Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-018-30686-1
Title: Anti-tumor efficacy of Selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor
Authors: Subhash, V.V
Yeo, M.S
Wang, L 
Tan, S.H
Wong, F.Y
Thuya, W.L 
Tan, W.L
Peethala, P.C 
Soe, M.Y
Tan, D.S.P
Padmanabhan, N 
Baloglu, E
Shacham, S
Tan, P 
Koeffler, H.P 
Yong, W.P 
Keywords: antineoplastic agent
hydrazine derivative
protein p53
selinexor
triazole derivative
adult
animal
apoptosis
cell cycle
cell nucleus
cell proliferation
drug effect
drug screening
female
human
male
metabolism
mouse
nucleocytoplasmic transport
pathology
stomach tumor
tumor cell line
Active Transport, Cell Nucleus
Adult
Animals
Antineoplastic Agents
Apoptosis
Cell Cycle
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Female
Humans
Hydrazines
Male
Mice
Stomach Neoplasms
Triazoles
Tumor Suppressor Protein p53
Xenograft Model Antitumor Assays
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Subhash, V.V, Yeo, M.S, Wang, L, Tan, S.H, Wong, F.Y, Thuya, W.L, Tan, W.L, Peethala, P.C, Soe, M.Y, Tan, D.S.P, Padmanabhan, N, Baloglu, E, Shacham, S, Tan, P, Koeffler, H.P, Yong, W.P (2018). Anti-tumor efficacy of Selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor. Scientific Reports 8 (1) : 12248. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-018-30686-1
Abstract: Exportin-1 (XPO1) controls the nucleo-cytoplasmic trafficking of several key growth regulatory and tumor suppressor proteins. Nuclear export blockade through XPO1 inhibition is a target for therapeutic inhibition in many cancers. Studies have suggested XPO1 upregulation as an indicator of poor prognosis in gastric cancer. In the current study, we investigated the anti-tumor efficacy of selective inhibitors of nuclear export (SINE) compounds KPT-185, KTP-276 and clinical stage selinexor (KPT-330) in gastric cancer. XPO1 was found to be overexpressed in gastric cancer as compared to adjacent normal tissues and was correlated with poor survival outcomes. Among the 3 SINE compounds, in vitro targeting of XPO1 with selinexor resulted in greatest potency with significant anti-proliferative effects at nano molar concentrations. XPO1 inhibition by selinexor resulted in nuclear accumulation of p53, causing cell cycle arrest and apoptosis. Also, inhibition of XPO1 lead to the cytoplasmic retention of p21 and suppression of survivin. Orally administered selienxor caused significant inhibition of tumor growth in xenograft models of gastric cancer. Furthermore, combination of selinexor with irinotecan exhibited greater anti-tumor effect compared to individual treatment. Taken together, our study underscores the therapeutic utility of XPO1 targeting in gastric cancer and suggests the potential benefits of XPO1 inhibition in-combination with chemotherapy. © 2018, The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/174208
ISSN: 2045-2322
DOI: 10.1038/s41598-018-30686-1
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1038_s41598-018-30686-1.pdf1.59 MBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

23
checked on Oct 14, 2021

Page view(s)

108
checked on Oct 14, 2021

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.