Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3

George, Prince; Bali, Purva; Cohen, Pamela S.; Tao, Jianguo; Guo, Fei; Sigua, Celia; Vishvanath, Anasuya; Fiskus, Warren; Scuto, Anna; Annavarapu, Srinivas; Moscinski, Lynn C.; Bhalla, Kapil N.

doi:10.1158/0008-5472.can-04-0006

Cited by 122 publications

(104 citation statements)

References 24 publications

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“…Our results show that 100 nmol/L SU11657 reduced phospho-STAT5 in MV4;11 cells to below detectable levels. In contrast, the ALL xenograft cells had no detectable phospho-STAT5, which is consistent with wild-type receptor signaling (34). Thus, when taken together, our results suggest that STAT5 does not play a direct role in the signaling leading to VEGF secretion.…”

Section: Discussionsupporting

confidence: 75%

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

Marković

MacKenzie

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2012

Molecular Cancer Therapeutics

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Human leukemia cells secrete VEGF, which can act in a paracrine manner within the bone marrow microenvironment to promote leukemia cell survival and proliferation. The FLT-3 receptor tyrosine kinase plays an essential role in regulating normal hematopoiesis, but its constitutive activation via mutation in acute leukemias is generally associated with poor outcome. The aim of this study was to investigate interactions between the FLT-3 and VEGF signaling pathways in acute leukemia using cell lines and ex vivo cultures of pediatric acute lymphoblastic leukemia cells following expansion of direct patient explants in immunodeficient mice. Different xenograft lines exhibited variable cell surface FLT-3 expression, as well as basal and FLT-3 ligand-induced VEGF secretion, whereas the MV4;11 cell line, which expresses constitutively active FLT-3, secreted high levels of VEGF. The FLT-3 inhibitor, SU11657, significantly reduced VEGF secretion in three of six xenograft lines and MV4;11 cells, in conjunction with inhibition of FLT-3 tyrosine phosphorylation. Moreover, exposure of xenograft cells to the FLT-3-blocking antibody, D43, also reduced VEGF secretion to basal levels and decreased FLT-3 tyrosine phosphorylation. In terms of downstream signaling, SU11657 and D43 both caused dephosphorylation of extracellular signal-regulated kinase 1/2, with no changes in AKT or STAT5 phosphorylation. Finally, partial knockdown of FLT-3 expression by short interfering RNA also resulted in inhibition of VEGF secretion. These results indicate that FLT-3 signaling plays a central role in the regulation of VEGF secretion and that inhibition of the FLT-3/VEGF pathway may disrupt paracrine signaling between leukemia cells and the bone marrow microenvironment.

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Section: Discussionsupporting

confidence: 75%

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

Marković

MacKenzie

Lock

2012

Molecular Cancer Therapeutics

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“…The geldanamycin analogues 17-allylamino-demethoxygeldanamycin (43) and 17-(2-dimethylaminoethyl)amino-17-demethoxy-geldanamycin (44) inhibit Hsp90, causing destabilization of Hsp90 client proteins, which leads to their degradation (43). Promising use of Hsp90-active agents was reported with imatinib against CML cell lines (45) and with the Flt3 inhibitor PKC412 in acute myelogenous leukemia lines expressing the mutant protein (46). Post-translational modifications are essential for protein function.…”

Section: Discussionmentioning

confidence: 99%

A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia

2006

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Some tumors are dependent on the continued activity of a single oncogene for maintenance of their malignant phenotype. The best-studied example is the Bcr-Abl fusion protein in chronic myelogenous leukemia (CML). Although the clinical success of the Abl kinase inhibitor imatinib against chronicphase CML emphasizes the importance of developing therapeutic strategies aimed at this target, resistance to imatinib poses a major problem for the ultimate success of CML therapy by this agent. We hypothesized a sequential blockade strategy that is designed to decrease the expression of the Bcr-Abl protein, with the goal of complementing the action of imatinib on kinase activity. In this study, flavopiridol, an inhibitor of transcription, homoharringtonine (HHT), a protein synthesis inhibitor, and imatinib were used singly and in combination against the Bcr-Abl-positive human CML cell line K562. Flavopiridol alone inhibited phosphorylation of the RNA polymerase II COOH-terminal domain, specifically reduced RNA polymerase II-directed mRNA synthesis, and decreased the Bcr-Abl transcript levels. HHT inhibited protein synthesis and reduced the Bcr-Abl protein level. Imatinib directly inhibited the kinase activity of Bcr-Abl. The combinations of flavopiridol and HHT and flavopiridol and imatinib synergistically decreased clonogenicity as evaluated by the median-effect method. Greater synergy was observed when HHT and imatinib were given sequentially compared with simultaneous administration. Imatinib-resistant Ba/F3 cells that were transfected to express the E255K and T315I mutations of Bcr-Abl were not cross-resistant to flavopiridol and HHT. These results provided a rationale for the combination of inhibitors of transcription and/or translation with specific kinase inhibitors. (Cancer Res 2006; 66(22): 10959-66)

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“…Deacetylation of HSP90 at K294 mediated by HDAC6 is critical for chaperon function; when HDAC6 was genetically knocked down, HSP90 k294 was acetylated and ATP binding to HSP90 was blocked, resulted in impairment of its chaperon function [17]. The hydroxamic acid analogue pan-HDACIs, LAQ824 and LBH589 preferentially inhibit HDAC6 [18].…”

Section: Introductionmentioning

confidence: 99%

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

et al. 2008

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Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3

Abstract: ABSTRACT

Cited by 122 publications

References 24 publications

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia

MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells

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