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7-Ketocholesterol overcomes drug resistance in chronic myeloid leukemia cell lines beyond MDR1 mechanism.
Rosa Fernandes, Lívia; Stern, Ana Carolina Bassi; Cavaglieri, Rita de Cássia; Nogueira, Fábio César Sousa; Domont, Gilberto; Palmisano, Giuseppe; Bydlowski, Sérgio Paulo.
Afiliação
  • Rosa Fernandes L; Laboratory of Genetics and Molecular Hematology (LIM31), University of São Paulo Medical School (FMUSP), São Paulo, Brazil.
  • Stern AC; Laboratory of Genetics and Molecular Hematology (LIM31), University of São Paulo Medical School (FMUSP), São Paulo, Brazil.
  • Cavaglieri RC; Laboratory of Genetics and Molecular Hematology (LIM31), University of São Paulo Medical School (FMUSP), São Paulo, Brazil.
  • Nogueira FC; Proteomic Unit, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Domont G; Proteomic Unit, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
  • Palmisano G; GlycoProteomics Laboratory, Department of Parasitology, ICB, University of Sao Paulo, Brazil. Electronic address: palmisano.gp@usp.br.
  • Bydlowski SP; Laboratory of Genetics and Molecular Hematology (LIM31), University of São Paulo Medical School (FMUSP), São Paulo, Brazil. Electronic address: spbydlow@usp.br.
J Proteomics ; 151: 12-23, 2017 01 16.
Article em En | MEDLINE | ID: mdl-27343758
Chronic myeloid leukemia (CML) is a myeloproliferative disease with a characteristic BCR-ABL tyrosine kinase (TK) fusion protein. Despite the clinical efficacy accomplished by TKIs therapies, disease progression may affect patient response rate to these inhibitors due to a multitude of factors that could lead to development of a mechanism known as multidrug resistance (MDR). 7-Ketocholesterol (7KC) is an oxidized cholesterol derivative that has been extensively reported to cause cell death in a variety of cancer models. In this study, we showed the in vitro efficacy of 7KC against MDR leukemia cell line, Lucena. 7KC treatment induced reduction in cell viability, together with apoptosis-mediated cell death. Moreover, downregulation of MDR protein caused intracellular drug accumulation and 7KC co-incubation with either Daunorubicin or Vincristine reduced cell viability compared to the use of each drug alone. Additionally, quantitative label-free mass spectrometry-based protein quantification showed alteration of different molecular pathways involved in cell cycle arrest, induction of apoptosis and misfolded protein response. Conclusively, this study highlights the effect of 7KC as a sensitizing agent of multidrug resistance CML and elucidates its molecular mechanisms. SIGNIFICANCE: CML patients treated with tyrosine kinase inhibitors (TKIs) have showed a 5-year estimated overall survival of 89%, with cumulative complete cytogenetic response of 87%. However, development of drug resistance is a common feature of the disease progression. This study aimed at showing the effect of 7KC as a cytotoxic and sensitizing agent of multidrug resistance CML cell lines. The cellular and molecular basis of this compound were elucidated using a comprehensive strategy based on quantitative proteomic and cell biology assays. We showed that 7KC induced cell death and overcomes drug resistance in CML through mechanisms that go beyond the classical MDR1 pathways.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Resistencia a Medicamentos Antineoplásicos / Cetocolesteróis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Proteomics Assunto da revista: BIOQUIMICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Resistencia a Medicamentos Antineoplásicos / Cetocolesteróis Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Proteomics Assunto da revista: BIOQUIMICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Brasil País de publicação: Holanda