title: APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines.
abstract: APR-246 (PRIMA-1(Met)) is able to bind mutant p53 and restore its normal conformation and function. The compound has also been shown to increase intracellular ROS levels. Importantly, the poly-[ADP-ribose] polymerase-1 (PARP-1) enzyme plays an important role in the repair of ROS-induced DNA damage. We hypothesize that by blocking this repair with the PARP-inhibitor AZD2281 (olaparib), DNA damage would accumulate in the cell leading to massive apoptosis. We observed that APR-246 synergistically enhanced the cytotoxic response of olaparib in TP53 mutant non-small cell lung cancer cell lines, resulting in a strong apoptotic response. In the presence of wild type p53 a G2/M cell cycle block was predominantly observed. NOXA expression levels were significantly increased in a TP53 mutant background, and remained unchanged in the wild type cell line. The combined treatment of APR-246 and olaparib induced cell death that was associated with increased ROS production, accumulation of DNA damage and translocation of p53 to the mitochondria. Out data suggest a promising targeted combination strategy in which the response to olaparib is synergistically enhanced by the addition of APR-246, especially in a TP53 mutant background.
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Deben
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Lardon
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Wouters
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Center for Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Prins Boudewijnlaan 43, 2650 Edegem, Antwerp, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Op de Beeck
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: Van den Bossche
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Jacobs
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Van Der Steen
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium; Phase-1 Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium. Electronic address: christian.rolfo@uza.be.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Deschoolmeester
authors.affiliation: Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1 2610 Wilrijk, Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10 2650 Edegem, Antwerp, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D010793:Phthalazines / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics; D011812:Quinuclidines / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011812:Quinuclidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib; C533410:eprenetapopt
keywords: APR-246; Olaparib; PARP; ROS; p53