Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy
Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various...
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MDPI AG
2023-10-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/10/1073 |
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| author | Koichi Fujisawa Toshihiko Matsumoto Naoki Yamamoto Takahiro Yamasaki Taro Takami |
| author_facet | Koichi Fujisawa Toshihiko Matsumoto Naoki Yamamoto Takahiro Yamasaki Taro Takami |
| author_sort | Koichi Fujisawa |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer. |
| first_indexed | 2024-03-10T21:04:01Z |
| format | Article |
| id | doaj.art-cc66af569e2f4e6ba71a8508f4220e1e |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T21:04:01Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-cc66af569e2f4e6ba71a8508f4220e1e2023-11-19T17:20:05ZengMDPI AGMetabolites2218-19892023-10-011310107310.3390/metabo13101073Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination TherapyKoichi Fujisawa0Toshihiko Matsumoto1Naoki Yamamoto2Takahiro Yamasaki3Taro Takami4Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, JapanDepartment of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, JapanDepartment of Oncology and Laboratory Medicine, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, JapanDepartment of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, JapanHepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.https://www.mdpi.com/2218-1989/13/10/1073hypoxiairon chelatorenergy metabolismsautophagyliver cancerglutamine |
| spellingShingle | Koichi Fujisawa Toshihiko Matsumoto Naoki Yamamoto Takahiro Yamasaki Taro Takami Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy Metabolites hypoxia iron chelator energy metabolisms autophagy liver cancer glutamine |
| title | Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy |
| title_full | Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy |
| title_fullStr | Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy |
| title_full_unstemmed | Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy |
| title_short | Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy |
| title_sort | metabolic analysis of dfo resistant huh7 cells and identification of targets for combination therapy |
| topic | hypoxia iron chelator energy metabolisms autophagy liver cancer glutamine |
| url | https://www.mdpi.com/2218-1989/13/10/1073 |
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