PRIMA-1MET induces death in soft-tissue sarcomas cell independent of p53

BMC Cancer

Research Article

Vanessa Chaire¹  Antoine Italiano²  Frédéric Chibon³  Audrey Laroche-Clary⁴  Thomas Grellety⁵  Agnes Neuville⁶  Pauline Lagarde⁶ 

[1] National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;Department of Medical Oncology, Institut Bergonié, Bordeaux, France;National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;Department of Pathology, Institut Bergonié, Bordeaux, France;National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;University of Bordeaux, Bordeaux, France;National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;University of Bordeaux, Bordeaux, France;Department of Medical Oncology, Institut Bergonié, Bordeaux, France;National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France;University of Bordeaux, Bordeaux, France;Department of Pathology, Institut Bergonié, Bordeaux, France;

关键词: Soft tissue sarcoma;    Apoptosis;    Oxidative stress;    PRIMA-1;    p53;   

DOI  :  10.1186/s12885-015-1667-1

 received in 2015-06-16, accepted in 2015-10-01,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1MET as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells.MethodsWe investigated effects of PRIMA-1MET on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status.ResultsCell viability reduction by PRIMA-1MET was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1MET was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1MET can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1MET toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1MET in STS.ConclusionsPRIMA-1MET anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.

【 授权许可】

CC BY   
© Grellety et al. 2015