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Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis
New treatment options, such as targeted therapies, are urgently needed for the treatment of colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide. The current study focuses on demonstrating the therapeutic efficacies of APG-1252-M1 (an active form of the prodrug, APG-12...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046866/ https://www.ncbi.nlm.nih.gov/pubmed/35462114 http://dx.doi.org/10.1016/j.neo.2022.100798 |
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author | Yao, Weilong Bai, Longchuan Wang, Shaomeng Zha, Yifan Sun, Shi-Yong |
author_facet | Yao, Weilong Bai, Longchuan Wang, Shaomeng Zha, Yifan Sun, Shi-Yong |
author_sort | Yao, Weilong |
collection | PubMed |
description | New treatment options, such as targeted therapies, are urgently needed for the treatment of colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide. The current study focuses on demonstrating the therapeutic efficacies of APG-1252-M1 (an active form of the prodrug, APG-1252 or pelcitoclax), a highly potent Bcl-2/Bcl-X(L) dual inhibitor in clinical trials, against CRC and understanding the underlying mechanisms. APG-1252-M1 effectively decreased the survival of CRC cell lines, particularly those expressing relatively low levels of Mcl-1, with the induction of apoptosis. High levels of Mcl-1 were significantly correlated with decreased sensitivity of CRC cell lines to APG-1252-M1. When combined with an Mcl-1 inhibitor, APG-1252-M1 synergistically decreased the survival and induced apoptosis of APG-1252-M1-insensitive cell lines with high levels of Mcl-1. This combination further decreased the survival and enhanced apoptosis even in sensitive cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG-1252-M1’s effects on decreasing cell survival and inducing apoptosis, which could be reversed by Mcl-1 inhibition. APG-1252-M1 rapidly induced cytochrome C and Smac release from mitochondria with caspase-3 and PARP cleavage. Deficiency of Bax in CRC cells abolished APG-1252-M1’s ability to induce apoptosis, indicating that APG-1252-M1 induces Bax-dependent apoptosis. The current study thus demonstrates the potential of APG-1252-M1 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with an Mcl-1 inhibitor, warranting further evaluation in vivo and in the clinic. |
format | Online Article Text |
id | pubmed-9046866 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-90468662022-05-03 Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis Yao, Weilong Bai, Longchuan Wang, Shaomeng Zha, Yifan Sun, Shi-Yong Neoplasia Original article New treatment options, such as targeted therapies, are urgently needed for the treatment of colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide. The current study focuses on demonstrating the therapeutic efficacies of APG-1252-M1 (an active form of the prodrug, APG-1252 or pelcitoclax), a highly potent Bcl-2/Bcl-X(L) dual inhibitor in clinical trials, against CRC and understanding the underlying mechanisms. APG-1252-M1 effectively decreased the survival of CRC cell lines, particularly those expressing relatively low levels of Mcl-1, with the induction of apoptosis. High levels of Mcl-1 were significantly correlated with decreased sensitivity of CRC cell lines to APG-1252-M1. When combined with an Mcl-1 inhibitor, APG-1252-M1 synergistically decreased the survival and induced apoptosis of APG-1252-M1-insensitive cell lines with high levels of Mcl-1. This combination further decreased the survival and enhanced apoptosis even in sensitive cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG-1252-M1’s effects on decreasing cell survival and inducing apoptosis, which could be reversed by Mcl-1 inhibition. APG-1252-M1 rapidly induced cytochrome C and Smac release from mitochondria with caspase-3 and PARP cleavage. Deficiency of Bax in CRC cells abolished APG-1252-M1’s ability to induce apoptosis, indicating that APG-1252-M1 induces Bax-dependent apoptosis. The current study thus demonstrates the potential of APG-1252-M1 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with an Mcl-1 inhibitor, warranting further evaluation in vivo and in the clinic. Neoplasia Press 2022-04-21 /pmc/articles/PMC9046866/ /pubmed/35462114 http://dx.doi.org/10.1016/j.neo.2022.100798 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original article Yao, Weilong Bai, Longchuan Wang, Shaomeng Zha, Yifan Sun, Shi-Yong Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title | Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title_full | Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title_fullStr | Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title_full_unstemmed | Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title_short | Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X(L) dual inhibitor that induces Bax-dependent apoptosis |
title_sort | mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to apg-1252-m1, a novel bcl-2/bcl-x(l) dual inhibitor that induces bax-dependent apoptosis |
topic | Original article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046866/ https://www.ncbi.nlm.nih.gov/pubmed/35462114 http://dx.doi.org/10.1016/j.neo.2022.100798 |
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