Imatinib increases apoptosis index through modulation of survivin subcellular localization in the blast phase of CML cells

Bernardo, Paula Sabbo; Reis, Flaviana Ruade de Souza; Maia, Raquel Ciuvalschi

doi:10.1016/j.leukres.2012.08.014

Cited by 9 publications

(8 citation statements)

References 45 publications

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“…This did not occur when the MDR cell line Lucena-1, that overexpresses Pgp/ABCB1, was studied. In this case, the low rate of apoptosis was related to survivin cytoplasmatic localization [ 86 ].…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

2013

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The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)–ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR–ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/β-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients’ samples are presented.

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Section: Introductionmentioning

confidence: 99%

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

2013

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“…The mean steady state C min of IM in CML patients with 400 mg dose daily is approximately 800–2400 nM [ 36 ]. Bernardo et al demonstrated that the cell viability were reduced by approximately 30% and 70% respectively by 250 and 1000 nM IM in K562 cells at 48 h [ 37 ]. In our study, 1000 nM IM reduced approximately 60% K562 cell viability at 48 h ( S2 Fig ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells

et al. 2016

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Chronic myeloid leukemia (CML) is a myeloproliferative disease. Imatinib (IM), the first line treatment for CML, is excessively expensive and induces various side effects in CML patients. Therefore, it is essential to investigate a new strategy for improving CML therapy. Our immunoblot data revealed that RanGTPase activating protein 1 (RanGAP1) protein levels increased by approximately 30-fold in K562 cells compared with those in normal cells. RanGAP1 is one of the important components of RanGTPase system, which regulates the export of nuclear protein. However, whether RanGAP1 level variation influences BCR-ABL nuclear export is still unknown. In this report, using shRNA to downregulate RanGAP1 expression level augmented K562 cell apoptosis by approximately 40% after treatment with 250 nM IM. Immunofluorescence assay also indicated that three-fold of nuclear BCR-ABL was detected. These data suggest that BCR-ABL nuclear entrapment induced by RanGAP1 downregulation can be used to improve IM efficacy. Moreover, our qRT-PCR data indicated a trend of inverse correlation between the RanGAP1 and microRNA (miR)-1301 levels in CML patients. MiR-1301, targeting the RanGAP1 3′ untranslated region, decreased by approximately 100-fold in K562 cells compared with that in normal cells. RanGAP1 downregulation by miR-1301 transfection impairs BCR-ABL nuclear export to increase approximately 60% of cell death after treatment of 250 nM IM. This result was almost the same as treatment with 1000 nM IM alone. Furthermore, immunofluorescence assay demonstrated that Tyr-99 of nuclear P73 was phosphorylated accompanied with nuclear entrapment of BCR-ABL after transfection with RanGAP1 shRNA or miR-1301 in IM-treated K562 cells. Altogether, we demonstrated that RanGAP1 downregulation can mediate BCR-ABL nuclear entrapment to activate P73-dependent apoptosis pathway which is a novel strategy for improving current IM treatment for CML.

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“…C). In contrast, Survivin is predominately expressed in the cytoplasm of cancer and leukemia cells and provides resistance against cell death . Survivin is differentially expressed in the nucleus at different stages of the cell cycle.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether Survivin is involved in inhibition of MSC apoptosis or regulation of cell proliferation, or both, we measured survival and proliferation of mouse MSCs treated with or without YM155. Inhibition of Survivin in ex vivo expanded mouse BM stromal cells with YM155 substantially enhanced caspase 3 and 7 expression in In contrast, Survivin is predominately expressed in the cytoplasm of cancer and leukemia cells and provides resistance against cell death [14,15]. Survivin is differentially expressed in the nucleus at different stages of the cell cycle.…”

Section: Survivin Inhibition Enhances Msc Apoptosis and Decreases Thementioning

confidence: 99%

Survivin Is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function

Singh¹,

Fukuda

Liu³

et al. 2017

Stem Cells

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Although mesenchymal stromal cells (MSCs) have significant potential in cell-based therapies, little is known about the factors that regulate their functions. While exploring regulatory molecules potentially involved in MSC activities, we found that the endogenous multifunctional factor Survivin is essential for MSC survival, expansion, lineage commitment, and migration. Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony-forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion. Survivin is also required for the MSC proliferative responses to basic fibroblast growth factor and platelet derived growth factor. In a wound healing model, Survivin inhibition results in suppression of MSC migration to the wound site. In addition, loss of Survivin in MSCs compromises their hematopoiesis-supporting capacity. These results demonstrate that Survivin is a key regulator of mouse and human MSC function, and suggest that targeted modulation of Survivin in MSCs may have clinical utility to enhance MSC recovery and activity following insult or stress. STEM CELLS 2018;36:123-129 SIGNIFICANCE STATEMENTResults of this study demonstrate that Survivin is essential for mouse and human mesenchymal stromal cell (MSC) survival, proliferation, and differentiation. The ability to enhance MSC expansion/survival by growth factor (i.e., basic fibroblast growth factor or platelet derived growth factor)-mediated Survivin modulation represents a novel therapeutic strategy particularly for hematopoietic regeneration after clinical transplantation, where HSC supportive niche forming MSCs are severely depleted as a consequence of irradiation exposure.

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Imatinib increases apoptosis index through modulation of survivin subcellular localization in the blast phase of CML cells

Cited by 9 publications

References 45 publications

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells

Survivin Is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function

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