Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis

Forchap, Sylvia; Pirmohamed, Munir; Clark, R E

doi:10.1038/leu.2011.231

Cited by 12 publications

(7 citation statements)

References 35 publications

(45 reference statements)

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“…Phosphorylation of Bcr-Abl is known to induce proliferation and apoptosis resistance. 24–26 However, phosphorylation of Bcr-Abl was significantly downregulated after 5–15 min of incubation with isononyl alcohol ( Figure 5b ). After 30 min of incubation, Bcr-Abl phosphorylation returned to basal levels.…”

Section: Resultsmentioning

confidence: 95%

Deorphanization and characterization of the ectopically expressed olfactory receptor OR51B5 in myelogenous leukemia cells

Manteniotis

Wojcik

Göthert

et al. 2016

Cell Death Discovery

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The ectopic expression of olfactory receptors (ORs) in the human body has been of major interest in the past decade. Several studies have reported the expression of ORs not only in healthy tissues such as heart, sperm or skin cells, but also in cancerous tissues of the liver, prostate or intestine. In the present study, we detected the expression of OR51B5 in the chronic myelogenous leukemia (CML) cell line K562 and in white blood cell samples of clinically diagnosed acute myelogenous leukemia (AML) patients by reverse transcription-PCR and immunocytochemical staining. The known OR51B5 ligand isononyl alcohol increased the levels of intracellular Ca2+ in both AML patient blood cells and K562 cells. With calcium imaging experiments, we characterized in greater detail the OR51B5-mediated signaling pathway. Here, we observed an involvement of adenylate cyclase and the downstream L-type and T-type calcium channels. In addition, the activation of OR51B5 leads to an inhibition of cell proliferation in K562 cells. In western blot experiments, we found that incubation with isononyl alcohol led to a reduction in p38-MAPK (mitogen-activated protein kinase) phosphorylation that might be responsible for the decreased cell proliferation. In the present study, we characterized the OR51B5-mediated signaling pathway downstream of the activation with isononyl alcohol, which leads to reduced proliferation and therefore provide a novel pharmacological target for CML and AML, the latter of which remains difficult to treat.

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Section: Resultsmentioning

confidence: 95%

Deorphanization and characterization of the ectopically expressed olfactory receptor OR51B5 in myelogenous leukemia cells

Manteniotis

Wojcik

Göthert

et al. 2016

Cell Death Discovery

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“…43 However, ER stress appears more likely to impair than to promote macrophage differentiation. 44 Our findings suggest that the differentiation-promoting effects of amantandine may depend on its ability to induce an increase in the expression of VDR.…”

Section: Discussionmentioning

confidence: 99%

Monocyte-macrophage differentiation of acute myeloid leukemia cell lines by small molecules identified through interrogation of the Connectivity Map database

et al. 2015

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The transcription factor C/EBPa is required for granulocytic differentiation of normal myeloid progenitors and is frequently inactivated in acute myeloid leukemia (AML) cells. Ectopic expression of C/EBPa in AML cells suppresses proliferation and induces differentiation suggesting that restoring C/EBPa expression/activity in AML cells could be therapeutically useful. Unfortunately, current approaches of gene or protein delivery in leukemic cells are unsatisfactory. However, "drug repurposing" is becoming a very attractive strategy to identify potential new uses for existing drugs. In this study, we assessed the biological effects of candidate C/EBPa-mimetics identified by interrogation of the Connectivity Map database. We found that amantadine, an antiviral and anti-Parkinson agent, induced a monocyte-macrophage-like differentiation of HL60, U937, Kasumi-1 myeloid leukemia cell lines, as indicated by morphology and differentiation antigen expression, when used in combination with suboptimal concentration of all trans retinoic acid (ATRA) or Vit D3. The effect of amantadine depends, in part, on increased activity of the vitamin D receptor (VDR), since it induced VDR expression and amantadine-dependent monocyte-macrophage differentiation of HL60 cells was blocked by expression of dominant-negative VDR. These results reveal a new function for amantadine and support the concept that screening of the Connectivity Map database can identify small molecules that mimic the effect of transcription factors required for myelo-monocytic differentiation.

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“…Also Gromicho et al [43] suggested that effective uptake of dasatinib is not likely to occur with the help of hOCT1. Forchap et al [47] concluded that dasatinib is not primarily transported by hOCT1.…”

Section: Discussionmentioning

confidence: 99%

Transport of six tyrosine kinase inhibitors: active or passive?

Honeywell¹,

Hitzerd²,

Kathmann³

et al. 2016

ADMET DMPK

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Release of intracellular calcium primes chronic myeloid leukaemia cells for tyrosine kinase inhibitor-induced apoptosis

Cited by 12 publications

References 35 publications

Deorphanization and characterization of the ectopically expressed olfactory receptor OR51B5 in myelogenous leukemia cells

Deorphanization and characterization of the ectopically expressed olfactory receptor OR51B5 in myelogenous leukemia cells

Monocyte-macrophage differentiation of acute myeloid leukemia cell lines by small molecules identified through interrogation of the Connectivity Map database

Transport of six tyrosine kinase inhibitors: active or passive?

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