Cargando…
Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells
Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leu...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ferrata Storti Foundation
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119157/ https://www.ncbi.nlm.nih.gov/pubmed/29880605 http://dx.doi.org/10.3324/haematol.2018.188185 |
_version_ | 1783352032636174336 |
---|---|
author | Wu, Dang Wang, Wanyan Chen, Wuyan Lian, Fulin Lang, Li Huang, Ying Xu, Yechun Zhang, Naixia Chen, Yinbin Liu, Mingyao Nussinov, Ruth Cheng, Feixiong Lu, Weiqiang Huang, Jin |
author_facet | Wu, Dang Wang, Wanyan Chen, Wuyan Lian, Fulin Lang, Li Huang, Ying Xu, Yechun Zhang, Naixia Chen, Yinbin Liu, Mingyao Nussinov, Ruth Cheng, Feixiong Lu, Weiqiang Huang, Jin |
author_sort | Wu, Dang |
collection | PubMed |
description | Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia. |
format | Online Article Text |
id | pubmed-6119157 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Ferrata Storti Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-61191572018-09-10 Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells Wu, Dang Wang, Wanyan Chen, Wuyan Lian, Fulin Lang, Li Huang, Ying Xu, Yechun Zhang, Naixia Chen, Yinbin Liu, Mingyao Nussinov, Ruth Cheng, Feixiong Lu, Weiqiang Huang, Jin Haematologica Article Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia. Ferrata Storti Foundation 2018-09 /pmc/articles/PMC6119157/ /pubmed/29880605 http://dx.doi.org/10.3324/haematol.2018.188185 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
spellingShingle | Article Wu, Dang Wang, Wanyan Chen, Wuyan Lian, Fulin Lang, Li Huang, Ying Xu, Yechun Zhang, Naixia Chen, Yinbin Liu, Mingyao Nussinov, Ruth Cheng, Feixiong Lu, Weiqiang Huang, Jin Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title | Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title_full | Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title_fullStr | Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title_full_unstemmed | Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title_short | Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
title_sort | pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119157/ https://www.ncbi.nlm.nih.gov/pubmed/29880605 http://dx.doi.org/10.3324/haematol.2018.188185 |
work_keys_str_mv | AT wudang pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT wangwanyan pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT chenwuyan pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT lianfulin pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT langli pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT huangying pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT xuyechun pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT zhangnaixia pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT chenyinbin pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT liumingyao pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT nussinovruth pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT chengfeixiong pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT luweiqiang pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells AT huangjin pharmacologicalinhibitionofdihydroorotatedehydrogenaseinducesapoptosisanddifferentiationinacutemyeloidleukemiacells |