PRIMA-1MET induces death in soft-tissue sarcomas cell independent of p53. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Grellety, Thomas; Laroche-Clary, Audrey; Chaire, Vanessa; Lagarde, Pauline; Chibon, Frédéric; Neuville, Agnes; Italiano, Antoine
• Is Part Of: BMC cancer. Volume 15:Issue 1(2015)
• Page Start: 1
• Page End: 8
• Publication Date: 2015-12
• Subjects: Soft tissue sarcoma -- Apoptosis -- Oxidative stress -- PRIMA-1MET -- p53; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-1667-1
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background The 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. Methods We 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. Results Cell 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. Conclusions PRIMA-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.