title: Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death.
abstract: Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells.
authors.affiliation: Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China. wangxiaobing@snnu.edu.cn.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Feng
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.forename: Quanhong
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003847:Deoxyglucose / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology; D011773:Pyruvates / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D016166:Free Radical Scavengers; D017319:Photosensitizing Agents; D011773:Pyruvates; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C017092:bromopyruvate; D003847:Deoxyglucose; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505407:CASP3 protein, human; D053148:Caspase 3; D000111:Acetylcysteine