA. 5. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.
Abstract
Aims: Hemangioendothelioma (HE) may be benign or malignant. Mouse hemangioendothelioma endothelial (EOMA) cells are validated to study mechanisms in HE. This work demonstrates that EOMA cells heavily rely on mitochondria to thrive. Thus, a combination therapy, including weak X-ray therapy (XRT, 0.5 Gy) and a standardized natural berry extract (NBE) was tested. This NBE is known to be effective in managing experimental HE and has been awarded with the Food and Drug Administration Investigational New Drug (FDA-IND) number 140318 for clinical studies on infantile hemangioma. Results: NBE treatment alone selectively attenuated basal oxygen consumption rate of EOMA cells. NBE specifically sensitized EOMA, but not murine aortic endothelial cells to XRT-dependent attenuation of mitochondrial respiration and adenosine triphosphate (ATP) production. Combination treatment, selectively and potently, influenced mitochondrial dynamics in EOMA cells such that fission was augmented. This was achieved by lowering of mitochondrial sirtuin 3 (SIRT3) causing increased phosphorylation of AMP-activated protein kinase (AMPK). A key role of SIRT3 in loss of EOMA cell viability caused by the combination therapy was evident when pyrroloquinoline quinone, an inducer of SIRT3, pretreatment rescued these cells. Innovation and Conclusion: Mitochondria-targeting NBE significantly extended survival of HE-affected mice. The beneficial effect of NBE in combination with weak X-ray therapy was, however, far more potent with threefold increase in murine survival. The observation that safe natural products may target tumor cell mitochondria and sharply lower radiation dosage required for tumor management warrants clinical testing.
Aims: Hemangioendothelioma (HE) may be benign or malignant. Mouse hemangioendothelioma endothelial (EOMA) cells are validated to study mechanisms in HE. This work demonstrates that EOMA cells heavily rely on mitochondria to thrive. Thus, a combination therapy, including weak X-ray therapy (XRT, 0.5 Gy) and a standardized natural berry extract (NBE) was tested. This NBE is known to be effective in managing experimental HE and has been awarded with the Food and Drug Administration Investigational New Drug (FDA-IND) number 140318 for clinical studies on infantile hemangioma. Results: NBE treatment alone selectively attenuated basal oxygen consumption rate of EOMA cells. NBE specifically sensitized EOMA, but not murine aortic endothelial cells to XRT-dependent attenuation of mitochondrial respiration and adenosine triphosphate (ATP) production. Combination treatment, selectively and potently, influenced mitochondrial dynamics in EOMA cells such that fission was augmented. This was achieved by lowering of mitochondrial sirtuin 3 (SIRT3) causing increased phosphorylation of AMP-activated protein kinase (AMPK). A key role of SIRT3 in loss of EOMA cell viability caused by the combination therapy was evident when pyrroloquinoline quinone, an inducer of SIRT3, pretreatment rescued these cells. Innovation and Conclusion: Mitochondria-targeting NBE significantly extended survival of HE-affected mice. The beneficial effect of NBE in combination with weak X-ray therapy was, however, far more potent with threefold increase in murine survival. The observation that safe natural products may target tumor cell mitochondria and sharply lower radiation dosage required for tumor management warrants clinical testing.
Authors: Gayle M Gordillo; Ayan Biswas; Savita Khanna; James M Spieldenner; Xueliang Pan; Chandan K Sen Journal: J Biol Chem Date: 2016-03-09 Impact factor: 5.157
Authors: Dagfinn Aune; Edward Giovannucci; Paolo Boffetta; Lars T Fadnes; NaNa Keum; Teresa Norat; Darren C Greenwood; Elio Riboli; Lars J Vatten; Serena Tonstad Journal: Int J Epidemiol Date: 2017-06-01 Impact factor: 7.196
Authors: Yashika Rustagi; Ahmed S Abouhashem; Priyanka Verma; Sumit S Verma; Edward Hernandez; Sheng Liu; Manishekhar Kumar; Poornachander R Guda; Rajneesh Srivastava; Sujit K Mohanty; Sedat Kacar; Sanskruti Mahajan; Kristen E Wanczyk; Savita Khanna; Michael P Murphy; Gayle M Gordillo; Sashwati Roy; Jun Wan; Chandan K Sen; Kanhaiya Singh Journal: Diabetes Date: 2022-05-01 Impact factor: 9.337
Authors: Ting Zhao; Sheng Liu; Xinchun Ding; Erica M Johnson; Nasser H Hanna; Kanhaiya Singh; Chandan K Sen; Jun Wan; Hong Du; Cong Yan Journal: JCI Insight Date: 2022-09-08