Abstract
BackgroundAdjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Impaired drug metabolism is associated with treatment resistance. We aimed to evaluate the chemosensitising effect of interferon-beta (IFN-β).MethodsBxPC-3, CFPAC-1, and Panc-1 cells were pre-treated with IFN-β followed by gemcitabine monotherapy. The effect on cell growth, colony formation, and cell cycle was determined. RT-qPCR was used to measure gene expression. BxPC-3 cells were used in a heterotopic subcutaneous mouse model.ResultsIFN-β increased sensitivity to gemcitabine (4-, 7.7-, and 1.7-fold EC50 decrease in BxPC-3, CFPAC-1, and Panc-1, respectively; all P < 0.001). Findings were confirmed when assessing colony formation. The percentage of cells in the S-phase was significantly increased after IFN-β treatment only in BxPC-3 and CFPAC-1 by 12 and 7%, respectively (p < 0.001 and p < 0.05, respectively). Thereby, IFN-β upregulated expression of the drug transporters SLC28A1 in BxPC-3 (252%) and SLC28A3 in BxPC-3 (127%) and CFPAC-1 (223%) (all p < 0.001). In vivo, combination therapy reduced tumor volume with 45% (P = 0.01). Both ex vivo and in vivo data demonstrate a significant reduction in the number of proliferating cells, whereas apoptosis was increased.ConclusionsFor the first time, we validated the chemosensitising effects of IFN-β when combined with gemcitabine in vitro, ex vivo, and in vivo. This was driven by cell cycle modulation and associated with an upregulation of genes involving intracellular uptake of gemcitabine. The use of IFN-β in combination with gemcitabine seems promising in patients with pancreatic cancer and needs to be further explored.
Highlights
Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting
IFN-β and gemcitabine dose-dependently inhibit proliferation in human pancreatic cancer cells To assess the growth inhibitory effect of IFN-β and gemcitabine, cells were treated with increasing concentrations (10–10.000 IU/ml) IFN-β or (0.1–5 ng/ml) gemcitabine during 3 or 7 days
Half maximal effective concentration (EC50) value after 7 days was lower for CFPAC-1 (0.19 ng/ml; 95% CI 0.17–0.2), compared to BxPC-3 (0.81 ng/ml; 95% CI 0.79–0.84; p < 0.001) and Panc-1 (1.0 ng/ml; 95% CI 0.98–1.02; p < 0.001)
Summary
Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Blaauboer et al BMC Cancer (2020) 20:913 gemcitabine is often the only therapeutic option The resistance of this chemotherapeutic is still a major impediment of successful systemic treatment for patients diagnosed with pancreatic cancer. The limited efficacy of gemcitabine has been associated with impaired drug metabolism, hindering its intracellular uptake and activation [6]. Several transporters have been identified, but its major uptake is through hENT1, hCNT1, and hCNT3 (encoded by SLC29A1, SLC28A1, and SLC28A3, respectively) [7]. Expression levels of these transporters correlate with gemcitabine sensitivity and OS in pancreatic cancer, making them good predictive markers [8, 9]
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