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

Abstract

BACKGROUND:

The aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1(MET) as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells.

METHODS:

We investigated effects of PRIMA-1(MET) 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-1(MET) was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1(MET) was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1(MET) can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1(MET) 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-1(MET) in STS.

CONCLUSIONS:

PRIMA-1(MET) 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.

• Authors: Thomas Grellety, Audrey Laroche-Clary, Vanessa Chaire, Pauline Lagarde, Frédéric Chibon, Agnes Neuville, Antoine Italiano
• Journal: BMC cancer (BMC Cancer) Vol. 15 Pg. 684 (Oct 13 2015) ISSN: 1471-2407 [Electronic] England
• PMID: 26463477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Quinuclidines
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• eprenetapopt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects, genetics)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Inhibitory Concentration 50
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Quinuclidines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sarcoma (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)