The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia
Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the <i>de novo</i> pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their eff...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/1003 |
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| author | Valentina Gaidano Mohammad Houshmand Nicoletta Vitale Giovanna Carrà Alessandro Morotti Valerio Tenace Stefania Rapelli Stefano Sainas Agnese Chiara Pippione Marta Giorgis Donatella Boschi Marco Lucio Lolli Daniela Cilloni Alessandro Cignetti Giuseppe Saglio Paola Circosta |
| author_facet | Valentina Gaidano Mohammad Houshmand Nicoletta Vitale Giovanna Carrà Alessandro Morotti Valerio Tenace Stefania Rapelli Stefano Sainas Agnese Chiara Pippione Marta Giorgis Donatella Boschi Marco Lucio Lolli Daniela Cilloni Alessandro Cignetti Giuseppe Saglio Paola Circosta |
| author_sort | Valentina Gaidano |
| collection | DOAJ |
| description | Dihydroorotate Dehydrogenase (DHODH) is a key enzyme of the <i>de novo</i> pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting <i>in human</i> activity. |
| first_indexed | 2024-03-09T06:14:40Z |
| format | Article |
| id | doaj.art-6457d0266b1f4413a61306dc30ae7316 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T06:14:40Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6457d0266b1f4413a61306dc30ae73162023-12-03T11:55:05ZengMDPI AGCancers2072-66942021-02-01135100310.3390/cancers13051003The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid LeukemiaValentina Gaidano0Mohammad Houshmand1Nicoletta Vitale2Giovanna Carrà3Alessandro Morotti4Valerio Tenace5Stefania Rapelli6Stefano Sainas7Agnese Chiara Pippione8Marta Giorgis9Donatella Boschi10Marco Lucio Lolli11Daniela Cilloni12Alessandro Cignetti13Giuseppe Saglio14Paola Circosta15Department of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyMolecular Biotechnology Center, University of Turin, 10126 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT 84112, USADepartment of Life Sciences and System Biology, University of Turin, 10124 Turin, ItalyDepartment of Drug Science and Technology, University of Turin, 10124 Turin, ItalyDepartment of Drug Science and Technology, University of Turin, 10124 Turin, ItalyDepartment of Drug Science and Technology, University of Turin, 10124 Turin, ItalyDepartment of Drug Science and Technology, University of Turin, 10124 Turin, ItalyDepartment of Drug Science and Technology, University of Turin, 10124 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyUniversity Division of Hematology and Cell Therapy, A.O. Ordine Mauriziano, University of Turin, 10128 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Orbassano, 10043 Turin, ItalyDihydroorotate Dehydrogenase (DHODH) is a key enzyme of the <i>de novo</i> pyrimidine biosynthesis, whose inhibition can induce differentiation and apoptosis in acute myeloid leukemia (AML). DHODH inhibitors had shown promising in vitro and in vivo activity on solid tumors, but their effectiveness was not confirmed in clinical trials, probably because cancer cells exploited the pyrimidine salvage pathway to survive. Here, we investigated the antileukemic activity of MEDS433, the DHODH inhibitor developed by our group, against AML. Learning from previous failures, we mimicked human conditions (performing experiments in the presence of physiological uridine plasma levels) and looked for synergic combinations to boost apoptosis, including classical antileukemic drugs and dipyridamole, a blocker of the pyrimidine salvage pathway. MEDS433 induced apoptosis in multiple AML cell lines, not only as a consequence of differentiation, but also directly. Its combination with antileukemic agents further increased the apoptotic rate, but when experiments were performed in the presence of physiological uridine concentrations, results were less impressive. Conversely, the combination of MEDS433 with dipyridamole induced metabolic lethality and differentiation in all AML cell lines; this extraordinary synergism was confirmed on AML primary cells with different genetic backgrounds and was unaffected by physiological uridine concentrations, predicting <i>in human</i> activity.https://www.mdpi.com/2072-6694/13/5/1003DHODHdipyridamoleacute myeloid leukemiaapoptosisdifferentiationpyrimidine depletion |
| spellingShingle | Valentina Gaidano Mohammad Houshmand Nicoletta Vitale Giovanna Carrà Alessandro Morotti Valerio Tenace Stefania Rapelli Stefano Sainas Agnese Chiara Pippione Marta Giorgis Donatella Boschi Marco Lucio Lolli Daniela Cilloni Alessandro Cignetti Giuseppe Saglio Paola Circosta The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia Cancers DHODH dipyridamole acute myeloid leukemia apoptosis differentiation pyrimidine depletion |
| title | The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia |
| title_full | The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia |
| title_fullStr | The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia |
| title_full_unstemmed | The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia |
| title_short | The Synergism between DHODH Inhibitors and Dipyridamole Leads to Metabolic Lethality in Acute Myeloid Leukemia |
| title_sort | synergism between dhodh inhibitors and dipyridamole leads to metabolic lethality in acute myeloid leukemia |
| topic | DHODH dipyridamole acute myeloid leukemia apoptosis differentiation pyrimidine depletion |
| url | https://www.mdpi.com/2072-6694/13/5/1003 |
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