Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines

Fuentes-Baile, María; Ventero, María Paz; Encinar, José Antonio; García-Morales, Pilar; Poveda-Deltell, María; Pérez-Valenciano, Elizabeth; Barberá, Víctor Manuel; Gallego-Plazas, Javier; Rodríguez-Lescure, Álvaro; Martı́n-Nieto, José; Saceda, Miguel

doi:10.3390/cancers12123717

Cited by 21 publications

(11 citation statements)

References 52 publications

(89 reference statements)

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“…A previous study has indicated that linsitinib (OSI-906, an IGF-1 receptor inhibitor) can reduce the expression of C/EBPα, C/EBPβ, PPARγ and adiponectin (67). In the present study, treatment with DAPT increased the expression levels of IGF-1 in HemSCs.…”

Section: Discussionsupporting

confidence: 66%

Notch pathway inhibitor DAPT accelerates in vitro proliferation and adipogenesis in infantile hemangioma stem cells

Xie

et al. 2021

Oncol Lett

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The Notch signaling pathway is crucial in both adipogenesis and tumor development. It serves a vital role in the development and stability of blood vessels and may be involved in the proliferative phase of infantile hemangiomas, which express various related receptors. Therefore, it was hypothesized that the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, might help accelerate the regression of infantile hemangiomas. The present in vitro study evaluated whether inhibition of the Notch signaling pathway using DAPT could alter adipogenesis in hemangioma stem cells (HemSCs) derived from infantile hemangioma (IH) specimens. A total of 20 infants (age, ≤6 months) with hemangiomas who had not yet received any treatment were selected, and their discarded hemangioma tissues were obtained. HemSCs were isolated from the fresh, sterile IH specimens and treated with DAPT. Reverse transcription-quantitative PCR and western blotting were used to demonstrate the inhibition of the Notch signaling pathway by DAPT. A proliferation assay (Cell Counting Kit-8), oil red O staining, flow cytometry and a transwell assay were used to detect proliferation, adipogenesis, apoptosis and migration of HemSCs. Treatment with DAPT upregulated the expression levels of CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ, peroxisome proliferator-activated receptor-γ, adiponectin and insulin-like growth factor 1, and promoted the proliferation, apoptosis, migration and lipid accumulation in HemSCs in vitro. Targeting the Notch signaling pathway using DAPT may potentially accelerate the regression of infantile hemangiomas.

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Section: Discussionsupporting

confidence: 66%

Notch pathway inhibitor DAPT accelerates in vitro proliferation and adipogenesis in infantile hemangioma stem cells

Xie

et al. 2021

Oncol Lett

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“…IGF-1R is a plasma membrane receptor with tyrosine kinase activity, whose inhibitors have been used to treat carcinoma cell lines, with a strong non-proliferative effect ( Fuentes-Baile et al, 2020 ). The IGF-1R elevated expression has also been associated with inhibition of apoptosis and increased proliferation rate and angiogenesis in patients with cancer ( Matsubara et al, 2009 ; Valsecchi et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Gestational Low Protein Diet Modulation on miRNA Transcriptome and Its Target During Fetal and Breastfeeding Nephrogenesis

