title: Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models.
abstract: OBJECTIVE
  Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model.
  
  
  METHODS
  BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum.
  
  
  RESULTS
  Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth.
  
  
  CONCLUSIONS
  Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients.
authors.affiliation: Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: D'Aronzo
authors.affiliation: Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.|Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom.|School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
authors.affiliation: Bioinformatics Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", Istituto Mendel, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Panebianco
authors.affiliation: Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Saracino
authors.affiliation: Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Pereira
authors.affiliation: Pathology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Graziano
authors.affiliation: Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D033721:Equilibrative Nucleoside Transporter 1; D019253:Proto-Oncogene Proteins c-bcl-2; C438649:SLC29A1 protein, human; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D058570:TOR Serine-Threonine Kinases; D000093542:Gemcitabine
keywords: gemcitabine; hENT1; pancreatic cancer