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SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

de Vasconcellos, Jaíra Ferreira ; Laranjeira, Angelo Brunelli Albertoni ; Leal, Paulo C ; Bhasin, Manoj K ; Zenatti, Priscila Pini ; Nunes, Ricardo J ; Yunes, Rosendo A ; Nowill, Alexandre E ; Libermann, Towia A ; Zerbini, Luiz Fernando ; Yunes, José Andrés Sarkar, Devanand

PloS one, 2015-08, Vol.10 (8), p.e0134783-e0134783 [Periódico revisado por pares]

United States: Public Library of Science

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SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1
Autor: de Vasconcellos, Jaíra Ferreira ; Laranjeira, Angelo Brunelli Albertoni ; Leal, Paulo C ; Bhasin, Manoj K ; Zenatti, Priscila Pini ; Nunes, Ricardo J ; Yunes, Rosendo A ; Nowill, Alexandre E ; Libermann, Towia A ; Zerbini, Luiz Fernando ; Yunes, José Andrés
Sarkar, Devanand
Assuntos: Acute lymphoblastic leukemia ; Acute lymphocytic leukemia ; Analysis ; Animals ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Antioxidants ; Apoptosis ; Apoptosis - drug effects ; Bioinformatics ; Biology ; Biotechnology ; Bladder ; Bladder cancer ; Blotting, Western ; Breast cancer ; Cancer ; Cell cycle ; Cell Cycle - drug effects ; Cell death ; Cell Death - drug effects ; Cell Line, Tumor ; Children ; Complications and side effects ; CXCR2 protein ; Dosage and administration ; Drug therapy ; Endoplasmic reticulum ; Ethics ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Silencing ; Genes ; Genetic aspects ; Genetic engineering ; Genomics ; Humans ; Inhibition ; Jurkat Cells ; Leukemia ; Lymphatic leukemia ; Lymphocytes B ; Lymphocytes T ; Malignancy ; Medical schools ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Proteins - drug effects ; Neoplasm Transplantation ; Nerve Tissue Proteins - drug effects ; Network analysis ; Oligonucleotide Array Sequence Analysis ; p53 Protein ; Phenylurea Compounds - pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Prostate cancer ; Proteins ; Proteomics ; Reactive Oxygen Species - metabolism ; Real-Time Polymerase Chain Reaction ; Target recognition ; Transcription activation ; Tubulin ; Urea
É parte de: PloS one, 2015-08, Vol.10 (8), p.e0134783-e0134783
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
Conceived and designed the experiments: JFV LFZ JAY. Performed the experiments: JFV ABAL PPZ. Analyzed the data: JFV ABAL MKB. Contributed reagents/materials/analysis tools: PCL RJN RAY AEN TAL. Wrote the paper: JFV TAL LFZ JAY.
Competing Interests: The authors have declared that no competing interests exist.
Descrição: Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002.
Editor: United States: Public Library of Science
Idioma: Inglês

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SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

de Vasconcellos, Jaíra Ferreira ; Laranjeira, Angelo Brunelli Albertoni ; Leal, Paulo C ; Bhasin, Manoj K ; Zenatti, Priscila Pini ; Nunes, Ricardo J ; Yunes, Rosendo A ; Nowill, Alexandre E ; Libermann, Towia A ; Zerbini, Luiz Fernando ; Yunes, José Andrés Sarkar, Devanand

United States: Public Library of Science

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