title: 2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells.
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.
authors.affiliation: Interdisciplinary Human Toxicology Program, The University of Iowa, Iowa City, IA, USA.
authors.forename: Arya
authors.initials: A
authors.lastname: Sobhakumari
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Orcutt
authors.forename: Laurie
authors.initials: L
authors.lastname: Love-Homan
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Kowalski
authors.forename: Arlene D
authors.initials: AD
authors.lastname: Parsons
authors.forename: C Michael
authors.initials: CM
authors.lastname: Knudson
authors.forename: Andrean L
authors.initials: AL
authors.lastname: Simons
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D013963:Thyroid Hormones / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D002738:Chloroquine; D003847:Deoxyglucose; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005947:Glucose; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D013963:Thyroid Hormones; D051742:Transcription Factor CHOP; D000097810:Thyroid Hormone-Binding Proteins; C497249:DDIT3 protein, human