Aspirin inhibits cell viability and mTOR downstream signaling in gastroenteropancreatic and bronchopulmonary neuroendocrine tumor cells

Spampatti, Matilde Pia; Vlotides, George; Spöttl, Gerald; Maurer, Julian; Göke, Burkhard; Auernhammer, Christoph J.

doi:10.3748/wjg.v20.i29.10038

Cited by 13 publications

(16 citation statements)

References 55 publications

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“…Although strong expression of p21 in gastroenteropancreatic neuroendocrine neoplasms has been previously associated with poor outcome [6], in our study, positive p21 expression showed limited correlations, possibly due to this duality. In vitro, induction of p21 has been associated with aspirin-induced inhibition of neuroendocrine tumour cell viability [63], further emphasising the controversies in the interpretation of p21 presence. Regarding other endocrine neoplasms, no difference of p21 levels in thyroid follicular adenomas and carcinomas has been found [64].…”

Section: P21mentioning

confidence: 99%

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

Simtniece¹,

Vanags²,

Štrumfa³

et al. 2015

pjp

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The study represents a comprehensive retrospective morphological and immunohistochemical profiling of pancreatic neuroendocrine neoplasms (PNENs) in order to reveal the associations between morphological and molecular parameters. The local tumour spread (T), presence of metastases in regional lymph nodes (N) and distant organs (M), tumour grade (G) and resection line status (R) by pathology findings (pTNMGR), mitotic activity, perineural, vascular and lymphatic invasion were assessed in 16 surgically resected PNENs. By immunohistochemistry, expression of Ki-67, p53, p27, p21, cyclin D1, Bcl-2, E-cadherin, CD44, vimentin, cyclooxygenase 2 (COX-2), microvascular density, and cytokeratin (CK) spectrum, along with neuroendocrine, intestinal and squamous markers were detected. Descriptive statistics, Chi-square test, Spearman's rank correlation, Mann-Whitney and Kruskal-Wallis methods were applied; p < 0.05 was considered significant. Ki-67, CK19, p63, vimentin and COX-2 were significantly up-regulated in PNENs in comparison to benign pancreatic islets. A complex network of morphological and molecular associations was identified. Ki-67 correlated with PNEN size (p = 0.022), the World Health Organization 2004 and 2010 classification grades (p = 0.021 and p = 0.002), stage (p = 0.028) and mitotic count (p = 0.007) but among molecular markers -with CK19 (p = 0.033) and vimentin (p = 0.045). CK19 was significantly up-regulated in PNENs, having higher pT (p = 0.018), pR (p = 0.025), vascular (p = 0.020), perineural (p = 0.026) and lymphatic invasion (p = 0.043). In conclusion, proliferation activity (by Ki-67), E-cadherin, vimentin and CK19 are important molecular characteristics of PNENs due to significant associations with morphological tumour characteristics, pTNMGR and invasive growth.

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Section: P21mentioning

confidence: 99%

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

Simtniece¹,

Vanags²,

Štrumfa³

et al. 2015

pjp

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“…All human neuroendocrine cell lines were received and cultured as recently described [22]. The human pancreatic neuroendocrine tumor cell line BON1 [23,24] (kindly provided by Prof. R. Göke, Marburg, Germany) was grown in DMEM/F12 (1:1) supplemented with 10% FBS, 1% penicillin/streptomycin and 0.4% amphotericin B.…”

Section: Methodsmentioning

confidence: 99%

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

et al. 2015

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Background/Aims: The hepatocyte growth factor/transmembrane tyrosine kinase receptor c-Met has been defined as a potential target in antitumoral treatment of various carcinomas. We aimed to investigate the direct effect of c-Met inhibition on neuroendocrine tumor cells in vitro. Methods: The effects of the multi-tyrosine kinase inhibitors cabozantinib and tivantinib and of the highly specific c-Met inhibitor INC280 were investigated in human pancreatic neuroendocrine BON1, bronchopulmonary NCI-H727 and midgut GOT1 cells in vitro. Results: INC280, cabozantinib and tivantinib inhibited c-Met phosphorylation, respectively. However, while equimolar concentrations (10 μM) of cabozantinib and tivantinib inhibited cell viability and cell migration, INC280 had no inhibitory effect. Knockdown experiments with c-Met siRNA also did not demonstrate effects on cell viability. Cabozantinib and tivantinib caused a G2 arrest in neuroendocrine tumor cells. Conclusions: Our in vitro data suggest that c-Met inhibition alone is not sufficient to exert direct antitumoral or antimigratory effects in neuroendocrine tumor cells. The multi-tyrosine kinase inhibitors cabozantinib and tivantinib show promising antitumoral and antimigratory effects in neuroendocrine tumor cells, which are most probably ‘off-target' effects, not mediated by c-Met.

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“…The GOT1 culture medium was additionally supplemented with 5 μg/mL apo-transferrin and 0.135 IU/mL insulin. All human neuroendocrine cell lines were received and cultured as described previously [16,17] . The cells were tested and determined to be mycoplasma free and incubated at 37 ° C and 5% CO 2 .…”

Section: Cell Culturementioning

confidence: 99%

The Novel Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) Alone and in Dual-Targeting Approaches Demonstrates Antitumoral Efficacy in Neuroendocrine Tumors in vitro

Prada¹,

Nölting²,

Spoettl³

et al. 2017

Neuroendocrinology

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Background/Aim: Cyclin-dependent kinases (CDKs) are crucial for cell cycle regulation, and alterations in the cell cycle are often observed in human cancer. CDK4/6 in particular orchestrates G1 phase progression and the G1/S transition. Here, we investigated the in vitro effects of the CDK4/6 inhibitor LEE011 in human neuroendocrine tumor cells. Methods: The human neuroendocrine tumor cell lines BON1, QGP1, NCI-H727 and GOT1 were treated with different concentrations of LEE011 alone and in combination with 5-fluorouracil and everolimus. Results: Cell viability decreased in a time- and dose-dependent manner in BON1, QGP1, and NCI-H727 cells upon LEE011 treatment, whereas GOT1 cells were treatment resistant. Treatment sensitivity towards LEE011 was associated with the high expression of cyclin D1 and Rb. LEE011 caused the dephosphorylation of Rb and a subsequent G1 phase cell cycle arrest. Combined treatment with LEE011 and 5-fluorouracil or everolimus showed a significant enhancement in the inhibition of cell viability when compared to single-substance treatments due to PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation and cooperative downregulation of cell cycle components. However, LEE011 also exhibited antagonizing effects with 5-fluorouracil, protecting NET cells from DNA-damaging chemotherapy by blocking PARP cleavage and caspase-3/7 activity. Conclusions: Our data demonstrate that the CDK 4/6 inhibitor LEE011 exhibits promising anti-tumoral properties alone and in combination treatment approaches with 5-fluorouracil or everolimus in human neuroendocrine tumor cell lines.

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Aspirin inhibits cell viability and mTOR downstream signaling in gastroenteropancreatic and bronchopulmonary neuroendocrine tumor cells

Abstract: Aspirin demonstrates promising anticancer properties for NETs in vitro. Further preclinical and clinical studies are needed.

Cited by 13 publications

References 55 publications

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

The Novel Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) Alone and in Dual-Targeting Approaches Demonstrates Antitumoral Efficacy in Neuroendocrine Tumors in vitro

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