title: Dichloroacetate blocks aerobic glycolytic adaptation to attenuated measles virus and promotes viral replication leading to enhanced oncolysis in glioblastoma.
abstract: Targeting reprogrammed energy metabolism such as aerobic glycolysis is a potential strategy for cancer treatment. However, tumors exhibiting low-rate glycolysis or metabolic heterogeneity might be resistant to such treatment. We hypothesized that a therapeutic modality that drove cancer cells to high-rate glycolysis might sensitize cancer cells to interference directed against metabolic flux. In this study, we found that attenuated oncolytic measles virus Edmonston strain (MV-Edm) caused glioblastoma cells to shift to high-rate aerobic glycolysis; this adaptation was blocked by dichloroacetate (DCA), an inhibitor of glycolysis, leading to profound cell death of cancer cells but not of normal cells. DCA enhanced viral replication by mitigating mitochondrial antiviral signaling protein (MAVS)-mediated innate immune responses. In a subcutaneous glioblastoma (GBM) xenograft mouse model, low-dose MV-Edm and DCA significantly inhibited tumor growth in vivo. We found that DCA impaired glycolysis (blocking bioenergetic generation) and enhanced viral replication (increasing bioenergetic consumption), which, in combination, accelerated bioenergetic exhaustion leading to necrotic cell death. Taken together, oncolytic MV-Edm sensitized cancer cells to DCA, and in parallel, DCA promoted viral replication, thus, improving oncolysis. This novel therapeutic approach should be readily incorporated into clinical trials.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.|Zhongda Hospital, Medical School of Southeast University, Nanjing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.|Nanjing University Hightech Institute at Suzhou, Suzhou, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Su
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Mao
authors.initials: M
authors.lastname: Xia
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.affiliation: Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Decai
authors.initials: D
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.|Nanjing University Hightech Institute at Suzhou, Suzhou, China.
authors.forename: Jiwu
authors.initials: J
authors.lastname: Wei
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005909:Glioblastoma / Q000628:therapy* / Q000821:virology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011897:Random Allocation; D014779:Virus Replication / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003999:Dichloroacetic Acid