Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models
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Martina D’Aronzo1,*, Manlio Vinciguerra1,2,3,*, Tommaso Mazza4, Concetta Panebianco1, Chiara Saracino1, Stephen P. Pereira2, Paolo Graziano5 and Valerio Pazienza1
1 Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG), Italy
2 Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom
3 School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
4 Bioinformatics Unit I.R.C.C.S. “Casa Sollievo della Sofferenza”, Istituto Mendel, Italy
5 Pathology Unit I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG), Italy
* These authors have contributed equally to this work
Valerio Pazienza, email:
Keywords: pancreatic cancer, gemcitabine, hENT1
Received: January 16, 2015 Accepted: May 12, 2015 Published: May 19, 2015
Background/aims: 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.
Materials and 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.
Conclusion: 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.
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