title: Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells.
abstract: Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: I-Lu
authors.initials: IL
authors.lastname: Lai
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chou
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Lai
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Fang
authors.affiliation: Division of Surgical Oncology, Department of Surgery.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Shirley
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: Ribai
authors.initials: R
authors.lastname: Yan
authors.affiliation: Center for Biostatistics and.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Surgical Oncology, Department of Surgery.
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, USA and.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan 704, Taiwan chen.844@osu.edu.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D050687:E2F1 Transcription Factor; D005260:Female; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D051246:Glucose Transport Proteins, Facilitative; C575048:MIRN520 microRNA, human; D035683:MicroRNAs; D045162:Thiazolidinediones; D003841:Deoxycytidine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D005947:Glucose; D000093542:Gemcitabine