title: Tamoxifen in combination with temozolomide induce a synergistic inhibition of PKC-pan in GBM cell lines.
abstract: BACKGROUND
  Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12 months, increasing to 14.6 months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signaling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM.
  
  
  METHODS
  We used two GBM cell lines incubated in absence and presence of TMX and/or TMZ and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan.
  
  
  RESULTS
  The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone.
  
  
  CONCLUSIONS
  The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC.
  
  
  CONCLUSIONS
  We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: joanabalca.silva@gmail.com.
authors.forename: Joana
authors.initials: J
authors.lastname: Balça-Silva
authors.affiliation: Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil. Electronic address: dimtias@gmail.com.
authors.forename: Diana
authors.initials: D
authors.lastname: Matias
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. Electronic address: analiacarmo@gmail.com.
authors.forename: Anália
authors.initials: A
authors.lastname: do Carmo
authors.affiliation: Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Portugal. Electronic address: hmgirao@fmed.uc.pt.
authors.forename: Henrique
authors.initials: H
authors.lastname: Girão
authors.affiliation: Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil. Electronic address: vivaldo@icb.ufrj.br.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura-Neto
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Coimbra, Portugal; Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Portugal. Electronic address: absarmento@fmed.uc.pt.
authors.forename: Ana Bela
authors.initials: AB
authors.lastname: Sarmento-Ribeiro
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Electronic address: celeste@ff.uc.pt.
authors.forename: Maria Celeste
authors.initials: MC
authors.lastname: Lopes
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: D013629:Tamoxifen; D003606:Dacarbazine; D011493:Protein Kinase C; D000077204:Temozolomide
keywords: Chemotherapy; Glioblastoma; Synergism; Tamoxifen; Temozolomide; p-PKC