Cargando…

Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations

Hsp70 is a promising anti-cancer target. Our JG-98 series of Hsp70 inhibitors show anti-cancer activities affecting both cancer cells and tumor-associated macrophages. They disrupt Hsp70 interaction with a co-chaperone Bag3 and affect signaling pathways important for cancer development. Due to a pri...

Descripción completa

Detalles Bibliográficos
Autores principales: Yaglom, Julia A., Wang, Yongmei, Li, Amy, Li, Zhenghu, Monti, Stephano, Alexandrov, Ilya, Lu, Xiongbin, Sherman, Michael Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813176/
https://www.ncbi.nlm.nih.gov/pubmed/29445088
http://dx.doi.org/10.1038/s41598-017-14900-0
_version_ 1783300140599083008
author Yaglom, Julia A.
Wang, Yongmei
Li, Amy
Li, Zhenghu
Monti, Stephano
Alexandrov, Ilya
Lu, Xiongbin
Sherman, Michael Y.
author_facet Yaglom, Julia A.
Wang, Yongmei
Li, Amy
Li, Zhenghu
Monti, Stephano
Alexandrov, Ilya
Lu, Xiongbin
Sherman, Michael Y.
author_sort Yaglom, Julia A.
collection PubMed
description Hsp70 is a promising anti-cancer target. Our JG-98 series of Hsp70 inhibitors show anti-cancer activities affecting both cancer cells and tumor-associated macrophages. They disrupt Hsp70 interaction with a co-chaperone Bag3 and affect signaling pathways important for cancer development. Due to a prior report that depletion of Hsp70 causes similar responses as depletion of Hsp90, interest to Hsp70 inhibitors as drug prototypes is hampered by potential similarity of their effects to effects of Hsp90 inhibitors. Here, using the Connectivity Map platform we demonstrate that physiological effects of JG-98 are dissimilar from effects of Hsp90 inhibitors, thus justifying development of these compounds. Using gene expression and ActivSignal IPAD platform, we identified pathways modulated by JG-98. Some of these pathways were affected by JG-98 in Bag3-dependent (e.g. ERK) and some in Bag3-independent manner (e.g. Akt or c-myc), indicating multiple effects of Hsp70 inhibition. Further, we identified genes that modulate cellular responses to JG-98, developed approaches to predict potent combinations of JG-98 with known drugs, and demonstrated that inhibitors of proteasome, RNApol, Akt and RTK synergize with JG-98. Overall, here we established unique effects of novel Hsp70 inhibitors on cancer cell physiology, and predicted potential drug combinations for pre-clinical development.
format Online
Article
Text
id pubmed-5813176
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-58131762018-02-21 Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations Yaglom, Julia A. Wang, Yongmei Li, Amy Li, Zhenghu Monti, Stephano Alexandrov, Ilya Lu, Xiongbin Sherman, Michael Y. Sci Rep Article Hsp70 is a promising anti-cancer target. Our JG-98 series of Hsp70 inhibitors show anti-cancer activities affecting both cancer cells and tumor-associated macrophages. They disrupt Hsp70 interaction with a co-chaperone Bag3 and affect signaling pathways important for cancer development. Due to a prior report that depletion of Hsp70 causes similar responses as depletion of Hsp90, interest to Hsp70 inhibitors as drug prototypes is hampered by potential similarity of their effects to effects of Hsp90 inhibitors. Here, using the Connectivity Map platform we demonstrate that physiological effects of JG-98 are dissimilar from effects of Hsp90 inhibitors, thus justifying development of these compounds. Using gene expression and ActivSignal IPAD platform, we identified pathways modulated by JG-98. Some of these pathways were affected by JG-98 in Bag3-dependent (e.g. ERK) and some in Bag3-independent manner (e.g. Akt or c-myc), indicating multiple effects of Hsp70 inhibition. Further, we identified genes that modulate cellular responses to JG-98, developed approaches to predict potent combinations of JG-98 with known drugs, and demonstrated that inhibitors of proteasome, RNApol, Akt and RTK synergize with JG-98. Overall, here we established unique effects of novel Hsp70 inhibitors on cancer cell physiology, and predicted potential drug combinations for pre-clinical development. Nature Publishing Group UK 2018-02-14 /pmc/articles/PMC5813176/ /pubmed/29445088 http://dx.doi.org/10.1038/s41598-017-14900-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yaglom, Julia A.
Wang, Yongmei
Li, Amy
Li, Zhenghu
Monti, Stephano
Alexandrov, Ilya
Lu, Xiongbin
Sherman, Michael Y.
Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title_full Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title_fullStr Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title_full_unstemmed Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title_short Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations
title_sort cancer cell responses to hsp70 inhibitor jg-98: comparison with hsp90 inhibitors and finding synergistic drug combinations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813176/
https://www.ncbi.nlm.nih.gov/pubmed/29445088
http://dx.doi.org/10.1038/s41598-017-14900-0
work_keys_str_mv AT yaglomjuliaa cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT wangyongmei cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT liamy cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT lizhenghu cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT montistephano cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT alexandrovilya cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT luxiongbin cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations
AT shermanmichaely cancercellresponsestohsp70inhibitorjg98comparisonwithhsp90inhibitorsandfindingsynergisticdrugcombinations