Oncotarget

Research Papers:

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

Jesús García-Cano _, Gorbatchev Ambroise, Raquel Pascual-Serra, M Carmen Carrión, Leticia Serrano-Oviedo, Marta Ortega-Muelas, Francisco J. Cimas, Sebastià Sabater, María José Ruiz-Hidalgo, Isabel Sanchez Perez, Antonio Mas, Félix A. Jalón, Aimé Vazquez and Ricardo Sánchez-Prieto

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Oncotarget. 2015; 6:15551-15565. https://doi.org/10.18632/oncotarget.3902

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Abstract

Jesús García-Cano1, Gorbatchev Ambroise2,*, Raquel Pascual-Serra1,*, Maria Carmen Carrión3,4, Leticia Serrano-Oviedo1, Marta Ortega-Muelas1, Francisco J. Cimas1, Sebastià Sabater5, María José Ruiz-Hidalgo6,7, Isabel Sanchez Perez8,7, Antonio Mas1,7,9, Félix A. Jalón3, Aimé Vazquez2, Ricardo Sánchez-Prieto1,4,7

1Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas. Universidad de Castilla-La Mancha, Albacete, Spain

2INSERM U.1197/Université Paris-Sud/Equipe Labellisée Ligue Nationale Contre le Cancer, Hôpital Paul Brousse, Villejuif, France

3Departamento de Química Inorgánica, Orgánica y Bioquímica, UCLM. Facultad de Ciencias y Tecnologías Químicas-IRICA, Ciudad Real, Spain

4Fundación Parque Científico y Tecnológico de Castilla-La Mancha, Albacete, Spain

5Radiation Oncology Department, Complejo Hospitalario Universitario Albacete (CHUA), Spain

6Departamento de Química Orgánica, Inorgánica y Bioquímica, Facultad de Medicina, Albacete, Spain

7Unidad asociada de Biomedicina, UCLM-CSIC, Albacete, Spain

8Department of Biochemistry, School of Medicine, UAM/Biomedical Research Institute of Madrid, Madrid CSIC/UAM, Madrid, Spain

9Facultad de Farmacia, Universidad de Castilla-La Mancha, Albacete, Spain

*These authors have contributed equally to this work

Correspondence to:

Ricardo Sánchez-Prieto, e-mail: [email protected]

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.


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