title: PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells.
abstract: There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA‑1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1MET for the treatment of EOC cells. PRIMA-1MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 µM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA‑1MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1MET-induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA‑1MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity.
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Yoshikawa
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiyama
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Utsumi
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Mitsui
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sekiya
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kiyosumi
authors.initials: K
authors.lastname: Shibata
authors.affiliation: Centre for Personalized Cancer Medicine, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Callen
authors.affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kikkawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D059748:Proteolysis; D011812:Quinuclidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011812:Quinuclidines; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C533410:eprenetapopt