Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3

Lanuti, Paola; Bertagnolo, Valeria; Pierdomenico, Laura; Bascelli, Adriana; Santavenere, Eugenio; Alinari, Lapo; Capitani, Silvano; Miscia, Sebastianó; Marchisio, Marco

doi:10.1038/cr.2009.80

Cited by 28 publications

(19 citation statements)

References 52 publications

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“…We found that STAT3 inhibition by AG490 induced PEL cell apoptosis mainly involving the extrinsic pathway. Interestingly, it has been recently shown that AG490 synergizes with tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) in the induction of apoptotic cell death in Jurkat and Acute Lymphoblastic Leukemia (ALL) cells [29]. Concomitant to apoptosis induction, AG490 dephosphorylated STAT3 and down-regulated HSP70 and HSF1, the main HSP transcription factor, in PEL cells.…”

Section: Discussionmentioning

confidence: 98%

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Granato¹,

Chiozzi²,

Filardi³

et al. 2015

Cancer Letters

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Section: Discussionmentioning

confidence: 98%

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Granato¹,

Chiozzi²,

Filardi³

et al. 2015

Cancer Letters

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“…Lanuti et al (43) previously reported that the combinatorial effect of TRAIL and AG490 on T-cell leukemia was characterized by a significant inhibition of STAT3 phosphorylation compared with the controls or TRAIL alone-treated samples (43). However, cell viability, CASP3 activity and TUNEL assay results of the present study showed that LNCaP cells are resistant to TRAIL-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro

et al. 2014

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The aim of the present study was to analyze the molecular mechanisms involved in blocking the signaling pathway and the effects of this on the progression of prostate cancer (CaP) cells in vitro. LNCaP human CaP cell line was stimulated with interleukin-6 (IL-6) in the presence/absence of Janus kinase (JAK) 2 (AG490), signal transducer and activator of transcription 3 [(STAT3) S3I-201] inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Cytotoxic activity, the activation of phosphorylated (p)-STAT3 protein, caspase (CASP) 3 activity at protein level, vascular endothelial growth factor (VEGF) A, VEGFC, vascular endothelial growth factor receptor 2, STAT3, matrix metalloproteinase-2, myeloid cell leukemia sequence 1 (MCL-1), CASP8 and CASP9 messenger RNA (mRNA) levels were determined. Morphology and apoptosis were confirmed by DAPI staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. IL-6 rapidly induced the phosphorylation of STAT3 in a dose- and time-dependent manner with a peak expression at 3 h at a concentration of 25 ng/ml. In addition, AG490 (50 μM) and S3I-201 (300 μM) inhibited STAT3 activation. Western blotting results revealed that p-STAT3 protein expression decreased significantly with AG490 and S3I-201 treatment in LNCaP cells. AG490 and S3I-201 induced the downregulation of VEGFA, MCL-1 and STAT3 and the upregulation of CASP8 and CASP9 mRNA transcription levels. In addition, the inhibitors increased the level of CASP3 protein. Combinations of AG490- and S3I-201-TRAIL did not result in an increase in this effect. Parallel results were found by DAPI staining and TUNEL assay. To the best of our knowledge, this is the first study to investigate the possible clinical use of AG490 or S3I-201, together with the reduced use of chemotherapeutic agents with high cytotoxicity, for their ability to exert an apoptotic effect, targeting the JAK/STAT3 pathway.

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“…Other evidences suggest that c-IAP-1 and c-IAP-2 are also important targets for T-ALL therapy. Thus, incubation of T-ALL blasts with A490, a JAK-2 inhibitor, inhibited Stat3 phosphorylation, greatly reduced c-IAP-1 and c-IAP-2 levels and enhanced TRAIL-induced apoptosis [Lanuti et al, 2009]. Another approach was proposed for B-ALL, based on the use of a TRAIL fusion protein designated scFvCD19:sTRAIL, consisting of a CD19-speciifc single-chain Fv antibody fragment (scFv) fused to the soluble extracellular domain of TRAIL (sTRAIL).…”

Section: Acute Lymphoblastic Leukemia (Alls)mentioning

confidence: 94%

TRAIL/TRAIL‐R in hematologic malignancies

Testa

2010

J of Cellular Biochemistry

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Defects in apoptosis are observed in many cancer cell types and contribute in a relevant way to tumorigenesis. Apoptosis is a complex and well-regulated cell death program that plays a key role in the control of cell homeostasis, particularly at the level of the hematopoietic system. Apoptosis can be initiated through two different mechanisms involving either activation of the death receptors (extrinsic pathway) or activation of a mitochondrial apoptotic process (intrinsic pathway). Among the various death receptors a peculiar role is played by TNF-related apoptosis-inducing ligand (TRAIL)-receptors (TRAIL-Rs) and their ligand TRAIL. TRAIL recently received considerable interest for its potent anti-tumor killing activity, sparing normal cells. Here, we will review the expression and the abnormalities of TRAIL/TRAIL-R system in hematologic malignancies. The large majority of primary hematologic tumors are resistant to TRAIL-mediated apoptosis, basically due to the activation of anti-apoptotic signaling pathway (such as NF-kappaB), overexpression of anti-apoptotic proteins (such as FLIP, Bcl-2, XIAP) or expression of TRAIL decoy receptors or reduced TRAIL-R1/-R2 expression. Strategies have been developed to bypass this TRAIL resistance and are based on the combination of TRAIL with chemotherapy or radiotherapy, or with proteasome or histone deacetylase or NF-kappaB inhibitors. The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, XIAP, Bcl-2). Many of these combinatorial therapies hold promise for future developments in treatment of hematologic malignancies.

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Enhancement of TRAIL cytotoxicity by AG-490 in human ALL cells is characterized by downregulation of cIAP-1 and cIAP-2 through inhibition of Jak2/Stat3

Cited by 28 publications

References 52 publications

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro

TRAIL/TRAIL‐R in hematologic malignancies

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