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Niclosamide and its analogs are potent inhibitors of Wnt/?-catenin, mTOR and
STAT3 signaling in ovarian cancer
#MMPMID27888804
Arend RC
; Londoņo-Joshi AI
; Gangrade A
; Katre AA
; Kurpad C
; Li Y
; Samant RS
; Li PK
; Landen CN
; Yang ES
; Hidalgo B
; Alvarez RD
; Straughn JM
; Forero A
; Buchsbaum DJ
Oncotarget
2016[Dec]; 7
(52
): 86803-86815
PMID27888804
show ga
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer
mortality worldwide. Platinum-based therapy is the standard first line treatment
and while most patients initially respond, resistance to chemotherapy usually
arises. Major signaling pathways frequently upregulated in chemoresistant cells
and important in the maintenance of cancer stem cells (CSCs) include
Wnt/?-catenin, mTOR, and STAT3. The major objective of our study was to
investigate the treatment of ovarian cancer with targeted agents that inhibit
these three pathways. Here we demonstrate that niclosamide, a salicylamide
derivative, and two synthetically manufactured niclosamide analogs (analog 11 and
32) caused significant inhibition of proliferation of two chemoresistant ovarian
cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the
ascites of EOC patients, and cells from a chemoresistant patient-derived
xenograft (PDX). This work shows that all three agents significantly decreased
the expression of proteins in the Wnt/?-catenin, mTOR and STAT3 pathways and
preferentially targeted cells that expressed the ovarian CSC surface protein
CD133. It also illustrates the potential of drug repurposing for chemoresistant
EOC and can serve as a basis for pathway-oriented in vivo studies.
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