Background: Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling.
Methods: The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts. Alterations in cell morphology were determined by immunofluorescence experiments. Flow-cytometry analysis and mRNA expression profiles were used to investigate cell differentiation. In vivo efficacy was investigated in human ovarian carcinoma implanted on the chicken chorioallantoic membrane (CAM).
Results: Crenolanib was found to inhibit endothelial cell viability, migration and sprout length, and induced apoptosis independently of PDGFR expression. Treated cells showed altered actin arrangement and nuclear aberrations. Mitosis was affected at several levels including mitosis entry and centrosome clustering. Crenolanib suppressed human ovarian carcinoma tumour growth and angiogenesis in the CAM model.
Conclusions: The PDGFR/FLT3 inhibitor crenolanib targets angiogenesis and inhibits tumour growth in vivo unrelated to PDGFR expression. Based on our findings, we suggest a broad mechanism of action of crenolanib.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738084 | PMC |
http://dx.doi.org/10.1038/s41416-019-0498-2 | DOI Listing |
Cancer Imaging
December 2024
Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Pudong District, 200127, Shanghai, China.
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Recent advent of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of GIST patients. However, responses to TKI therapy can vary depending on the specific gene mutation.
View Article and Find Full Text PDFCells
November 2024
Department of Translational Neuroscience, University Medical Center Utrecht (UMCU) Brain Center, Utrecht University, 3584 CX Utrecht, The Netherlands.
Background: Previous works have shown that the expression of Class-II-Transactivator (CIITA) in tumor cells reduces the growth of glioblastoma (GB) in animal models, but immune effects cannot solely explain this. Here, we searched for immune-independent effects of CIITA on the proliferation of GB.
Methods: Murine GL261 and human U87, GM2 and GM3 malignant glioma cells were transfected with CIITA.
Cell Biol Int
January 2025
Division of Neurobiology, Department of Zoology, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
The interactions between platelet-derived growth factor/PDGF receptor and integrin signaling are crucial for cells to respond to extracellular stimuli. Integrin interactions with PDGFR within the lipid rafts activate downstream cellular signaling pathways that regulate cell proliferation, cell migration, cell differentiation, and cell death processes. The mechanisms underlying PDGFR activation mediated receptor internalization, interactions with other cell-surface receptors, particularly extracellular matrix receptors, integrins, and how these cellular mechanisms switch on anchorage-independent cell survival, leading to anoikis resistance are discussed.
View Article and Find Full Text PDFJ Am Heart Assoc
November 2024
Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital National Yang Ming Chiao Tung University College of Medicine Taipei Taiwan.
Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events. However, the precise mechanisms beyond glycemic control are not fully understood. The objective of this study was to determine the role of PDGF (platelet-derived growth factor)-related signaling in empagliflozin-mediated inhibition of neointima formation.
View Article and Find Full Text PDFVasc Med
October 2024
Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
Renin and prorenin promote the proliferation of vascular smooth muscle cells (VSMCs) through the (pro)renin receptor, or (P)RR, to promote restenosis occurrence. This study aimed to explore whether prorenin promoted the proliferation of VSMCs in a (P)RR-mediated Ang II-independent manner. : Losartan and PD123319 were used to block the interaction between (P)RR and angiotensin in vitro.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!