Potent Inhibitory Effects of Type I Interferons on Human Adrenocortical Carcinoma Cell Growth

Koetsveld, Peter M. van; Vitale, Giovanni; Herder, Wouter W. de; Feelders, Richard A; Wansem, Katy van der; Waaijers, Marlijn; Eijck, Casper H.J. van; Speel, Ernst J. M.; Croze, Ed; Lely, Aart Jan van der; Lamberts, Steven W. J.; Hofland, Leo J.

doi:10.1210/jc.2006-0620

Cited by 39 publications

(37 citation statements)

References 32 publications

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“…Culture conditions of human NCI-H295R and SW13 ACC cells have been described previously (van Koetsveld et al 2006). Briefly, the cells were cultured without (vehicle only) or with substances for 7 days.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

“…In both cell lines, type 1 IFNs block the S-phase of the cell cycle. In H295 cells, but not in SW13 cells, IFN-b strongly induced apoptosis, partially mediated via inhibition of IGF2 expression, an important growth factor in ACC (de Fraipont et al 2005, van Koetsveld et al 2006. There are no data with respect to the effects of both mitotane and type 1 IFNs in primary cultures of ACC.…”

Section: Introductionmentioning

confidence: 98%

“…We have recently shown that type 1 IFNs, in particular IFN-b, have a very potent antiproliferative effect on the human adrenal carcinoma cell lines H295 and SW13 (van Koetsveld et al 2006). In both cell lines, type 1 IFNs block the S-phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

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Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

Koetsveld¹,

Vitale²,

Feelders³

et al. 2013

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-b (IFN-b), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines. Moreover, the interrelationship between the effects of IGF2 and IFN-b was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC 50 : 38G9.2 mM) and cortisol secretion in 5/5 ACC cultures (IC 50 : 4.5G 0.1 mM). IFN-b reduced cell number in 10/11 (IC 50 : 83G18 IU/ml) and cortisol secretion in 5/5 ACC cultures (IC 50 : 7.3G1.5 IU/ml). The effect of IFN-b on cell number included the induction of apoptosis. IFN-b strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1, and CYP11B1. Mitotane and IFN-b induced an additive inhibitory effect on cell number and cortisol secretion. IGF2 (10 nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-b treatment. Finally, IFN-b inhibited IGF2 secretion and mRNA expression. In conclusion, IFN-b is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF2, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-b may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-b is a novel mechanism that may explain its inhibitory effect on cortisol production. Key Words" adrenocortical carcinoma " type 1 interferons " interferon receptor " mitotane " insulin-like growth factor 2

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Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

Koetsveld¹,

Vitale²,

Feelders³

et al. 2013

Endocrine-Related Cancer

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“…Notwithstanding IFN-␤ half-life (1 h) is shorter than that of IFN-␣ (4 -7 h), several studies showed that IFN-␤ has more potent antitumor effects than IFN-␣, via the activation of apoptosis (6,8,12,16,27,(31)(32)(33). In addition, new strategies could improve in future the pharmacokinetic and pharmacodynamic profile of IFN-␤, like the pegylated formulation (21).…”

Section: Discussionmentioning

confidence: 99%

“…The primer and probe sequences were purchased from Biosource (Nivelles, Belgium). The sequence of the primers for IGF-II and the concentrations of primers and probes used in the assay have been described previously by van Koetsveld et al (31). The other primer and probe sequences were as follows: IGF-I forward, 5Ј-TTGTGATTTCTTGAAGGTGAA-GATG-3Ј; IGF-I reverse, 5Ј-CGTGGCAGAGCTGGTGAAG-3Ј; IGF-I probe, 5Ј-FAM-TACCTGGCGCTGTGCCTGCTCA-TAMRA-3Ј; IGF-IR forward, 5Ј-CCAAAACTGAAGCCGAGAAG-3Ј; IGF-IR reverse, 5Ј-GGGTCGGTGATGTTGTAGGT-3Ј; IGF-IR probe, 5Ј-FAM-AAGCAGGAACACCACGGCCG-TAMRA-3Ј; insulin receptor forward, 5Ј-GCTCACGGAGACCTGAAGAG-3Ј; insulin receptor reverse, 5Ј-CACAAACTTCTTGGCGTTCA-3Ј; insulin receptor probe, 5Ј-FAM-CGTTCTCTGCGGCCAGAGGC-TAMRA-3Ј.…”

Section: Methodsmentioning

confidence: 99%

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

Vitale

Koetsveld

Herder

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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We recently demonstrated that interferon (IFN)-β has a more potent antitumor activity than IFN-α in BON cells, a neuroendocrine tumor (NET) cell line. The present study showed the role of type I IFNs in the modulation of the insulin-like growth factor (IGF) system in NETs. BON cells expressed IGF-I, IGF-II, IGF-I receptor, and insulin receptor mRNA. In addition, IGF-I and IGF-II stimulated the proliferation of BON cells and induced an inhibition of DNA fragmentation (apoptosis). As evaluated by quantitative RT-PCR, treatment with IFN-α (100 IU/ml) or IFN-β (100 IU/ml) inhibited the expression of IGF-II mRNA (−42% and −65%, respectively, both P < 0.001), whereas IGF-I receptor mRNA was significantly upregulated by IFN-α (+28%, P < 0.001) and downregulated by IFN-β (−47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-α (−16%, P < 0.05) and IFN-β (−69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (−54%) after IFN-β treatment. Scatchard analysis of 125I-labeled IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-β. Finally, the proapoptotic activity of IFN-β was partially counteracted by the coadministration of IGF-I and IGF-II (both at 50 nM). In conclusion, these data demonstrate that the IGF system has an important role in autocrine/paracrine growth of BON cells. The more potent antitumor activity of IFN-β compared with IFN-α could be explained by several effects on this system: 1) both IFNs inhibit the transcription of IGF-II, but the suppression is significantly higher after IFN-β than IFN-α and 2) only IFN-β inhibits the expression of IGF-I receptor.

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Adrenocortical Cell Lines

Parmar¹,

Kulharya²,

Rainey³

2009

Adrenocortical Carcinoma

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Potent Inhibitory Effects of Type I Interferons on Human Adrenocortical Carcinoma Cell Growth

Abstract: IFNbeta1a is much more potent than IFNalpha2b to suppress ACC cell proliferation in vitro by induction of apoptosis and cell cycle arrest. Further studies are required to evaluate the potency of IFNbeta1a to inhibit tumor growth in vivo.

Cited by 39 publications

References 32 publications

Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

Interferon-β is a potent inhibitor of cell growth and cortisol production in vitro and sensitizes human adrenocortical carcinoma cells to mitotane

Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

Adrenocortical Cell Lines

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