Ganetespib radiosensitization for liver cancer therapy
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress re...
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Taylor & Francis
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910914/ |
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pubmed-49109142016-06-29 Ganetespib radiosensitization for liver cancer therapy Chettiar, Sivarajan T. Malek, Reem Annadanam, Anvesh Nugent, Katriana M. Kato, Yoshinori Wang, Hailun Cades, Jessica A. Taparra, Kekoa Belcaid, Zineb Ballew, Matthew Manmiller, Sarah Proia, David Lim, Michael Anders, Robert A. Herman, Joseph M. Tran, Phuoc T. Research Paper Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. Taylor & Francis 2016-03-16 /pmc/articles/PMC4910914/ /pubmed/26980196 http://dx.doi.org/10.1080/15384047.2016.1156258 Text en © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. |
| 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 |
Chettiar, Sivarajan T. Malek, Reem Annadanam, Anvesh Nugent, Katriana M. Kato, Yoshinori Wang, Hailun Cades, Jessica A. Taparra, Kekoa Belcaid, Zineb Ballew, Matthew Manmiller, Sarah Proia, David Lim, Michael Anders, Robert A. Herman, Joseph M. Tran, Phuoc T. |
| spellingShingle |
Chettiar, Sivarajan T. Malek, Reem Annadanam, Anvesh Nugent, Katriana M. Kato, Yoshinori Wang, Hailun Cades, Jessica A. Taparra, Kekoa Belcaid, Zineb Ballew, Matthew Manmiller, Sarah Proia, David Lim, Michael Anders, Robert A. Herman, Joseph M. Tran, Phuoc T. Ganetespib radiosensitization for liver cancer therapy |
| author_facet |
Chettiar, Sivarajan T. Malek, Reem Annadanam, Anvesh Nugent, Katriana M. Kato, Yoshinori Wang, Hailun Cades, Jessica A. Taparra, Kekoa Belcaid, Zineb Ballew, Matthew Manmiller, Sarah Proia, David Lim, Michael Anders, Robert A. Herman, Joseph M. Tran, Phuoc T. |
| author_sort |
Chettiar, Sivarajan T. |
| title |
Ganetespib radiosensitization for liver cancer therapy |
| title_short |
Ganetespib radiosensitization for liver cancer therapy |
| title_full |
Ganetespib radiosensitization for liver cancer therapy |
| title_fullStr |
Ganetespib radiosensitization for liver cancer therapy |
| title_full_unstemmed |
Ganetespib radiosensitization for liver cancer therapy |
| title_sort |
ganetespib radiosensitization for liver cancer therapy |
| description |
Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. |
| publisher |
Taylor & Francis |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910914/ |
| _version_ |
1613595909638062080 |