rhodanine and Carcinoma--Squamous-Cell

Aldose Reductase (AR), a polyol pathway enzyme that mediates diabetic complications is implicated in tumour development and progression. This study was undertaken to determine whether gedunin, a neem limonoid prevents the hallmarks of cancer by inhibiting AR and the associated downstream PI3K/Akt/mTOR/ERK/NF-κB signalling axis in the SCC131 oral cancer cell line.. The expression of AR and key molecules involved in cell proliferation, apoptosis, autophagy, invasion and angiogenesis was analysed by qRT-PCR, and immunoblotting. ROS generation and cell cycle were analysed by FACS. Alamar blue assay and scratch assay were used to evaluate cell proliferation and migration in the endothelial cell line Eahy926.. Gedunin and the AR inhibitor epalrestat inhibited AR expression and ROS generation. Cell cycle arrest at G1/S was associated with cell death by autophagy with subsequent switch over to apoptosis. Furthermore, hypoxia-induced cell migration was inhibited in Eahy926 cells with downregulation of pro-invasive and proangiogenic proteins in SCC131 as well as Eahy926 cells. Co-inactivation of Akt and ERK was coupled with abrogation of IKK/NF-κB signaling. However, the combination of gedunin and epalrestat was more effective than single agents.. Inhibition of AR-mediated ROS signalling may be a key mechanism by which gedunin and epalrestat exert their anticancer effects. Our results provide compelling evidence that the combination of gedunin and epalrestat modulates expression of key oncogenic signalling kinases and transcription factors primarily by influencing phosphorylation and subcellular localisation. AR inhibitors such as gedunin and epalrestat are novel candidate agents for cancer prevention and therapy.

Topics: Aldehyde Reductase; Azadirachta; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Endothelial Cells; Enzyme Inhibitors; Humans; Limonins; Mouth Neoplasms; NF-kappa B; Oncogenes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Rhodanine; Signal Transduction; Thiazolidines

Phosphatase of regenerating liver-3 (PRL-3) is a molecule associated with metastasis in a diverse of cancers, which, however, remains largely unknown in esophageal squamous cell carcinoma (ESCC). We examined both the clinical significance of PRL-3 expression and its biological roles, and assessed possibilities as a therapeutic target in ESCC. PRL-3 expression was found in 78% (69 of 88) of the primary ESCC on immunohistochemistry; it was the strong independent predictor for lymph node metastasis (LNM) on a multivariate logistic regression model (p = 0.0014, relative risk =15.20). Additionally, gene amplification was found in 3 (7.9%) of the 38 primary tumors with PRL-3 overexpression by fluorescence in situ hybridization, but in none of the 19 tumors without it. PRL-3 small interfering RNA robustly repressed cell proliferation, anchorage-independent colony formation and invasion and augmented 5-FU-induced apoptosis in all the tested ESCC cell lines with PRL-3 overexpression, irrespective of its gene amplification status. PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) also suppressed such metastatic properties in the cell lines with PRL-3 overexpression, but not with its low expression. Inverse effects were observed by PRL-3 forced expression. Collectively, PRL-3 overexpression is a frequent event associated with LNM and plays a causative role in promoting cancer progression. Moreover, the expression status may be a landmark to select patients with benefit from PRL-3-targeted therapy. Thus, PRL-3 could be a convergent therapeutic target against ESCC with LNM.

Topics: Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Esophageal Neoplasms; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphatic Metastasis; Middle Aged; Multivariate Analysis; Neoplasm Proteins; Polymerase Chain Reaction; Protein Tyrosine Phosphatases; Rhodanine; RNA, Small Interfering