title: Dual inhibition of histone deacetylases and phosphoinositide 3-kinases: effects on Burkitt lymphoma cell growth and migration.
abstract: Burkitt lymphoma is a highly aggressive non-Hodgkin lymphoma that is characterized by MYC deregulation. Recently, the PI3K pathway has emerged as a cooperative prosurvival mechanism in Burkitt lymphoma. Despite the highly successful results of treatment that use high-dose chemotherapy regimens in pediatric Burkitt lymphoma patients, the survival rate of pediatric patients with progressive or recurrent disease is low. PI3Ks are also known to regulate cell migration, and abnormal cell migration may contribute to cancer progression and dissemination in Burkitt lymphoma. Little is known about Burkitt lymphoma cell migration, but the cooperation between MYC and PI3K in Burkitt lymphoma pathogenesis suggests that a drug combination could be used to target the different steps involved in Burkitt lymphoma cell dissemination and disease progression. The aim of this study was to investigate the effects of the histone deacetylase inhibitor suberoylanilide hydroxamic acid combined with the PI3K inhibitor LY294002 on Burkitt lymphoma cell growth and migration. The combination enhanced the cell growth inhibition and cell-cycle arrest induced by the PI3K inhibitor or histone deacetylase inhibitor individually. Moreover, histone deacetylase inhibitor/PI3K inhibitor cotreatment suppressed Burkitt lymphoma cell migration and decreased cell polarization, Akt and ERK1/2 phosphorylation, and leads to RhoB induction. In summary, the histone deacetylase inhibitor/PI3Ki combination inhibits cell proliferation and migration via alterations in PI3K signaling and histone deacetylase activity, which is involved in the acetylation of α-tubulin and the regulation of RhoB expression.
authors.affiliation: *Programa de Pesquisa em Hemato-Oncologia Molecular, Laboratório de Hemato-oncologia Celular e Molecular, and Programa de Biologia Celular, Laboratório de Biologia Estrutural-Instituto Nacional de Câncer, Rio de Janeiro, Brazil; and Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors.forename: Ana Carolina dos Santos
authors.initials: AC
authors.lastname: Ferreira
authors.affiliation: *Programa de Pesquisa em Hemato-Oncologia Molecular, Laboratório de Hemato-oncologia Celular e Molecular, and Programa de Biologia Celular, Laboratório de Biologia Estrutural-Instituto Nacional de Câncer, Rio de Janeiro, Brazil; and Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors.forename: Julio Cesar Madureira
authors.initials: JC
authors.lastname: de-Freitas-Junior
authors.affiliation: *Programa de Pesquisa em Hemato-Oncologia Molecular, Laboratório de Hemato-oncologia Celular e Molecular, and Programa de Biologia Celular, Laboratório de Biologia Estrutural-Instituto Nacional de Câncer, Rio de Janeiro, Brazil; and Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors.forename: Jose Andres
authors.initials: JA
authors.lastname: Morgado-Díaz
authors.affiliation: *Programa de Pesquisa em Hemato-Oncologia Molecular, Laboratório de Hemato-oncologia Celular e Molecular, and Programa de Biologia Celular, Laboratório de Biologia Estrutural-Instituto Nacional de Câncer, Rio de Janeiro, Brazil; and Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
authors.affiliation: *Programa de Pesquisa em Hemato-Oncologia Molecular, Laboratório de Hemato-oncologia Celular e Molecular, and Programa de Biologia Celular, Laboratório de Biologia Estrutural-Instituto Nacional de Câncer, Rio de Janeiro, Brazil; and Randall Division of Cell and Molecular Biophysics, King's College London, United Kingdom cklumb@inca.gov.br.
authors.forename: Claudete Esteves
authors.initials: CE
authors.lastname: Klumb
mesh_terms: D002051:Burkitt Lymphoma / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D020743:rhoB GTP-Binding Protein / Q000096:biosynthesis
chemical_list: D002867:Chromones; D056572:Histone Deacetylase Inhibitors; C489427:MYC protein, human; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006655:Histone Deacetylases; D020743:rhoB GTP-Binding Protein
keywords: Rho GTPase; histone deacetylase inhibitor; non-Hodgkin lymphoma; phosphoinositide 3-kinase inhibitor