Academic Journal
The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia
| Τίτλος: | The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia |
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| Συγγραφείς: | Lawson, H, Holt-Martyn, JP, Dembitz, V, Kabayama, Y, Wang, LM, Bellani, A, Atwal, S, Saffoon, N, Durko, J, van de Lagemaat, LN, De Pace, AL, Tumber, A, Corner, T, Salah, E, Arndt, C, Brewitz, L, Bowen, M, Dubusse, L, George, D, Allen, L, Guitart, AV, Fung, TK, So, CWE, Schwaller, J, Gallipoli, P, O'Carroll, D, Schofield, CJ, Kranc, KR |
| Συνεισφορές: | University of Zagreb. University of Zagreb, School of Medicine. Department of Physiology and Immunology, Bellani, Aarushi, Kranc, Kamil |
| Πηγή: | Nat Cancer Lawson, H, Holt-Martyn, J P, Dembitz, V, Kabayama, Y, Wang, L M, Bellani, A, Atwal, S, Saffoon, N, Durko, J, van de Lagemaat, L N, De Pace, A L, Tumber, A, Corner, T, Salah, E, Arndt, C, Brewitz, L, Bowen, M, Dubusse, L, George, D, Allen, L, Guitart, A V, Fung, T K, So, C W E, Schwaller, J, Gallipoli, P, O'Carroll, D, Schofield, C J & Kranc, K R 2024, 'The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia', nature cancer, vol. 5, no. 6, pp. 916-937. https://doi.org/10.1038/s43018-024-00761-w |
| Στοιχεία εκδότη: | Springer Science and Business Media LLC, 2024. |
| Έτος έκδοσης: | 2024 |
| Θεματικοί όροι: | Myeloid, 0301 basic medicine, Sulfonamides / therapeutic use, Proto-Oncogene Proteins / metabolism, Hypoxia-Inducible Factor 1, alpha Subunit / metabolism, Apoptosis, Mice, Temeljne medicinske znanosti, Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors, Sulfonamides, 0303 health sciences, Leukemia, Tumor, Protein Stability, Heterocyclic, Protein Stability / drug effects, Prolyl-Hydroxylase Inhibitors / pharmacology, Membrane Proteins / metabolism, 3. Good health, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-bcl-2, Biomedicina i zdravstvo, Leukemia, Myeloid, Acute / metabolism, Disease Progression, Hypoxia-Inducible Factor 1, Proto-Oncogene Proteins c-bcl-2 / metabolism, Acute, alpha Subunit, Apoptosis / drug effects, Article, Cell Line, Hypoxia-Inducible Factor-Proline Dioxygenases, Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism, Bridged Bicyclo Compounds, 03 medical and health sciences, Proto-Oncogene Proteins, Cell Line, Tumor, Humans, Animals, Biomedicine and Health Sciences, Sulfonamides / pharmacology, Membrane Proteins / genetics, Prolyl-Hydroxylase Inhibitors / therapeutic use, Membrane Proteins, Basic Medical Sciences, Prolyl-Hydroxylase Inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit, Bridged Bicyclo Compounds, Heterocyclic, Human Physiology, fiziologija čovjeka, Leukemia, Myeloid, Acute / drug therapy |
| Περιγραφή: | Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. |
| Τύπος εγγράφου: | Article |
| Περιγραφή αρχείου: | application/pdf; Print-Electronic |
| Γλώσσα: | English |
| ISSN: | 2662-1347 |
| DOI: | 10.1038/s43018-024-00761-w |
| Σύνδεσμος πρόσβασης: | https://pubmed.ncbi.nlm.nih.gov/38637657 https://www.research.ed.ac.uk/en/publications/493491ab-d111-46df-b299-a28599f819ec https://hdl.handle.net/20.500.11820/493491ab-d111-46df-b299-a28599f819ec https://doi.org/10.1038/s43018-024-00761-w https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE232644 https://www.pure.ed.ac.uk/ws/files/508611763/s43018-024-00761-w.pdf |
| Rights: | CC BY |
| Αριθμός Καταχώρησης: | edsair.doi.dedup.....c3ffbd33d56d8858d6860493682c3c81 |
| Βάση Δεδομένων: | OpenAIRE |
| ISSN: | 26621347 |
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| DOI: | 10.1038/s43018-024-00761-w |