Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment
In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primar...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/10/2565 |
| _version_ | 1797500957504831488 |
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| author | Cristina Banella Gianfranco Catalano Serena Travaglini Elvira Pelosi Tiziana Ottone Alessandra Zaza Gisella Guerrera Daniela Francesca Angelini Pasquale Niscola Mariadomenica Divona Luca Battistini Maria Screnci Emanuele Ammatuna Ugo Testa Clara Nervi Maria Teresa Voso Nelida Ines Noguera |
| author_facet | Cristina Banella Gianfranco Catalano Serena Travaglini Elvira Pelosi Tiziana Ottone Alessandra Zaza Gisella Guerrera Daniela Francesca Angelini Pasquale Niscola Mariadomenica Divona Luca Battistini Maria Screnci Emanuele Ammatuna Ugo Testa Clara Nervi Maria Teresa Voso Nelida Ines Noguera |
| author_sort | Cristina Banella |
| collection | DOAJ |
| description | In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options. |
| first_indexed | 2024-03-10T03:11:21Z |
| format | Article |
| id | doaj.art-296aa271fa424b9ea07aff16ab9ea369 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:11:21Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-296aa271fa424b9ea07aff16ab9ea3692023-11-23T10:24:59ZengMDPI AGCancers2072-66942022-05-011410256510.3390/cancers14102565Ascorbate Plus Buformin in AML: A Metabolic Targeted TreatmentCristina Banella0Gianfranco Catalano1Serena Travaglini2Elvira Pelosi3Tiziana Ottone4Alessandra Zaza5Gisella Guerrera6Daniela Francesca Angelini7Pasquale Niscola8Mariadomenica Divona9Luca Battistini10Maria Screnci11Emanuele Ammatuna12Ugo Testa13Clara Nervi14Maria Teresa Voso15Nelida Ines Noguera16Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyDepartment of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyHematology Unit, Saint’ Eugenio Hospital, University of Rome Tor Vergata, 00144 Rome, ItalyPoliclinico Tor Vergata, University of Rome Tor Vergata, 00133 Rome, ItalyNeuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyBanca Regionale Sangue Cordone Ombelicale UOC Immunoematologia e Medicina Trasfusionale, Policlinico Umberto I, 00161 Roma, ItalyDepartment of Hematology, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Medical and Surgical Sciences and Biotechnologies, University of Roma La Sapienza, 04100 Latina, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyNeurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, ItalyIn the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.https://www.mdpi.com/2072-6694/14/10/2565Acute Myeloid LeukemiaSeahorse XFmetabolismpharmacologic activityascorbatebuformin |
| spellingShingle | Cristina Banella Gianfranco Catalano Serena Travaglini Elvira Pelosi Tiziana Ottone Alessandra Zaza Gisella Guerrera Daniela Francesca Angelini Pasquale Niscola Mariadomenica Divona Luca Battistini Maria Screnci Emanuele Ammatuna Ugo Testa Clara Nervi Maria Teresa Voso Nelida Ines Noguera Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment Cancers Acute Myeloid Leukemia Seahorse XF metabolism pharmacologic activity ascorbate buformin |
| title | Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment |
| title_full | Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment |
| title_fullStr | Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment |
| title_full_unstemmed | Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment |
| title_short | Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment |
| title_sort | ascorbate plus buformin in aml a metabolic targeted treatment |
| topic | Acute Myeloid Leukemia Seahorse XF metabolism pharmacologic activity ascorbate buformin |
| url | https://www.mdpi.com/2072-6694/14/10/2565 |
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