Cargando…
The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer
BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspas...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240213/ https://www.ncbi.nlm.nih.gov/pubmed/28095907 http://dx.doi.org/10.1186/s13046-016-0470-4 |
_version_ | 1782496023779737600 |
---|---|
author | Hashim, Yassar M. Vangveravong, Suwanna Sankpal, Narendra V. Binder, Pratibha S. Liu, Jingxia Goedegebuure, S. Peter Mach, Robert H. Spitzer, Dirk Hawkins, William G. |
author_facet | Hashim, Yassar M. Vangveravong, Suwanna Sankpal, Narendra V. Binder, Pratibha S. Liu, Jingxia Goedegebuure, S. Peter Mach, Robert H. Spitzer, Dirk Hawkins, William G. |
author_sort | Hashim, Yassar M. |
collection | PubMed |
description | BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. METHODS: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. RESULTS: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. CONCLUSION: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-016-0470-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5240213 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-52402132017-01-19 The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer Hashim, Yassar M. Vangveravong, Suwanna Sankpal, Narendra V. Binder, Pratibha S. Liu, Jingxia Goedegebuure, S. Peter Mach, Robert H. Spitzer, Dirk Hawkins, William G. J Exp Clin Cancer Res Research BACKGROUND: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. METHODS: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. RESULTS: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. CONCLUSION: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-016-0470-4) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-17 /pmc/articles/PMC5240213/ /pubmed/28095907 http://dx.doi.org/10.1186/s13046-016-0470-4 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Hashim, Yassar M. Vangveravong, Suwanna Sankpal, Narendra V. Binder, Pratibha S. Liu, Jingxia Goedegebuure, S. Peter Mach, Robert H. Spitzer, Dirk Hawkins, William G. The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title | The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title_full | The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title_fullStr | The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title_full_unstemmed | The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title_short | The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
title_sort | targeted smac mimetic sw iv-134 is a strong enhancer of standard chemotherapy in pancreatic cancer |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240213/ https://www.ncbi.nlm.nih.gov/pubmed/28095907 http://dx.doi.org/10.1186/s13046-016-0470-4 |
work_keys_str_mv | AT hashimyassarm thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT vangveravongsuwanna thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT sankpalnarendrav thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT binderpratibhas thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT liujingxia thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT goedegebuurespeter thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT machroberth thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT spitzerdirk thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT hawkinswilliamg thetargetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT hashimyassarm targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT vangveravongsuwanna targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT sankpalnarendrav targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT binderpratibhas targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT liujingxia targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT goedegebuurespeter targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT machroberth targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT spitzerdirk targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer AT hawkinswilliamg targetedsmacmimeticswiv134isastrongenhancerofstandardchemotherapyinpancreaticcancer |