Flurbiprofen benzyl nitrate (NBS-242) inhibits the growth of A-431 human epidermoid carcinoma cells and targets β-catenin
نویسندگان
چکیده
BACKGROUND The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitric-oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are chemopreventive agents consisting of a traditional NSAID attached to an NO-releasing moiety through a chemical spacer. Previously we showed that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer. METHODS We synthesized an NO-releasing NSAID with an aromatic spacer (flurbiprofen benzyl nitrate, NBS-242), and using the human skin cancer cell line A-431, we evaluated its effects on cell kinetics, Wnt/β-catenin, cyclin D1, and caspase-3. RESULTS NBS-242 inhibited the growth of A-431 cancer cells, being ~15-fold more potent than flurbiprofen and up to 5-fold more potent than NO-flurbiprofen with an aliphatic spacer, the half maximal inhibitory concentrations (IC50) for growth inhibition being 60 ± 4 μM, 320 ± 20 μM, and 880 ± 65 μM for NBS-242, NO-flurbiprofen, and flurbiprofen, respectively. This effect was associated with inhibition of proliferation, accumulation of cells in the G0/G1 phase of the cell cycle, and an increase in apoptotic cell population. NBS-242 cleaved β-catenin both in the cytoplasm and the nucleus of A-431 cells. NBS-242 activated caspase-3 whose activation was reflected in the cleavage of procaspase-3. To test the functional consequence of β-catenin cleavage, we determined the expression of cyclin D1, a Wnt-response gene. NBS-242 reduced cyclin D1 levels in a concentration dependent manner. CONCLUSION These findings establish a strong inhibitory effect of NBS-242 in A-431 human epidermoid carcinoma cells. NBS-242 modulates parameters that are important in determining cellular mass.
منابع مشابه
l DDDT-43771-flurbiprofen-benzylnitrate--nbs-242--inhibits-the-growth-of
Correspondence: Khosrow Kashfi Department of Physiology, Pharmacology, and Neuroscience, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY, USA 10031 Tel +1 212 650 6641 Fax +1 212 650 7692 Email [email protected] Background: The Wnt/β-catenin/T cell factor (TCF) signaling pathway is important in the development of nonmelanoma skin cancers (NMSCs). Nitr...
متن کاملAngiopoietin-like protein 8 (betatrophin) may inhibit hepatocellular carcinoma through suppressing of the Wnt signaling pathway
Objective(s): Hepatocellular carcinoma (HCC) is one of the leading fatal neoplasms and the most common primary liver malignancy worldwide. Peptide hormone ANGPTL8 (betatrophin) may act as an important regulator in HCC development through the Wnt/β-catenin pathway. We aimed to evaluate the effects of recombinant ANGPTL8 on Wnt/β-catenin signaling in human liver carcinom...
متن کاملThe protective effect of propofol on hydrogen peroxide-induced human esophageal carcinoma via blocking the Wnt/β-catenin signaling pathway
Objective(s): To analyze the potential influences of propofol on the oxidative stress of H2O2-induced human esophageal squamous cell carcinoma (ESCC) Eca109 cell through mediating the Wnt/β-catenin signaling pathway.Materials and Methods: Eca109 cells were classified into 5 groups: Control group, H2O2 group, Propofol + H2O2 group, Dkk1 (Dickkopf-1, Wnt/β-catenin pathway antagonist) + H2O2 group...
متن کاملThe Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy
Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt-signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseas...
متن کاملImmunohistochemical Evaluation of β-catenin Marker in Papillary Thyroid Cancer Clinicopathologic Behavior
Background & objective: papillary thyroid cancer is the most common cancer of thyroid accounting for 75%-85% of all thyroid malignancies. Recently, β-catenin has been determined to play a role in clinical course of human epithelial cancers. This study was designed to reveal the association of β-catenin marker and papillary thyroid carcinoma behavior.<b...
متن کامل