Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

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 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. 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.

Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation

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Anlotinib suppresses proliferation, migration, and immune escape of gastric cancer cells by activating the cGAS-STING/IFN-β pathway

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The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma

“…Clinical studies have shown that TAM infiltration in PDAC cells depends on the expression of CCR2 and ZEB1, of which CCL2 and CD74 determine poor prognosis ( 38 ). An important process in the therapeutic resistance of PDAC is the interaction between TAMs and cancer stem cells (CSCs), that is, TAMs can be recruited into TME to regulate the start-up state of pancreatic CSCs ( 39 ), which secrete IFN-β ( 40 ) and other factors to stimulate TAMs to maintain the active state, thus initiating the proliferation and differentiation effect of tumor cells. TAMs can express more Arg1 to interfere with the metabolism of effecting T cells, and TGF-β, IL-10, prostaglandin E2 (PGE2) and other factors released by TAMs can help Tregs recruit and inhibit CD8+T cells ( 41 , 42 ).…”