MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells

Wong, Shuit Mun; Liu, Fu Hwa; Lee, Yueh Lun; Huang, Huei Mei

doi:10.1371/journal.pone.0148093

Cited by 4 publications

(1 citation statement)

References 42 publications

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“…[33][34][35] Induction of mitochondrial apoptosis has been reported to enhance cytotoxicity in imatinib-sensitive and -resistant CML cells. [36,37] Mitochondrial channel VDAC proteins, located at mitochondrial outer membranes, play a key role in mitochondria-mediated apoptosis and programmed cell death. [8] Erastin directly targets VDAC2/3 to induce mitochondria-dependent cell death in tumor cells and facilitates radiotherapy and chemotherapy in the treatment of cancers.…”

Section: Synergistic Effects Of Erastin and Gla In Enhancing Mitochon...mentioning

confidence: 99%

Chemoproteomics Reveals Glaucocalyxin A Induces Mitochondria‐Dependent Apoptosis of Leukemia Cells via Covalently Binding to VDAC1

An,

Zhang,

Chen

et al. 2023

Advanced Biology

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Chronic myelogenous leukemia (CML) that is resistant to tyrosine kinase inhibitors is one of the deadliest hematologic malignancies, and the T315I mutation in the breakpoint cluster region‐Abelson (BCR‐ABL) kinase domain is the most prominent point mutation responsible for imatinib resistance in CML. Glaucocalyxin A (GLA), a natural bioactive product derived from the Rabdosia rubescens plant, has strong anticancer activity. In this study, the effect and molecular mechanism of GLA on imatinib‐sensitive and imatinib‐resistant CML cells harboring T315I mutation via a combined deconvolution strategy of chemoproteomics and label‐free proteomics is investigated. The data demonstrated that GLA restrains proliferation and induces mitochondria‐dependent apoptosis in both imatinib‐sensitive and resistant CML cells. GLA covalently binds to the cysteine residues of mitochondrial voltage‐dependent anion channels (VDACs), resulting in mitochondrial damage and overflow of intracellular apoptotic factors, eventually leading to apoptosis. In addition, the combination of GLA with elastin, a mitochondrial channel VDAC2/3 inhibitor, enhances mitochondria‐dependent apoptosis in imatinib‐sensitive and ‐resistant CML cells, representing a promising therapeutic approach for leukemia treatment. Taken together, the results show that GLA induces mitochondria‐dependent apoptosis via covalently targeting VDACs in CML cells. GLA may thus be a candidate compound for the treatment of leukemia.

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Section: Synergistic Effects Of Erastin and Gla In Enhancing Mitochon...mentioning

confidence: 99%

Chemoproteomics Reveals Glaucocalyxin A Induces Mitochondria‐Dependent Apoptosis of Leukemia Cells via Covalently Binding to VDAC1

An,

Zhang,

Chen

et al. 2023

Advanced Biology

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MPT0B002, a novel microtubule inhibitor, downregulates T315I mutant Bcr-Abl and induces apoptosis of imatinib-resistant chronic myeloid leukemia cells

et al. 2017

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Chronic myeloid leukemia (CML) is a hematopoietic malignancy caused by the constitutive activation of Bcr-Abl tyrosine kinase. The Bcr-Abl inhibitor imatinib and other second-generation tyrosine kinase inhibitors such as dasatinib and nilotinib have remarkable efficacy in CML treatment. However, gene mutation-mediated drug resistance remains a critical problem. Among point mutations, the Bcr-Abl T315I mutation confers resistance to these Bcr-Abl inhibitors. Previously, we have synthesized the compound (1-methyl-1H-indol-5-yl)-(3,4,5-trimethoxy-phenyl)-methanone (MPT0B002) as a novel microtubule inhibitor. In this study, we evaluated its effects on the proliferation, cell cycle, and apoptosis of K562 CML cells and BaF3 cells expressing either wild-type Bcr-Abl (BaF3/p210) or T315I-mutated Bcr-Abl (BaF3/T315I). MPT0B002 inhibited cell viability in a dose-dependent manner in these cells but did not affect the proliferation of human umbilical vein endothelial cells. It disrupted tubulin polymerization and arrested cell cycle at the G2/M phase. Treatment with MPT0B002 induced apoptosis, and this induction was associated with increased levels of cleaved caspase-3 and cleaved PARP. Furthermore, MPT0B002 can downregulate both Bcr-Abl and Bcr-Abl-T315I mRNA expressions and protein levels and the downstream signaling pathways. Taken together, our findings suggest that MPT0B002 may be considered a promising compound to downregulate not only wild type Bcr-Abl but also the T315I mutant to overcome Bcr-Abl-T315I mutation-mediated resistance in CML cells.

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Correction: MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells

Wong¹,

Liu²,

Lee³

et al. 2017

PLoS ONE

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MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells

Cited by 4 publications

References 42 publications

Chemoproteomics Reveals Glaucocalyxin A Induces Mitochondria‐Dependent Apoptosis of Leukemia Cells via Covalently Binding to VDAC1

Chemoproteomics Reveals Glaucocalyxin A Induces Mitochondria‐Dependent Apoptosis of Leukemia Cells via Covalently Binding to VDAC1

MPT0B002, a novel microtubule inhibitor, downregulates T315I mutant Bcr-Abl and induces apoptosis of imatinib-resistant chronic myeloid leukemia cells

Correction: MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells

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