title: Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways that affect patient survival.
abstract: Experimental and epidemiological data support the potential activity of acetaminophen against ovarian cancer (OVCA). In this study, we sought to confirm the activity of acetaminophen in OVCA cell lines and to investigate the molecular basis of response. A total of 16 OVCA cell lines underwent pretreatment (baseline) genome-wide expression measurements and were then treated with and analyzed for acetaminophen sensitivity. Pearson's correlation analysis was performed to identify genes that were associated with OVCA acetaminophen response. The identified genes were subjected to pathway analysis, and the expression of each represented pathway was summarized using principal component analysis. OVCA acetaminophen response pathways were analyzed in 4 external clinico-genomic datasets from 820 women for associations with overall survival from OVCA. Acetaminophen exhibited antiproliferative activity against all tested OVCA cell lines, with half maximal inhibitory concentration values ranging from 63.2 to 403 µM. Pearson's correlation followed by biological pathway analysis identified 13 pathways to be associated with acetaminophen sensitivity (P<0.01). Associations were observed between patient survival from OVCA and expression of the following pathways: Development/angiotensin signaling via β-arrestin (P=0.04), protein folding and maturation/angiotensin system maturation (P=0.02), signal transduction/c-Jun N-terminal kinase (JNK) pathway (P=0.03) and androstenedione and testosterone biosynthesis and metabolism (P=0.02). We confirmed that acetaminophen was active against OVCA cellsin vitro. Furthermore, we identified 4 molecular signaling pathways associated with acetaminophen response that may also affect overall survival in women with OVCA, including the JNK pathway, which has been previously implicated in the mechanism of action of acetaminophen and is predictive of decreased survival in women with OVCA.
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Bush
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Tollin
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Marchion
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Forough
authors.initials: F
authors.lastname: Abbasi
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Ramirez
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Nadim Bou
authors.initials: NB
authors.lastname: Zgheib
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Boac
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Judson
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Hye Sook
authors.initials: HS
authors.lastname: Chon
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Wenham
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Sachin M
authors.initials: SM
authors.lastname: Apte
authors.affiliation: Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Cubitt
authors.affiliation: Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Anders E
authors.initials: AE
authors.lastname: Berglund
authors.affiliation: Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Havrilesky
authors.affiliation: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Johnathan M
authors.initials: JM
authors.lastname: Lancaster
keywords: acetaminophen; c-Jun N-terminal kinase pathway; molecular signaling pathways; ovarian cancer; paracetamol