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Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma
High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we repo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226162/ https://www.ncbi.nlm.nih.gov/pubmed/32260077 http://dx.doi.org/10.3390/cancers12040869 |
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author | Khan, Tashbib He, Yaowu Kryza, Thomas Harrington, Brittney S. Gunter, Jennifer H. Sullivan, Mitchell A. Cuda, Tahleesa Rogers, Rebecca Davies, Claire M. Broomfield, Amy Gough, Madeline Wu, Andy C. McGann, Thomas Weroha, S. John Haluska, Paul Forbes, Josephine M. Armes, Jane E. Barry, Sinead C. Coward, Jermaine I. Jagasia, Nisha Chetty, Naven Snell, Cameron E. Lourie, Rohan Perrin, Lewis C. Hooper, John D. |
author_facet | Khan, Tashbib He, Yaowu Kryza, Thomas Harrington, Brittney S. Gunter, Jennifer H. Sullivan, Mitchell A. Cuda, Tahleesa Rogers, Rebecca Davies, Claire M. Broomfield, Amy Gough, Madeline Wu, Andy C. McGann, Thomas Weroha, S. John Haluska, Paul Forbes, Josephine M. Armes, Jane E. Barry, Sinead C. Coward, Jermaine I. Jagasia, Nisha Chetty, Naven Snell, Cameron E. Lourie, Rohan Perrin, Lewis C. Hooper, John D. |
author_sort | Khan, Tashbib |
collection | PubMed |
description | High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients. |
format | Online Article Text |
id | pubmed-7226162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72261622020-05-18 Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma Khan, Tashbib He, Yaowu Kryza, Thomas Harrington, Brittney S. Gunter, Jennifer H. Sullivan, Mitchell A. Cuda, Tahleesa Rogers, Rebecca Davies, Claire M. Broomfield, Amy Gough, Madeline Wu, Andy C. McGann, Thomas Weroha, S. John Haluska, Paul Forbes, Josephine M. Armes, Jane E. Barry, Sinead C. Coward, Jermaine I. Jagasia, Nisha Chetty, Naven Snell, Cameron E. Lourie, Rohan Perrin, Lewis C. Hooper, John D. Cancers (Basel) Article High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients. MDPI 2020-04-03 /pmc/articles/PMC7226162/ /pubmed/32260077 http://dx.doi.org/10.3390/cancers12040869 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Khan, Tashbib He, Yaowu Kryza, Thomas Harrington, Brittney S. Gunter, Jennifer H. Sullivan, Mitchell A. Cuda, Tahleesa Rogers, Rebecca Davies, Claire M. Broomfield, Amy Gough, Madeline Wu, Andy C. McGann, Thomas Weroha, S. John Haluska, Paul Forbes, Josephine M. Armes, Jane E. Barry, Sinead C. Coward, Jermaine I. Jagasia, Nisha Chetty, Naven Snell, Cameron E. Lourie, Rohan Perrin, Lewis C. Hooper, John D. Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title | Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title_full | Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title_fullStr | Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title_full_unstemmed | Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title_short | Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma |
title_sort | disruption of glycogen utilization markedly improves the efficacy of carboplatin against preclinical models of clear cell ovarian carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226162/ https://www.ncbi.nlm.nih.gov/pubmed/32260077 http://dx.doi.org/10.3390/cancers12040869 |
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