Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases.
Methods And Materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model.
Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation.
Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ijrobp.2005.11.014 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Pharmacological inactivation of a non-canonical gp130 signaling arm attenuates chronic systemic inflammation and multimorbidity induced by a high-fat diet.
Sci Rep
December 2024
Department of Orthopaedic Surgery, Keck School of Medicine, Stem Cell Research and Regenerative Medicine, University of Southern California, Los Angeles, CA, USA.
Interleukin-6 (IL-6) is a major pro-inflammatory cytokine that demonstrates a robust correlation with age and body mass index (BMI) as part of the senescence-associated secretory phenotype. IL-6 cytokines also play a crucial role in metabolic homeostasis and regenerative processes primarily via the canonical STAT3 pathway. Thus, selective modulation of IL-6 signaling may offer a unique opportunity for therapeutic interventions.
View Article and Find Full Text PDFCsk controls leukocyte extravasation via local regulation of Src family kinases and cortactin signaling.
Front Immunol
November 2024
Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
C-terminal Src kinase (Csk) targets Src family kinases (SFKs) and thereby inactivates them. We have previously shown that Csk binds to phosphorylated tyrosine 685 of VE-cadherin, an adhesion molecule of major importance for the regulation of endothelial junctions. This tyrosine residue is an SFK target, and its mutation (VE-cadherin-Y685F) inhibits the induction of vascular permeability in various inflammation models.
View Article and Find Full Text PDFThe SRC family kinase inhibitor NXP900 demonstrates potent antitumor activity in squamous cell carcinomas.
J Biol Chem
September 2024
Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland, USA. Electronic address:
NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the "closed" conformation, thereby inhibiting both kinase-dependent catalytic activity and kinase-independent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active "open" conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases.
View Article and Find Full Text PDFA major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a human -mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal.
View Article and Find Full Text PDFSyngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.
Dis Model Mech
July 2024
Institute for Research in Immunology and Cancer, Montreal, Quebec H3T 1J4, Canada.
Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!