Abstract
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. 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. 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. 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.
Highlights
Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer related deaths worldwide [1]
Xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth
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
Summary
Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer related deaths worldwide [1]. A standard therapy for treatment of patients with PC with either curative or palliative intent is gemcitabine [4, 5] The latter is a nucleoside analogue (similar to cytosine) with tumor growth arrest properties due to the two fluorines on the carbon 2’, instead of the hydrogen atoms, which render instability in the DNA chain during the replication process. Several studies analyzed the expression of hENT1 as it was expected to be predictive for clinical outcomes in pancreatic cancer patients treated with gemcitabine [7, 8] Another target of gemcitabine is the human ribonucleotide reductase (RRM1), a key enzyme involved in the homeostasis of nucleotide pools affecting cell proliferation, migration and metastasis [9], which was found to improve survival in gemcitabine-treated patients displaying lower levels of RRM1, whereas higher levels did not [10, 11]. We sought to investigate whether fasting is able to improve chemotherapeutic efficacy in pancreatic cancer cells and in a PC xenograft mouse model
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