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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 |
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