Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity
Acute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the...
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MDPI AG
2020-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1155 |
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| author | Ida Sofie Grønningsæter Håkon Reikvam Elise Aasebø Sushma Bartaula-Brevik Tor Henrik Tvedt Øystein Bruserud Kimberley Joanne Hatfield |
| author_facet | Ida Sofie Grønningsæter Håkon Reikvam Elise Aasebø Sushma Bartaula-Brevik Tor Henrik Tvedt Øystein Bruserud Kimberley Joanne Hatfield |
| author_sort | Ida Sofie Grønningsæter |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the in vitro antileukemic effects of seven metabolic inhibitors that target different metabolic pathways. The metabolic inhibitors were tested on AML cells derived from 81 patients using proliferation and viability assays; we also compared global gene expression and proteomic profiles for various patient subsets. Metformin, 2DG, 6AN, BPTES and ST1326 had strong antiproliferative and proapoptotic effects for most patients, whereas lonidamine and AZD3965 had an effect only for a minority. Antiproliferative effects on AML cells were additive when combined with the chemotherapeutic agent AraC. Using unsupervised hierarchical clustering, we identified a strong antiproliferative effect on AML cells after treatment with metabolic inhibitors for a subset of 29 patients. Gene expression and proteomic studies suggested that this subset was characterized by altered metabolic and transcriptional regulation. In addition, the Bcl-2 inhibitor venetoclax, in combination with 2DG or 6AN, increased the antiproliferative effects of these metabolic inhibitors on AML cells. Therapeutic targeting of cellular metabolism may have potential in AML, but the optimal strategy will likely differ between patients. |
| first_indexed | 2024-03-10T19:58:23Z |
| format | Article |
| id | doaj.art-5f40a3c0e3e740798134cb98273fe632 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:58:23Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-5f40a3c0e3e740798134cb98273fe6322023-11-19T23:44:42ZengMDPI AGCells2073-44092020-05-0195115510.3390/cells9051155Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient HeterogeneityIda Sofie Grønningsæter0Håkon Reikvam1Elise Aasebø2Sushma Bartaula-Brevik3Tor Henrik Tvedt4Øystein Bruserud5Kimberley Joanne Hatfield6Department of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayAcute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the in vitro antileukemic effects of seven metabolic inhibitors that target different metabolic pathways. The metabolic inhibitors were tested on AML cells derived from 81 patients using proliferation and viability assays; we also compared global gene expression and proteomic profiles for various patient subsets. Metformin, 2DG, 6AN, BPTES and ST1326 had strong antiproliferative and proapoptotic effects for most patients, whereas lonidamine and AZD3965 had an effect only for a minority. Antiproliferative effects on AML cells were additive when combined with the chemotherapeutic agent AraC. Using unsupervised hierarchical clustering, we identified a strong antiproliferative effect on AML cells after treatment with metabolic inhibitors for a subset of 29 patients. Gene expression and proteomic studies suggested that this subset was characterized by altered metabolic and transcriptional regulation. In addition, the Bcl-2 inhibitor venetoclax, in combination with 2DG or 6AN, increased the antiproliferative effects of these metabolic inhibitors on AML cells. Therapeutic targeting of cellular metabolism may have potential in AML, but the optimal strategy will likely differ between patients.https://www.mdpi.com/2073-4409/9/5/1155leukemiaglycolysismetabolismoxidative phosphorylation |
| spellingShingle | Ida Sofie Grønningsæter Håkon Reikvam Elise Aasebø Sushma Bartaula-Brevik Tor Henrik Tvedt Øystein Bruserud Kimberley Joanne Hatfield Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity Cells leukemia glycolysis metabolism oxidative phosphorylation |
| title | Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity |
| title_full | Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity |
| title_fullStr | Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity |
| title_full_unstemmed | Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity |
| title_short | Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity |
| title_sort | targeting cellular metabolism in acute myeloid leukemia and the role of patient heterogeneity |
| topic | leukemia glycolysis metabolism oxidative phosphorylation |
| url | https://www.mdpi.com/2073-4409/9/5/1155 |
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