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Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells
MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melan...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564524/ https://www.ncbi.nlm.nih.gov/pubmed/27086916 http://dx.doi.org/10.18632/oncotarget.8695 |
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author | Mukherjee, Nabanita Lu, Yan Almeida, Adam Lambert, Karoline Shiau, Chung-Wai Su, Jung-Chen Luo, Yuchun Fujita, Mayumi Robinson, William A. Robinson, Steven E. Norris, David A. Shellman, Yiqun G. |
author_facet | Mukherjee, Nabanita Lu, Yan Almeida, Adam Lambert, Karoline Shiau, Chung-Wai Su, Jung-Chen Luo, Yuchun Fujita, Mayumi Robinson, William A. Robinson, Steven E. Norris, David A. Shellman, Yiqun G. |
author_sort | Mukherjee, Nabanita |
collection | PubMed |
description | MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH(+) cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma. |
format | Online Article Text |
id | pubmed-5564524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-55645242017-08-23 Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells Mukherjee, Nabanita Lu, Yan Almeida, Adam Lambert, Karoline Shiau, Chung-Wai Su, Jung-Chen Luo, Yuchun Fujita, Mayumi Robinson, William A. Robinson, Steven E. Norris, David A. Shellman, Yiqun G. Oncotarget Research Paper MCL-1 (BCL-2 family anti-apoptotic protein) is responsible for melanoma's resistance to therapy. Cancer initiating cells also contribute to resistance and relapse from treatments. Here we examined the effects of the MCL-1 inhibitor SC-2001 in killing non melanoma-initiating-cells (bulk of melanoma), and melanoma-initiating-cells (MICs). By itself, SC-2001 significantly kills melanoma cells under monolayer conditions in vitro and in a conventional mouse xenograft model. However, even at high doses (10μM), SC-2001 does not effectively eliminate MICs. In contrast, the combination of SC-2001 with ABT-737 (a BCL-2/BCL-XL/BCL-W inhibitor) significantly decreases ALDH(+) cells, disrupts primary spheres, and inhibits the self-renewability of MICs. These results were observed in multiple melanomas, including short term cultures of relapsed tumors from current treatments, independent of the mutation status of BRAF or NRAS. Using a low-cell-number mouse xenograft model, we examined the effects of these treatments on the tumor initiating ability of MIC-enriched cultures. The combination therapy reduces tumor formation significantly compared to either drug alone. Mechanistic studies using shRNA and the CRISPR-Cas9 technology demonstrated that the upregulation of pro-apoptotic proteins NOXA and BIM contribute to the combination-induced cell death. These results indicate that the MCL-1 inhibitor SC-2001 combined with ABT-737 is a promising treatment strategy for targeting melanoma. Impact Journals LLC 2016-04-12 /pmc/articles/PMC5564524/ /pubmed/27086916 http://dx.doi.org/10.18632/oncotarget.8695 Text en Copyright: © 2017 Mukherjee et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Mukherjee, Nabanita Lu, Yan Almeida, Adam Lambert, Karoline Shiau, Chung-Wai Su, Jung-Chen Luo, Yuchun Fujita, Mayumi Robinson, William A. Robinson, Steven E. Norris, David A. Shellman, Yiqun G. Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title | Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title_full | Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title_fullStr | Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title_full_unstemmed | Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title_short | Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
title_sort | use of a mcl-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564524/ https://www.ncbi.nlm.nih.gov/pubmed/27086916 http://dx.doi.org/10.18632/oncotarget.8695 |
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