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Hydrogen Sulfide as a Radiosensitizer for Glioblastoma

硫化氢作为胶质母细胞瘤的放射增敏剂

基本信息

批准号：
9813138
负责人：
LYNN HARRISON
金额：
$ 43.57万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813138
关键词：
Accounting Acute Adjuvant Chemotherapy Adoption Adult Aftercare Antioxidants Apoptosis Astrocytes Biological Assay Brain Brain Neoplasms Breast Epithelial Cells Cancer Biology Carcinoma Cell Death Cell Line Cell Survival Cells Cerebrum Clinical Trials Comet Assay DNA Damage DNA Repair DNA Repair Inhibition Development Dose Education Endothelial Cells Excision Fibroblasts Funding Future Gamma-H2AX Glioblastoma Glutathione Disulfide Goals High Pressure Liquid Chromatography High School Student Histone Deacetylase Human Hydrogen Sulfide Intracranial Neoplasms Ionizing radiation Learning Low Dose Radiation Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of central nervous system Measurement Measures Mitochondria NADH Neurons Normal Cell Normal tissue morphology Operative Surgical Procedures Oxidative Phosphorylation Oxidative Stress Oxygen Consumption Patients Pharmaceutical Preparations Photons Physiological Physiology Plasmids Poly(ADP-ribose) Polymerases Primary Neoplasm Production Protein Acetylation Proteins Proteus Protons Quality of life Radiation Radiation Dose Unit Radiation therapy Radiation-Sensitizing Agents Radiobiology Radioresistance Radiosensitization Reactive Oxygen Species Recurrence Regimen Reporter Resolution Role Sirtuins Source Students Testing Therapeutic Time Work anti-cancer brain endothelial cell brain tissue cell killing cell type chemotherapy conventional therapy cytotoxicity enhancing factor fetal improved insight malignant breast neoplasm mitochondrial dysfunction neoplastic cell nicotinamide-beta-riboside novel oxidative DNA damage prevent programs proton therapy radiosensitizing rho sodium sulfide standard of care tumor undergraduate student

项目摘要

ABSTRACT Glioblastoma multiforme (GBM) is the most common malignant central nervous system cancer in adults. Conventional treatment consisting of tumor surgical resection followed by photon radiation in combination with adjuvant chemotherapy results in a median survival of 14.6 months. Therapeutic advancements have been limited by the extreme chemo- and radio-resistance of GBM. Combination photon and proton therapy has been found to increase survival time, but complications due to radionecrosis have prevented the implementation of this therapy regimen. Addition of a radiosensitizing agent could allow the use of lower radiation doses to achieve tumor cytotoxicity while sparing normal tissue. This application aims to investigate the use of hydrogen sulfide (H2S) as a novel radiosensitizing agent for the treatment of GBM. H2S has been identified as the third endogenous gasotransmitter and sodium sulfide (Na2S), DATS and AP39 are used experimentally to increase cellular H2S. Our preliminary studies suggest acute, high doses of Na2S significantly induce oxidative DNA damage and can kill GBM cell lines in culture, while sparing normal cerebral endothelial cells. Na2S also altered GBM mitochondrial function, increased protein acetylation, increased oxidized glutathione in GBM cell lines and radiosensitized GBM cells to proton or photon ionizing radiation. Our hypothesis is that H2S enhances ionizing radiation-selective killing of GBM cells by increasing reactive oxygen species (ROS) production from the mitochondria, enhancing DNA damage and leading to hyper-activation of poly(ADP-ribose) polymerase (PARP). We further hypothesize that hyper-activation of PARP decreases cellular NAD+ levels, inhibiting HDAC/ sirtuins, resulting in cell death due to inhibition of DNA repair and higher DNA damage levels. This hypothesis will be tested in two aims using two GBM cell lines, an astrocyte cell line, a neuronal cell line and a cerebral microvascular cell line. Aim 1 will test whether Na2S, DATS and AP39 enhance only GBM proton or photon ionizing radiation cell killing. We will probe the mechanism by examining ROS, DNA damage production, and mitochondrial dysfunction. MitoTEMPOL, a mitochondrial antioxidant, and two GBM rho zero cell lines deficient in oxidative phosphorylation will also be used to determine if the ROS is generated in the mitochondria. Aim 2 will test whether Na2S-induced radiosensitization is through hyper-activation of PARP and reduced DNA repair. Upon completion of this work, we will understand why H2S radiosensitizes GBM cells and know which H2S-releasing compound is the best radiosensitizer of GBM cells. This will potentially open avenues for development of H2S-releasing compounds as radiosensitizers. Work in this proposal will be performed by graduate, undergraduate and high school students. These students will learn about radiation biology, oxidative stress and DNA repair and will gain novel insight into radiotherapy and the use of the Proteus®ONE pencil beam. This proposal meets the R15 goals of enhancing education of students in Shreveport. Funding will significantly improve the ability of the PI to perform these studies, and will enhance the institutional graduate program.

摘要