Auranofin Synergizes with the PARP Inhibitor Olaparib to Induce ROS-Mediated Cell Death in Mutant p53 Cancers

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Auranofin (AF) is a thioredoxin reductase (TrxR) inhibitor that induces cancer cell death via reactive oxygen species (ROS) and DNA damage.
• Olaparib is a poly(ADP-ribose) polymerase-1 (PARP) inhibitor used in cancer therapy.

Purpose of the Study:

• To enhance Auranofin (AF) efficacy by combining it with olaparib (aurola) for cancer treatment.
• To investigate the role of mutant p53 in sensitizing non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) cells to AF and olaparib.
• To determine the synergistic cytotoxicity and underlying mechanisms of the AF-olaparib combination.

Main Methods:

• Utilized p53 knock-in and knock-out models of NSCLC and PDAC cells.
• Assessed synergistic cytotoxicity and ROS accumulation.
• Investigated cell death mechanisms including apoptosis and ferroptosis.
• Evaluated the combination strategy in murine 3D spheroids and a syngeneic lung cancer model.

Main Results:

• High concentrations of AF and olaparib synergistically induced cytotoxicity in NSCLC and PDAC cell lines with low mutant p53 levels.
• The aurola combination led to increased ROS accumulation, causing ROS-dependent cytotoxicity via apoptosis and ferroptosis.
• Synergistic cytotoxicity was observed in 3D spheroids but not in 2D cultures of 344SQ cells.
• Oral administration of aurola significantly delayed tumor growth in a syngeneic mouse model, while single agents had no effect.
• RNA sequencing revealed negative enrichment of immune-related gene sets and downregulation of cell cycle genes in aurola-treated tumors.

Conclusions:

• The combination of Auranofin (AF) and olaparib (aurola) is a promising strategy for treating mutant p53 cancers.
• The combination induces synergistic cytotoxicity through increased ROS accumulation, leading to apoptosis and ferroptosis.
• Effective tumor growth inhibition was observed in vivo, highlighting the potential of this therapeutic approach.
• High concentrations of both drugs are required for substantial cytotoxic effects.