Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance

// Jesus Garcia-Cano 1 , Gorbatchev Ambroise 2, * , Raquel Pascual-Serra 1, * , Maria Carmen Carrion 3, 4 , Leticia Serrano-Oviedo 1 , Marta Ortega-Muelas 1 , Francisco J. Cimas 1 , Sebastia Sabater 5 , Maria Jose Ruiz-Hidalgo 6, 7 , Isabel Sanchez Perez 8, 7 , Antonio Mas 1, 7, 9 , Felix A. Jalon 3 , Aime Vazquez 2 , Ricardo Sanchez-Prieto 1, 4, 7 1 Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomedicas. Universidad de Castilla-La Mancha, Albacete, Spain 2 INSERM U.1197/Universite Paris-Sud/Equipe Labellisee Ligue Nationale Contre le Cancer, Hopital Paul Brousse, Villejuif, France 3 Departamento de Quimica Inorganica, Organica y Bioquimica, UCLM. Facultad de Ciencias y Tecnologias Quimicas-IRICA, Ciudad Real, Spain 4 Fundacion Parque Cientifico y Tecnologico de Castilla-La Mancha, Albacete, Spain 5 Radiation Oncology Department, Complejo Hospitalario Universitario Albacete (CHUA), Spain 6 Departamento de Quimica Organica, Inorganica y Bioquimica, Facultad de Medicina, Albacete, Spain 7 Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain 8 Department of Biochemistry, School of Medicine, UAM/Biomedical Research Institute of Madrid, Madrid CSIC/UAM, Madrid, Spain 9 Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain * These authors have contributed equally to this work Correspondence to: Ricardo Sanchez-Prieto, e-mail: Ricardo.Sanchez@uclm.es Keywords: cisplatin, apoptosis, autophagy, synthetic lethality, monoplatin Received: April 10, 2015      Accepted: April 24, 2015      Published: May 06, 2015 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.