et al. 2021

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BackgroundThe kidney ontogenesis is the most structurally affected by gestational protein restriction, reducing 28% of their functional units. The reduced nephron number is predictive of hypertension and cardiovascular dysfunctions that are generally observed in the adult age of most fetal programming models. We demonstrate miRNAs and predict molecular pathway changes associated with reduced reciprocal interaction between metanephros cap (CM) and ureter bud (UB) and a 28% decreased nephron stem cells in the 17 gestational days (17GD) low protein (LP) intake male fetal kidney. Here, we evaluated the same miRNAs and predicted targets in the kidneys of 21GD and at 7 days of life (7DL) LP offspring to elucidate the molecular modulations during nephrogenesis.MethodsPregnant Wistar rats were allocated into two groups: NP (regular protein diet- 17%) or LP (diet-6%). miRNA transcriptome sequencing (miRNA-Seq) was performed on the MiSeq platform from 21GD and 7DL male offspring kidneys using previously described methods. Among the top 10 dysfunctional regulated miRNAs, we validated 7 related to proliferation, differentiation, and apoptosis processes and investigated predicted target genes and proteins by RT-qPCR and immunohistochemistry.ResultsIn 21GD, LP fetuses were identified alongside 21 differently expressed miRNAs, of which 12 were upregulated and 9 downregulated compared to age-matched NP offspring. In 7-DL LP offspring, the differentially expressed miRNAs were counted to be 74, of which 46 were upregulated and 28 downregulated. The curve from 17-GD to 7-DL shows that mTOR was fundamental in reducing the number of nephrons in fetal kidneys where the mothers were subjected to a protein restriction. IGF1 and TGFβ curves also seemed to present the same mTOR pattern and were modulated by miRNAs 181a-5p, 181a-3p, and 199a-5p. The miRNA 181c-3p modulated SIX2 and Notch1 reduction in 7-DL but not in terms of the enhanced expression of both in the 21-GD, suggesting the participation of an additional regulator. We found enhanced Bax in 21-GD; it was regulated by miRNA 298-5p, and Bcl2 and Caspase-3 were controlled by miRNA (by 7a-5p and not by the predicted 181a-5p). The miRNA 144-3p regulated BCL6, which was enhanced, as well as Zeb 1 and 2 induced by BCL6. These results revealed that in 21GD, the compensatory mechanisms in LP kidneys led to the activation of UB ramification. Besides, an increase of 32% in the CM stem cells and a possible cell cycle halt of renal progenitor cells, which remaining undifferentiated, were observed. In the 7DL, much more altered miRNA expression was found in LP kidneys, and this was probably due to an increased maternal diet content. Additionally, we verified the activation of pathways related to differentiation and consumption of progenitor cells.

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“…IGF1R depletion/inhibition sensitizes CRC cells to radiotherapy (converting them to radiosensitive), as shown in HT-29 and SW480 cell lines where IGF1R was inhibited by NVP-ADW742 [ 213 ] and in HT-29, SW480 and DLD-1 cells pretreated with BMS-754807 [ 214 ]. The inhibitory effect of BMS-754807 on colon cancer cell growth was stronger compared to the effect of linsitinib, and the anti-neoplastic effect was mostly independent of IGF1R [ 215 ]. A prolonged treatment of colon cancer cells with BMS-754807 and GSK1838705A (inhibitors of IGF1R and IR) leads to cell survival, due to the activation of ribosomal protein S6 kinase 1 [ 216 ].…”

Section: Therapeutic Potential Of the Insulin-like Growth Factor Sign...mentioning

confidence: 99%

The Insulin-like Growth Factor System and Colorectal Cancer

Gligorijević

Dobrijević

Šunderić

et al. 2022

Life

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Insulin-like growth factors (IGFs) are peptides which exert mitogenic, endocrine and cytokine activities. Together with their receptors, binding proteins and associated molecules, they participate in numerous pathophysiological processes, including cancer development. Colorectal cancer (CRC) is a disease with high incidence and mortality rates worldwide, whose etiology usually represents a combination of the environmental and genetic factors. IGFs are most often increased in CRC, enabling excessive autocrine/paracrine stimulation of the cell growth. Overexpression or increased activation/accessibility of IGF receptors is a coinciding step which transmits IGF-related signals. A number of molecules and biochemical mechanisms exert modulatory effects shaping the final outcome of the IGF-stimulated processes, frequently leading to neoplastic transformation in the case of irreparable disbalance. The IGF system and related molecules and pathways which participate in the development of CRC are the focus of this review.

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Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines

Cited by 21 publications

References 52 publications

Notch pathway inhibitor DAPT accelerates in vitro proliferation and adipogenesis in infantile hemangioma stem cells

Notch pathway inhibitor DAPT accelerates in vitro proliferation and adipogenesis in infantile hemangioma stem cells

Gestational Low Protein Diet Modulation on miRNA Transcriptome and Its Target During Fetal and Breastfeeding Nephrogenesis

The Insulin-like Growth Factor System and Colorectal Cancer

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