Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism
The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-tar...
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MDPI AG
2023-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/23/5537 |
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| author | Hiroki Yamazaki Seio Onoyama Shunichi Gotani Tatsuya Deguchi Masahiro Tamura Hiroshi Ohta Hidetomo Iwano Hidetaka Nishida Peter J. Dickinson Hideo Akiyoshi |
| author_facet | Hiroki Yamazaki Seio Onoyama Shunichi Gotani Tatsuya Deguchi Masahiro Tamura Hiroshi Ohta Hidetomo Iwano Hidetaka Nishida Peter J. Dickinson Hideo Akiyoshi |
| author_sort | Hiroki Yamazaki |
| collection | DOAJ |
| description | The transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism. |
| first_indexed | 2024-03-09T01:54:40Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T01:54:40Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3c95bff745d04ebd911aa4f43a17c1a12023-12-08T15:12:28ZengMDPI AGCancers2072-66942023-11-011523553710.3390/cancers15235537Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer MetabolismHiroki Yamazaki0Seio Onoyama1Shunichi Gotani2Tatsuya Deguchi3Masahiro Tamura4Hiroshi Ohta5Hidetomo Iwano6Hidetaka Nishida7Peter J. Dickinson8Hideo Akiyoshi9Laboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Internal Medicine, Companion Animal Internal Medicine, Department of Companion Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Veterinary Biochemistry, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, 582-1 Bunkyodai-Midorimachi, Ebetsu 069-0836, JapanLaboratory of Small Animal Clinics, Veterinary Teaching Hospital, Graduate School of Veterinary Science, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 52-5201, JapanDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USALaboratory of Veterinary Surgery, Graduate School of Life and Environmental Sciences, Osaka Metropolitan University, 1-58 Rinku-Oraikita, Izumisano 598-8531, JapanThe transcription factor hypoxia-inducible factor 1α (HIF-1α) drives metabolic reprogramming in gliomas (GLs) under hypoxic conditions, promoting glycolysis for tumor development. Evofosfamide (EVO) releases a DNA-alkylating agent within hypoxic regions, indicating that it may serve as a hypoxia-targeted therapy. The aim of this study was to investigate the glycolytic metabolism and antitumor effects of EVO in a canine GL model. Our clinical data showed that overall survival was significantly decreased in GL dog patients with higher HIF-1α expression compared to that of those with lower HIF-1α expression, and there was a positive correlation between HIF-1α and pyruvate dehydrogenase kinase 1 (PDK1) expression, suggesting that glycolytic activity under hypoxia conditions may contribute to poor outcomes in canine GL. Our glycolysis assay tests showed that the glycolytic ATP level was higher than the mitochondrial ATP level in three types of canine GL cell lines by activating the HIF-1 signal pathway under hypoxia conditions, resulting in an overall increase in total cellular ATP production. However, treatment with EVO inhibited the glycolytic ATP level in the GL cell lines under hypoxia conditions by targeting HIF-1α-positive cells, leading to decrease in total cellular ATP production. Our in vivo tests showed that EVO significantly reduced tumor development compared to controls and temozolomide in murine GL models. A metabolic analysis demonstrated that EVO effectively suppressed glycolytic metabolism by eliminating HIF-1α-positive cells, suggesting that it may restore metabolism in canine GLs. The evidence presented here supports the favorable preclinical evaluation of EVO as a potential improvement in cancer metabolism.https://www.mdpi.com/2072-6694/15/23/5537HIF-1αevofosfamideglycolysisgliomadogs |
| spellingShingle | Hiroki Yamazaki Seio Onoyama Shunichi Gotani Tatsuya Deguchi Masahiro Tamura Hiroshi Ohta Hidetomo Iwano Hidetaka Nishida Peter J. Dickinson Hideo Akiyoshi Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism Cancers HIF-1α evofosfamide glycolysis glioma dogs |
| title | Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism |
| title_full | Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism |
| title_fullStr | Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism |
| title_full_unstemmed | Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism |
| title_short | Influence of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) on Glycolytic Metabolism of Canine Glioma: A Potential Improvement in Cancer Metabolism |
| title_sort | influence of the hypoxia activated prodrug evofosfamide th 302 on glycolytic metabolism of canine glioma a potential improvement in cancer metabolism |
| topic | HIF-1α evofosfamide glycolysis glioma dogs |
| url | https://www.mdpi.com/2072-6694/15/23/5537 |
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