Cargando…

Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation

Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. T315I Bcr-Abl is the most notorious point mutation to elicit acquired resistance to imatinib (IM), leading to poor prognosis. Therefore, it is urgent to search for additional approaches and targeting strateg...

Descripción completa

Detalles Bibliográficos
Autores principales: Lan, Xiaoying, Zhao, Chong, Chen, Xin, Zhang, Peiquan, Zang, Dan, Wu, Jinjie, Chen, Jinghong, Long, Huidan, Yang, Li, Huang, Hongbiao, Wang, Xuejun, Shi, Xianping, Liu, Jinbao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550844/
https://www.ncbi.nlm.nih.gov/pubmed/28682311
http://dx.doi.org/10.1038/cddis.2017.284
_version_ 1783256196258463744
author Lan, Xiaoying
Zhao, Chong
Chen, Xin
Zhang, Peiquan
Zang, Dan
Wu, Jinjie
Chen, Jinghong
Long, Huidan
Yang, Li
Huang, Hongbiao
Wang, Xuejun
Shi, Xianping
Liu, Jinbao
author_facet Lan, Xiaoying
Zhao, Chong
Chen, Xin
Zhang, Peiquan
Zang, Dan
Wu, Jinjie
Chen, Jinghong
Long, Huidan
Yang, Li
Huang, Hongbiao
Wang, Xuejun
Shi, Xianping
Liu, Jinbao
author_sort Lan, Xiaoying
collection PubMed
description Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. T315I Bcr-Abl is the most notorious point mutation to elicit acquired resistance to imatinib (IM), leading to poor prognosis. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that platinum pyrithione (PtPT) potently inhibits the ubiquitin–proteasome system (UPS) via targeting the 26 S proteasome-associated deubiquitinases (DUBs), without effecting on the 20 S proteasome. Here we further report that (i) PtPT induces apoptosis in Bcr-Abl wild-type and Bcr-Abl-T315I mutation cells including the primary mononuclear cells from CML patients clinically resistant to IM, as well as inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) PtPT downregulates Bcr-Abl level through restraining Bcr-Abl transcription, and decreasing Bcr-Abl protein mediated by DUBs inhibition-induced caspase activation; (iii) UPS inhibition is required for PtPT-induced caspase activation and cell apoptosis. These findings support that PtPT overcomes IM resistance through both Bcr-Abl-dependent and -independent mechanisms. We conclude that PtPT can be a lead compound for further drug development to overcome imatinib resistance in CML patients.
format Online
Article
Text
id pubmed-5550844
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-55508442017-08-14 Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation Lan, Xiaoying Zhao, Chong Chen, Xin Zhang, Peiquan Zang, Dan Wu, Jinjie Chen, Jinghong Long, Huidan Yang, Li Huang, Hongbiao Wang, Xuejun Shi, Xianping Liu, Jinbao Cell Death Dis Original Article Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. T315I Bcr-Abl is the most notorious point mutation to elicit acquired resistance to imatinib (IM), leading to poor prognosis. Therefore, it is urgent to search for additional approaches and targeting strategies to overcome IM resistance. We recently reported that platinum pyrithione (PtPT) potently inhibits the ubiquitin–proteasome system (UPS) via targeting the 26 S proteasome-associated deubiquitinases (DUBs), without effecting on the 20 S proteasome. Here we further report that (i) PtPT induces apoptosis in Bcr-Abl wild-type and Bcr-Abl-T315I mutation cells including the primary mononuclear cells from CML patients clinically resistant to IM, as well as inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) PtPT downregulates Bcr-Abl level through restraining Bcr-Abl transcription, and decreasing Bcr-Abl protein mediated by DUBs inhibition-induced caspase activation; (iii) UPS inhibition is required for PtPT-induced caspase activation and cell apoptosis. These findings support that PtPT overcomes IM resistance through both Bcr-Abl-dependent and -independent mechanisms. We conclude that PtPT can be a lead compound for further drug development to overcome imatinib resistance in CML patients. Nature Publishing Group 2017-07 2017-07-06 /pmc/articles/PMC5550844/ /pubmed/28682311 http://dx.doi.org/10.1038/cddis.2017.284 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Lan, Xiaoying
Zhao, Chong
Chen, Xin
Zhang, Peiquan
Zang, Dan
Wu, Jinjie
Chen, Jinghong
Long, Huidan
Yang, Li
Huang, Hongbiao
Wang, Xuejun
Shi, Xianping
Liu, Jinbao
Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title_full Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title_fullStr Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title_full_unstemmed Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title_short Platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via DUB inhibition-dependent caspase activation and Bcr-Abl downregulation
title_sort platinum pyrithione induces apoptosis in chronic myeloid leukemia cells resistant to imatinib via dub inhibition-dependent caspase activation and bcr-abl downregulation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550844/
https://www.ncbi.nlm.nih.gov/pubmed/28682311
http://dx.doi.org/10.1038/cddis.2017.284
work_keys_str_mv AT lanxiaoying platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT zhaochong platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT chenxin platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT zhangpeiquan platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT zangdan platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT wujinjie platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT chenjinghong platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT longhuidan platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT yangli platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT huanghongbiao platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT wangxuejun platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT shixianping platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation
AT liujinbao platinumpyrithioneinducesapoptosisinchronicmyeloidleukemiacellsresistanttoimatinibviadubinhibitiondependentcaspaseactivationandbcrabldownregulation