Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer
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RESEARCH ARTICLE
Open Access
Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer Amber Blaauboer1,2*†, Stephanie Booy1,2†, Peter M. van Koetsveld2, Bas Karels2, Fadime Dogan2, Suzanne van Zwienen2, Casper H. J. van Eijck1 and Leo J. Hofland2
Abstract Background: Adjuvant 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). Methods: BxPC-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. Results: IFN-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 Sphase 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. Conclusions: For 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. Keywords: Pancreatic cancer, Interferon-beta, Gemcitabine, Chemosensitising effect, Drug transporters
Background Pancreatic cancer is a highly malignant disease, with an estimated 5-years survival of 9% [1]. At diagnosis, approximately 15% of the patients have resectable disease (stage I or II), which indicates surgery followed by systemic therapy [2]. The CONKO-001 trial is the first randomized controlled trial in pancreatic cancer that reported longer * Correspondence: [email protected] † Amber Blaauboer and Stephanie Booy contributed equally to this work. 1 Department of Surgery, Erasmus Medical Center, Room Ee-514, Doctor Molewaterplein 40, 3015, GD, Rotterdam, The Netherlands 2 Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands
overall survival (OS) rates in patients treated with adjuvant gemcitabine compared with observation alone. However, the median OS with this regimen is still only 22 months [3]. Recently, Conroy et al. demonstrated a significant survival benefit with modified FOLFIRINOX compared
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