Modulation of reactive oxygen species by antioxidants in chronic myeloid leukemia cells enhances imatinib sensitivity through survivin downregulation

Kwee, Jolie Kiemlian; Luque, Diogo Gomes; Ferreira, Ana Carolina dos Santos; Vasconcelos, Flavia da Cunha; Silva, Karina Lani; Klumb, Claudete Esteves; Maia, Raquel Ciuvalschi

doi:10.1097/cad.0b013e3283140c6f

Cited by 16 publications

(15 citation statements)

References 32 publications

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“…It has been demonstrated by our group that treatment of K562 CML cells with imatinib resulted in survivin downregulation and cell death [147]. Consistent with this, imatinib-induced apoptosis was increased when survivin expression was disrupted in BCR-ABL cells, as shown by enhanced cytochrome c release, caspase-9 activity, and BCR-ABL cleavage 199, which indicate that targeting survivin might be a useful tool to sensitize BCR-ABL cells to imatinib.…”

Section: Inhibitor Of Apoptosis Proteins (Iaps)supporting

confidence: 72%

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

Moraes

Souza

Costas

et al. 2012

Leukemia Research and Treatment

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Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

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Section: Inhibitor Of Apoptosis Proteins (Iaps)supporting

confidence: 72%

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

Moraes

Souza

Costas

et al. 2012

Leukemia Research and Treatment

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“…Additionally, Kwee J. K et al . [29] reported that survivin could induces mitochondrial fragmentation, and reduces mitochondrial respiration, thereby preventing the accumulation of reactive oxygen species, inhibiting apoptosis, and promoting drug resistance. Consistent with these reports, our results also indicated that inhibition of survivin could dramatically decrease LSCs growth, induces apoptosis, suppress self-renewal, and sensitizes cells to chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway

et al. 2015

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BackgroundAcute myeloid leukemia (AML) is initiated and maintained by a subset of self-renewing leukemia stem cells (LSCs), which contribute to the progression, recurrence and therapeutic resistance of leukemia. However, the mechanisms underlying the maintenance of LSCs drug resistance have not been fully defined. In this study, we attempted to elucidate the mechanisms of LSCs drug resistance.MethodsWe performed reverse phase protein arrays to analyze the expression of anti-apoptotic proteins in the LSC-enriched leukemia cell line KG-1a. Immuno-blotting, cell viability and clinical AML samples were evaluated to verify the micro-assay results. The characteristics and transcriptional regulation of survivin were analyzed with the relative luciferase reporter assay, mutant constructs, chromatin immuno-precipitation (ChIP), quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), and western blotting. The levels of Sp1, c-Myc, phospho-extracellular signal-regulated kinase (p-ERK), phospho-mitogen and stress-activated protein kinase (p-MSK) were investigated in paired CD34+ and CD34- AML patient samples.ResultsSurvivin was highly over-expressed in CD34 + CD38- KG-1a cells and paired CD34+ AML patients compared with their differentiated counterparts. Functionally, survivin contributes to the drug resistance of LSCs, and Sp1 and c-Myc concurrently regulate levels of survivin transcription. Clinically, Sp1 and c-Myc were significantly up-regulated and positively correlated with survivin in CD34+ AML patients. Moreover, Sp1 and c-Myc were further activated by the ERK/MSK mitogen-activated protein kinase (MAPK) signaling pathway, modulating survivin levels.ConclusionOur findings demonstrated that ERK/MSK/Sp1/c-Myc axis functioned as a critical regulator of survivin expression in LSCs, offering a potential new therapeutic strategy for LSCs therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0326-0) contains supplementary material, which is available to authorized users.

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“…Apoptosis was measured in both K562 and K562-Lucena cell lines incubated with imatinib in parallel to the incubation with LQB-118. The concentrations of imatinib were chosen according to our previous work [29] and based on similar concentrations used in the clinical scenario. The index of apoptosis induced by imatinib was time-and dose-dependent in sensitive K562 as well as in resistant K562-Lucena cell lines.…”

Section: Apoptosis Induced By Imatinib In K562 Sensitive and K562-lucmentioning

confidence: 99%

LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells

et al. 2010

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Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]. LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein). In agreement with these results, the induction of caspase-3 activation by this compound indicated that a significant rate of apoptosis was taking place. In these cell lines, apoptosis induced by LQB-118 was accompanied by a reduction of P-glycoprotein, survivin, and XIAP expression. Moreover, this effect was not restricted to cell lines as LQB-118 produced significant apoptosis rate in cells from CML patients exhibiting multifactorial drug resistance phenotype such as P-glycoprotein, MRP1 and p53 overexpression. The data suggest that LQB-118 has a potent anti-CML activity that can overcome multifactorial drug resistance mechanisms, making this compound a promising new anti-CML agent.

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Modulation of reactive oxygen species by antioxidants in chronic myeloid leukemia cells enhances imatinib sensitivity through survivin downregulation

Cited by 16 publications

References 32 publications

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway

LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells

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