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ARTICLE
2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells
Arya Sobhakumari*1, Kevin P. Orcutt†‡1, Laurie Love-Homan§, Christopher E. Kowalski†‡, Arlene D. Parsons†, C. Michael Knudson†‡§¶, Andrean L. Simons*†‡§¶
* Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA
† Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA
‡ Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA
§ Department of Pathology, The University of Iowa, Iowa City, IA, USA
¶ Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA
1 These authors provided equal contribution to this work.
Oncology Research 2016, 24(1), 55-64. https://doi.org/10.3727/096504016X14586627440192
Abstract
Poor tumor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a significant challenge for effective treatment of head and neck squamous cell carcinoma (HNSCC). Therefore,
strategies that may increase tumor response to EGFR TKIs are warranted in order to improve HNSCC patient
treatment and overall survival. HNSCC tumors are highly glycolytic, and increased EGFR signaling has been
found to promote glucose metabolism through various mechanisms. We have previously shown that inhibition of glycolysis with 2-deoxy-d-glucose (2DG) significantly enhanced the antitumor effects of cisplatin and
radiation, which are commonly used to treat HNSCC. The goal of the current studies is to determine if 2DG
will enhance the antitumor activity of the EGFR TKI erlotinib in HNSCC. Erlotinib transiently suppressed
glucose consumption accompanied by alterations in pyruvate kinase M2 (PKM2) expression. 2DG enhanced
the cytotoxic effect of erlotinib in vitro but reversed the antitumor effect of erlotinib in vivo. 2DG altered the
N-glycosylation status of EGFR and induced the endoplasmic reticulum (ER) stress markers CHOP and BiP
in vitro. Additionally, the effects of 2DG+erlotinib on cytotoxicity and ER stress in vitro were reversed by
mannose but not glucose or antioxidant enzymes. Lastly, the protective effect of 2DG on erlotinib-induced
cytotoxicity in vivo was reversed by chloroquine. Altogether, 2DG suppressed the antitumor efficacy of erlotinib in a HNSCC xenograft mouse model, which may be due to increased cytoprotective autophagy mediated
by ER stress activation.
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APA Style
Sobhakumari, A., Orcutt, K.P., Love-Homan, L., Kowalski, C.E., Parsons, A.D. et al. (2016). 2-deoxy-d-glucose suppresses the in vivo antitumor efficacy of erlotinib in head and neck squamous cell carcinoma cells. Oncology Research, 24(1), 55-64. https://doi.org/10.3727/096504016X14586627440192
Vancouver Style
Sobhakumari A, Orcutt KP, Love-Homan L, Kowalski CE, Parsons AD, Knudson CM, et al. 2-deoxy-d-glucose suppresses the in vivo antitumor efficacy of erlotinib in head and neck squamous cell carcinoma cells. Oncol Res. 2016;24(1):55-64 https://doi.org/10.3727/096504016X14586627440192
IEEE Style
A. Sobhakumari et al., "2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells," Oncol. Res., vol. 24, no. 1, pp. 55-64. 2016. https://doi.org/10.3727/096504016X14586627440192