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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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