SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1

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dc.contributor.authorDe Vasconcellos, Jaíra Ferreiraen_ZA
dc.contributor.authorLaranjeira, Angelo Brunelli Albertonien_ZA
dc.contributor.authorLeal, Paulo Cen_ZA
dc.contributor.authorBhasin, Manoj Ken_ZA
dc.contributor.authorZenatti, Priscila Pinien_ZA
dc.contributor.authorNunes, Ricardo Jen_ZA
dc.contributor.authorYunes, Rosendo Aen_ZA
dc.contributor.authorNowill, Alexandre Een_ZA
dc.contributor.authorLibermann, Towia Aen_ZA
dc.contributor.authorZerbini, Luiz Fernandoen_ZA
dc.contributor.authorYunes, José Andrésen_ZA
dc.date.accessioned2016-02-10T14:47:18Z
dc.date.available2016-02-10T14:47:18Z
dc.date.issued2015en_ZA
dc.description.abstractAcute 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.en_ZA
dc.identifier.apacitationDe Vasconcellos, J. F., Laranjeira, A. B. A., Leal, P. C., Bhasin, M. K., Zenatti, P. P., Nunes, R. J., ... Yunes, J. A. (2015). SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1. <i>PLoS One</i>, http://hdl.handle.net/11427/16953en_ZA
dc.identifier.chicagocitationDe Vasconcellos, Jaíra Ferreira, Angelo Brunelli Albertoni Laranjeira, Paulo C Leal, Manoj K Bhasin, Priscila Pini Zenatti, Ricardo J Nunes, Rosendo A Yunes, et al "SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1." <i>PLoS One</i> (2015) http://hdl.handle.net/11427/16953en_ZA
dc.identifier.citationde Vasconcellos, J. F., Laranjeira, A. B., Leal, P. C., Bhasin, M. K., Zenatti, P. P., Nunes, R. J., ... & Yunes, J. A. (2014) .SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1. PloS one, 10(8), e0134783-e0134783. doi:10.1371/journal.pone.0134783en_ZA
dc.identifier.ris TY - Journal Article AU - De Vasconcellos, Jaíra Ferreira AU - Laranjeira, Angelo Brunelli Albertoni AU - Leal, Paulo C AU - Bhasin, Manoj K AU - Zenatti, Priscila Pini AU - Nunes, Ricardo J AU - Yunes, Rosendo A AU - Nowill, Alexandre E AU - Libermann, Towia A AU - Zerbini, Luiz Fernando AU - Yunes, José Andrés AB - 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. DA - 2015 DB - OpenUCT DO - 10.1371/journal.pone.0134783 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1 TI - SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1 UR - http://hdl.handle.net/11427/16953 ER - en_ZA
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0134783en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16953
dc.identifier.vancouvercitationDe Vasconcellos JF, Laranjeira ABA, Leal PC, Bhasin MK, Zenatti PP, Nunes RJ, et al. SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1. PLoS One. 2015; http://hdl.handle.net/11427/16953.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDivision of Medical Biochemistryen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2015 de Vasconcellos et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherAcute lymphoblastic leukemiaen_ZA
dc.subject.otherApoptosisen_ZA
dc.subject.otherCell cycle and cell divisionen_ZA
dc.subject.otherGene expressionen_ZA
dc.subject.otherReactive oxygen speciesen_ZA
dc.subject.otherTubulinsen_ZA
dc.subject.otherLymphocytesen_ZA
dc.subject.otherCloningen_ZA
dc.titleSB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1en_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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