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Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1
The antiapoptotic Bcl‐2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl‐2‐selective inhibitor ABT‐199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl‐1 limits its antileukaemic activity. XPO1 is a nuclear exporte...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237582/ https://www.ncbi.nlm.nih.gov/pubmed/30596398 http://dx.doi.org/10.1111/jcmm.13886 |
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author | Luedtke, Daniel A. Su, Yongwei Liu, Shuang Edwards, Holly Wang, Yue Lin, Hai Taub, Jeffrey W. Ge, Yubin |
author_facet | Luedtke, Daniel A. Su, Yongwei Liu, Shuang Edwards, Holly Wang, Yue Lin, Hai Taub, Jeffrey W. Ge, Yubin |
author_sort | Luedtke, Daniel A. |
collection | PubMed |
description | The antiapoptotic Bcl‐2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl‐2‐selective inhibitor ABT‐199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl‐1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl‐1 levels in cancer cells. Thus, we hypothesized that the XPO1‐selective inhibitor KPT‐330 (Selinexor) can synergize with ABT‐199 to induce apoptosis in AML cells through down‐regulation of Mcl‐1. The combination of KPT‐330 and ABT‐199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT‐330 treatment decreased Mcl‐1 protein after apoptosis initiation. However, binding of Bim to Mcl‐1 induced by ABT‐199 was abrogated by KPT‐330 at the same time as apoptosis initiation. KPT‐330 treatment increased binding of Bcl‐2 to Bim but was overcome by ABT‐199 treatment, demonstrating that KPT‐330 and ABT‐199 reciprocally overcome apoptosis resistance. Mcl‐1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT‐330 treatment, alone and in combination with ABT‐199, modulates Mcl‐1, which plays an important role in the antileukaemic activity of the combination. |
format | Online Article Text |
id | pubmed-6237582 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62375822018-12-01 Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 Luedtke, Daniel A. Su, Yongwei Liu, Shuang Edwards, Holly Wang, Yue Lin, Hai Taub, Jeffrey W. Ge, Yubin J Cell Mol Med Original Articles The antiapoptotic Bcl‐2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl‐2‐selective inhibitor ABT‐199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl‐1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl‐1 levels in cancer cells. Thus, we hypothesized that the XPO1‐selective inhibitor KPT‐330 (Selinexor) can synergize with ABT‐199 to induce apoptosis in AML cells through down‐regulation of Mcl‐1. The combination of KPT‐330 and ABT‐199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT‐330 treatment decreased Mcl‐1 protein after apoptosis initiation. However, binding of Bim to Mcl‐1 induced by ABT‐199 was abrogated by KPT‐330 at the same time as apoptosis initiation. KPT‐330 treatment increased binding of Bcl‐2 to Bim but was overcome by ABT‐199 treatment, demonstrating that KPT‐330 and ABT‐199 reciprocally overcome apoptosis resistance. Mcl‐1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT‐330 treatment, alone and in combination with ABT‐199, modulates Mcl‐1, which plays an important role in the antileukaemic activity of the combination. John Wiley and Sons Inc. 2018-09-14 2018-12 /pmc/articles/PMC6237582/ /pubmed/30596398 http://dx.doi.org/10.1111/jcmm.13886 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Luedtke, Daniel A. Su, Yongwei Liu, Shuang Edwards, Holly Wang, Yue Lin, Hai Taub, Jeffrey W. Ge, Yubin Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title | Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title_full | Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title_fullStr | Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title_full_unstemmed | Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title_short | Inhibition of XPO1 enhances cell death induced by ABT‐199 in acute myeloid leukaemia via Mcl‐1 |
title_sort | inhibition of xpo1 enhances cell death induced by abt‐199 in acute myeloid leukaemia via mcl‐1 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237582/ https://www.ncbi.nlm.nih.gov/pubmed/30596398 http://dx.doi.org/10.1111/jcmm.13886 |
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