Cargando…

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, th...

Descripción completa

Detalles Bibliográficos
Autores principales: Shekhar, Tanmay M., Miles, Mark A., Gupte, Ankita, Taylor, Scott, Tascone, Brianna, Walkley, Carl R., Hawkins, Christine J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085125/
https://www.ncbi.nlm.nih.gov/pubmed/27129149
http://dx.doi.org/10.18632/oncotarget.8980
_version_ 1782463508846215168
author Shekhar, Tanmay M.
Miles, Mark A.
Gupte, Ankita
Taylor, Scott
Tascone, Brianna
Walkley, Carl R.
Hawkins, Christine J.
author_facet Shekhar, Tanmay M.
Miles, Mark A.
Gupte, Ankita
Taylor, Scott
Tascone, Brianna
Walkley, Carl R.
Hawkins, Christine J.
author_sort Shekhar, Tanmay M.
collection PubMed
description Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors.
format Online
Article
Text
id pubmed-5085125
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-50851252016-10-31 IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα Shekhar, Tanmay M. Miles, Mark A. Gupte, Ankita Taylor, Scott Tascone, Brianna Walkley, Carl R. Hawkins, Christine J. Oncotarget Research Paper Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. Impact Journals LLC 2016-04-25 /pmc/articles/PMC5085125/ /pubmed/27129149 http://dx.doi.org/10.18632/oncotarget.8980 Text en Copyright: © 2016 Shekhar et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Shekhar, Tanmay M.
Miles, Mark A.
Gupte, Ankita
Taylor, Scott
Tascone, Brianna
Walkley, Carl R.
Hawkins, Christine J.
IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title_full IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title_fullStr IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title_full_unstemmed IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title_short IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα
title_sort iap antagonists sensitize murine osteosarcoma cells to killing by tnfα
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085125/
https://www.ncbi.nlm.nih.gov/pubmed/27129149
http://dx.doi.org/10.18632/oncotarget.8980
work_keys_str_mv AT shekhartanmaym iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT milesmarka iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT gupteankita iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT taylorscott iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT tasconebrianna iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT walkleycarlr iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa
AT hawkinschristinej iapantagonistssensitizemurineosteosarcomacellstokillingbytnfa