Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models

Persistent Link:
http://hdl.handle.net/10150/610318
Title:
Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
Author:
Baker, Amanda F.; Hanke, Neale T.; Sands, Barbara J.; Carbajal, Liliana; Anderl, Janet L.; Garland, Linda L.
Affiliation:
University of Arizona Cancer Center, College of Medicine, Section of Hematology/Oncology; Onyx Pharmaceuticals, Inc., an Amgen subsidiary
Issue Date:
2014
Publisher:
BioMed Central
Citation:
Baker et al. Journal of Experimental & Clinical Cancer Research (2014) 33:111 DOI 10.1186/s13046-014-0111-8
Journal:
Journal of Experimental & Clinical Cancer Research
Rights:
© 2014 Baker et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.
EISSN:
1756-9966
PubMed ID:
25551693
DOI:
10.1186/s13046-014-0111-8
Keywords:
Carfilzomib; Proteasome inhibitor; Lung cancer; Cisplatin
Version:
Final published version
Additional Links:
http://jeccr.biomedcentral.com/articles/10.1186/s13046-014-0111-8

Full metadata record

DC FieldValue Language
dc.contributor.authorBaker, Amanda F.en
dc.contributor.authorHanke, Neale T.en
dc.contributor.authorSands, Barbara J.en
dc.contributor.authorCarbajal, Lilianaen
dc.contributor.authorAnderl, Janet L.en
dc.contributor.authorGarland, Linda L.en
dc.date.accessioned2016-05-20T09:04:05Z-
dc.date.available2016-05-20T09:04:05Z-
dc.date.issued2014en
dc.identifier.citationBaker et al. Journal of Experimental & Clinical Cancer Research (2014) 33:111 DOI 10.1186/s13046-014-0111-8en
dc.identifier.pmid25551693en
dc.identifier.doi10.1186/s13046-014-0111-8en
dc.identifier.urihttp://hdl.handle.net/10150/610318-
dc.description.abstractBACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC₅₀ values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC₅₀ values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://jeccr.biomedcentral.com/articles/10.1186/s13046-014-0111-8en
dc.rights© 2014 Baker et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)en
dc.subjectCarfilzomiben
dc.subjectProteasome inhibitoren
dc.subjectLung canceren
dc.subjectCisplatinen
dc.titleCarfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer modelsen
dc.typeArticleen
dc.identifier.eissn1756-9966en
dc.contributor.departmentUniversity of Arizona Cancer Center, College of Medicine, Section of Hematology/Oncologyen
dc.contributor.departmentOnyx Pharmaceuticals, Inc., an Amgen subsidiaryen
dc.identifier.journalJournal of Experimental & Clinical Cancer Researchen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.