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Open AccessArticle

Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma

1
Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
2
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102, Australia
3
Mater Brisbane Hospital, Mater Health Services, South Brisbane, QLD 4101, Australia
4
Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA
5
Bristol-Myers Squibb, Princeton, NJ 08540, USA
6
ICON Cancer Care, South Brisbane, QLD 4101, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 869; https://doi.org/10.3390/cancers12040869
Received: 10 March 2020 / Revised: 30 March 2020 / Accepted: 1 April 2020 / Published: 3 April 2020
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. View Full-Text
Keywords: 2DG; glycogen; clear cell ovarian cancer 2DG; glycogen; clear cell ovarian cancer
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Khan, T.; He, Y.; Kryza, T.; Harrington, B.S.; Gunter, J.H.; Sullivan, M.A.; Cuda, T.; Rogers, R.; Davies, C.M.; Broomfield, A.; Gough, M.; Wu, A.C.; McGann, T.; Weroha, S.J.; Haluska, P.; Forbes, J.M.; Armes, J.E.; Barry, S.C.; Coward, J.I.; Jagasia, N.; Chetty, N.; Snell, C.E.; Lourie, R.; Perrin, L.C.; Hooper, J.D. Disruption of Glycogen Utilization Markedly Improves the Efficacy of Carboplatin against Preclinical Models of Clear Cell Ovarian Carcinoma. Cancers 2020, 12, 869.

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