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

Xiaoying Lan, Chong Zhao, Xin Chen, Peiquan Zhang, Dan Zang, Jinjie Wu, Jinghong Chen, Huidan Long, Li Yang, Hongbiao Huang, Xuejun Wang, Xianping Shi, Jinbao Liu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere2913
JournalCell Death and Disease
Volume8
Issue number7
DOIs
StatePublished - Jul 6 2017

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Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Caspases
Platinum
Down-Regulation
Proteasome Endopeptidase Complex
Apoptosis
Ubiquitin
bcr-abl Fusion Proteins
Point Mutation
Heterografts
Imatinib Mesylate
Deubiquitinating Enzymes
pyrithione
Mutation
Growth
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

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.

In: Cell Death and Disease, Vol. 8, No. 7, e2913, 06.07.2017.

Research output: Contribution to journalArticle

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. In: Cell Death and Disease. 2017 ; Vol. 8, No. 7.
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abstract = "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.",
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AU - Zang, Dan

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AU - Chen, Jinghong

AU - Long, Huidan

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AU - Shi, Xianping

AU - Liu, Jinbao

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