title: Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance.
abstract: Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach.
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Cano
authors.affiliation: INSERM U.1197/Université Paris-Sud/Equipe Labellisée Ligue Nationale Contre le Cancer, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Gorbatchev
authors.initials: G
authors.lastname: Ambroise
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pascual-Serra
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, UCLM. Facultad de Ciencias y Tecnologías Químicas-IRICA, Ciudad Real, Spain.|Fundación Parque Científico y Tecnológico de Castilla-La Mancha, Albacete, Spain.
authors.forename: Maria Carmen
authors.initials: MC
authors.lastname: Carrión
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Serrano-Oviedo
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ortega-Muelas
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Cimas
authors.affiliation: Radiation Oncology Department, Complejo Hospitalario Universitario Albacete (CHUA), Spain.
authors.forename: Sebastià
authors.initials: S
authors.lastname: Sabater
authors.affiliation: Departamento de Química Orgánica, Inorgánica y Bioquímica, Facultad de Medicina, Albacete, Spain.|Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Ruiz-Hidalgo
authors.affiliation: Department of Biochemistry, School of Medicine, UAM/Biomedical Research Institute of Madrid, Madrid CSIC/UAM, Madrid, Spain.|Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sanchez Perez
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.|Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain.|Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mas
authors.affiliation: Departamento de Química Inorgánica, Orgánica y Bioquímica, UCLM. Facultad de Ciencias y Tecnologías Químicas-IRICA, Ciudad Real, Spain.
authors.forename: Félix A
authors.initials: FA
authors.lastname: Jalón
authors.affiliation: INSERM U.1197/Université Paris-Sud/Equipe Labellisée Ligue Nationale Contre le Cancer, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain.|Fundación Parque Científico y Tecnológico de Castilla-La Mancha, Albacete, Spain.|Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D017671:Platinum Compounds / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D017671:Platinum Compounds; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607114:monoplatin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin
keywords: apoptosis; autophagy; cisplatin; monoplatin; synthetic lethality