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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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de Vasconcellos, Jaira Ferreira [1, 2, 3, 4] ; Albertoni Laranjeira, Angelo Brunelli [3] ; Leal, Paulo C. [5] ; Bhasin, Manoj K. [1, 4] ; Zenatti, Priscila Pini [3] ; Nunes, Ricardo J. [5] ; Yunes, Rosendo A. [5] ; Nowill, Alexandre E. [6] ; Libermann, Towia A. [1, 4] ; Zerbini, Luiz Fernando [1, 4, 7, 8] ; Yunes, Jose Andres [3, 2]
Total Authors: 11
Affiliation:
[1] Harvard Univ, Sch Med, Boston, MA - USA
[2] Univ Estadual Campinas, Fac Med Sci, Dept Med Genet, Campinas, SP - Brazil
[3] Ctr Infantil Boldrini, Campinas, SP - Brazil
[4] Beth Israel Deaconess Med Ctr, BIDMC Genom Prote Bioinformat & Syst Biol Ctr, Boston, MA 02215 - USA
[5] Univ Fed Santa Catarina, Dept Chem, Florianopolis, SC - Brazil
[6] Univ Estadual Campinas, Ctr Integrado Pesquisas Oncohematol Infancia, Campinas, SP - Brazil
[7] Univ Cape Town, Canc Genom Grp, Int Ctr Genet Engn, ZA-7925 Cape Town - South Africa
[8] Univ Cape Town, Biotechnol & Med Biochem Div, ZA-7925 Cape Town - South Africa
Total Affiliations: 8
Document type: Journal article
Source: PLoS One; v. 10, n. 8 AUG 24 2015.
Web of Science Citations: 5
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. (AU)

FAPESP's process: 05/02390-4 - Role of CCL2 and IL-8 on the survival and proliferation of childhood B-lineage acute lymphoblastic leukemia cells co-cultured with bone marrow stromal cells
Grantee:José Andrés Yunes
Support type: Regular Research Grants
FAPESP's process: 08/02106-2 - IGFBP7 role in chemotherapy resistance of Pediatric Acute Lymphoblastic Leukemia
Grantee:Angelo Brunelli Albertoni Laranjeira
Support type: Scholarships in Brazil - Doctorate