Synergistic antitumor effect of interferon-ß with gemcitabine in interferon-α-non-responsive pancreatic cancer cells

Tomimaru, Yoshito; Eguchi, Hidetoshi; Wada, Hiroshi; Tomokuni, Akira; Kobayashi, Shogo; Marubashi, Shigeru; Takeda, Yutaka; Tanemura, Masahiro; Umeshita, Koji; Mori, Masaki; Doki, Yuichiro; Nagano, Hiroaki

doi:10.3892/ijo.2011.954

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…Tomimaru et al . confirms this hypothesis and showed that IFN-β combined with gemcitabine was able to induce synergistically anti-tumour effects even in the pancreatic cancer cells with low IFN receptor expression [22]. Taken this together, this seems promising and further in vivo research is definitely necessary.…”

Section: Discussionmentioning

confidence: 56%

“…[20, 32, 33] established a trend towards the importance of the IFN receptor in the response of IFN-α and –β; however, the number of cell lines used in these studies was very low. Furthermore, although some studies did show promising results [11, 17, 18, 22], the effect of IFN-β in the treatment of pancreatic cancer still remains underexposed. Therefore, in this study, we evaluated the type-I IFN receptor expression in a large panel of available human pancreatic cancer cell lines and associated the receptor expression with the anti-tumour potencies of IFN-α and IFN-β.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, very few studies investigated the effect of IFN-β, even though some in vitro studies showed that IFN-β binds the receptor complex with a higher affinity and has greater anti-tumour effects than IFN-α [11, 17, 18, 22]. Although the approximate amount of receptors may determine the effect [10], the relationship of type-I IFNs receptor expression with the anti-tumour effect of IFN-α/β in pancreatic cancer cell lines is not established.…”

Section: Introductionmentioning

confidence: 99%

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Influence of type‐I Interferon receptor expression level on the response to type‐I Interferons in human pancreatic cancer cells

Booy

Eijck

Dogan

et al. 2014

J Cellular Molecular Medi

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Pancreatic cancer is a highly aggressive malignancy with limited treatment options. Type-I interferons (e.g. IFN-α/-β) have several anti-tumour activities. Over the past few years, clinical studies evaluating the effect of adjuvant IFN-α therapy in pancreatic cancer yielded equivocal results. Although IFN-α and-β act via the type-I IFN receptor, the role of the number of receptors present on tumour cells is still unknown. Therefore, this study associated, for the first time, in a large panel of pancreatic cancer cell lines the effects of IFN-α/-β with the expression of type-I IFN receptors. The anti-tumour effects of IFN-α or IFN-β on cell proliferation and apoptosis were evaluated in 11 human pancreatic cell lines. Type-I IFN receptor expression was determined on both the mRNA and protein level. After 7 days of incubation, IFN-α significantly reduced cell growth in eight cell lines by 5–67%. IFN-β inhibited cell growth statistically significant in all cell lines by 43–100%. After 3 days of treatment, IFN-β induced significantly more apoptosis than IFN-α. The cell lines variably expressed the type-I IFN receptor. The maximal inhibitory effect of IFN-α was positively correlated with the IFNAR-1 mRNA (P < 0.05, r = 0.63), IFNAR-2c mRNA (P < 0.05, r = 0.69) and protein expression (P < 0.05, r = 0.65). Human pancreatic cancer cell lines variably respond to IFN-α and-β. The expression level of the type-I IFN receptor is of predictive value for the direct anti-tumour effects of IFN-α treatment. More importantly, IFN-β induces anti-tumour effects already at much lower concentrations, is less dependent on interferon receptor expression and seems, therefore, more promising than IFN-α.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of type‐I Interferon receptor expression level on the response to type‐I Interferons in human pancreatic cancer cells

Booy

Eijck

Dogan

et al. 2014

J Cellular Molecular Medi

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“…inhibition of cell proliferation, induction of apoptosis, and cell cycle arrest. Importantly, type I IFNs have been shown to sensitize cancer cells to chemo- and radiotherapy [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

et al. 2020

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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.

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An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

Pizzuto

Silic-Benussi

Ciminale

et al. 2016

Journal of General Virology

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Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virusencoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

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Synergistic antitumor effect of interferon-ß with gemcitabine in interferon-α-non-responsive pancreatic cancer cells

Cited by 5 publications

References 28 publications

Influence of type‐I Interferon receptor expression level on the response to type‐I Interferons in human pancreatic cancer cells

Influence of type‐I Interferon receptor expression level on the response to type‐I Interferons in human pancreatic cancer cells

Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

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