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2016 ; 4
(3
): 399-404
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Sensitivity of ovarian cancer cells to acetaminophen reveals biological pathways
that affect patient survival
#MMPMID26998291
Bush SH
; Tollin S
; Marchion DC
; Xiong Y
; Abbasi F
; Ramirez IJ
; Zgheib NB
; Boac B
; Judson PL
; Chon HS
; Wenham RM
; Apte SM
; Cubitt CL
; Berglund AE
; Havrilesky LJ
; Lancaster JM
Mol Clin Oncol
2016[Mar]; 4
(3
): 399-404
PMID26998291
show ga
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 ?-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 cells in 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.
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