title: SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1.
abstract: 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.
authors: Centro Infantil Boldrini, Campinas, SP, Brazil; Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil; BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jaíra Ferreira
authors: JF
authors: de Vasconcellos
authors: Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: Angelo Brunelli Albertoni
authors: AB
authors: Laranjeira
authors: Department of Chemistry, Santa Catarina Federal University, Florianopólis, SC, Brazil.
authors: Paulo C
authors: PC
authors: Leal
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Manoj K
authors: MK
authors: Bhasin
authors: Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: Priscila Pini
authors: PP
authors: Zenatti
authors: Department of Chemistry, Santa Catarina Federal University, Florianopólis, SC, Brazil.
authors: Ricardo J
authors: RJ
authors: Nunes
authors: Department of Chemistry, Santa Catarina Federal University, Florianopólis, SC, Brazil.
authors: Rosendo A
authors: RA
authors: Yunes
authors: Centro Integrado de Pesquisas Oncohematológicas da Infancia, University of Campinas, Campinas, SP, Brazil.
authors: Alexandre E
authors: AE
authors: Nowill
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Towia A
authors: TA
authors: Libermann
authors: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America; Cancer Genomics Group, International Center for Genetic Engineering and Biotechnology and Medical Biochemistry Division, University of Cape Town, Cape Town, South Africa.
authors: Luiz Fernando
authors: LF
authors: Zerbini
authors: Centro Infantil Boldrini, Campinas, SP, Brazil; Department of Medical Genetics, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors: José Andrés
authors: JA
authors: Yunes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000187:drug effects*; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; C112019:SB 225002