2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells

Arya Sobhakumari; Kevin P Orcutt; Laurie Love-Homan; Christopher E Kowalski; Arlene D Parsons; C Michael Knudson; Andrean L Simons

doi:10.3727/096504016X14586627440192

Back

2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells

Journal article

Open access

Peer reviewed

2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells

Arya Sobhakumari, Kevin P Orcutt, Laurie Love-Homan, Christopher E Kowalski, Arlene D Parsons, C Michael Knudson and Andrean L Simons

Oncology research, Vol.24(1), pp.55-64

2016

DOI: 10.3727/096504016X14586627440192

PMCID: PMC5282972

PMID: 27178822

Files and links (1)

url

https://doi.org/10.3727/096504016X14586627440192View

Published (Version of record) Open Access

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.

Carcinoma, Squamous Cell - metabolism

Humans

Endoplasmic Reticulum - metabolism

Autophagy - drug effects

Head and Neck Neoplasms - metabolism

Chloroquine - pharmacology

Squamous Cell Carcinoma of Head and Neck

Deoxyglucose - pharmacology

Endoplasmic Reticulum - drug effects

Female

Antineoplastic Agents - pharmacology

Membrane Proteins - metabolism

ErbB Receptors - metabolism

Head and Neck Neoplasms - drug therapy

Xenograft Model Antitumor Assays

Animals

Carcinoma, Squamous Cell - drug therapy

Carrier Proteins - metabolism

Mice, Nude

Thyroid Hormones - metabolism

Erlotinib Hydrochloride - pharmacology

Cell Line, Tumor

Glucose - metabolism

Mice

Protein Kinase Inhibitors - pharmacology

Transcription Factor CHOP - metabolism

Details

Title: Subtitle: 2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells
Creators: Arya Sobhakumari - Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA
Kevin P Orcutt
Laurie Love-Homan
Christopher E Kowalski
Arlene D Parsons
C Michael Knudson
Andrean L Simons
Resource Type: Journal article
Publication Details: Oncology research, Vol.24(1), pp.55-64
DOI: 10.3727/096504016X14586627440192
PMID: 27178822
PMCID: PMC5282972
NLM abbreviation: Oncol Res
ISSN: 0965-0407
eISSN: 1555-3906
Publisher: United States
Grant note: K01 CA134941 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 DE024550 / NIDCR NIH HHS
Language: English
Date published: 2016
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047689202771

Metrics

29 Record Views

20 Times Cited - Web of Science