HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer

SCLC at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for m...

Full description

Bibliographic Details
Main Authors:	Lai, Chien-Hao, Park, Kang-Seo, Lee, Dae-Hao, Alberobello, Anna Teresa, Raffeld, Mark, Pierobon, Mariaelena, Pin, Elisa, Petricoin, Emanuel F., Wang, Yisong, Giaccone, Giuseppe
Format:	Online
Language:	English
Published:	2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002667/

id	pubmed-4002667
recordtype	oai_dc
spelling	pubmed-40026672015-04-02 HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer Lai, Chien-Hao Park, Kang-Seo Lee, Dae-Hao Alberobello, Anna Teresa Raffeld, Mark Pierobon, Mariaelena Pin, Elisa Petricoin, Emanuel F. Wang, Yisong Giaccone, Giuseppe Article SCLC at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models, but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31nM) was much more potent than 17-AAG, a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of RIP1, a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 siRNA or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib + doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immuocompromised mice. We conclude that genetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing. 2013-10-28 2014-10-02 /pmc/articles/PMC4002667/ /pubmed/24166505 http://dx.doi.org/10.1038/onc.2013.439 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lai, Chien-Hao Park, Kang-Seo Lee, Dae-Hao Alberobello, Anna Teresa Raffeld, Mark Pierobon, Mariaelena Pin, Elisa Petricoin, Emanuel F. Wang, Yisong Giaccone, Giuseppe
spellingShingle	Lai, Chien-Hao Park, Kang-Seo Lee, Dae-Hao Alberobello, Anna Teresa Raffeld, Mark Pierobon, Mariaelena Pin, Elisa Petricoin, Emanuel F. Wang, Yisong Giaccone, Giuseppe HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
author_facet	Lai, Chien-Hao Park, Kang-Seo Lee, Dae-Hao Alberobello, Anna Teresa Raffeld, Mark Pierobon, Mariaelena Pin, Elisa Petricoin, Emanuel F. Wang, Yisong Giaccone, Giuseppe
author_sort	Lai, Chien-Hao
title	HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
title_short	HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
title_full	HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
title_fullStr	HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
title_full_unstemmed	HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer
title_sort	hsp-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer
description	SCLC at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models, but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31nM) was much more potent than 17-AAG, a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of RIP1, a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 siRNA or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib + doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immuocompromised mice. We conclude that genetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002667/
_version_	1612083184420257792

HSP-90 Inhibitor Ganetespib is Synergistic with Doxorubicin in Small Cell Lung Cancer

Similar Items