A Novel Imidazopyridine Derivative Exhibits Anticancer Activity in Breast Cancer by Inhibiting Wnt/ß­catenin Signaling.

BACKGROUND: Breast cancer exhibits poor prognosis and high relapse rates following chemotherapy therapeutics. Thus, this study aims to develop effective novel agents regulating the core molecular pathway of breast cancer such as Wnt/ß-catenin signaling. METHODS: The present study screened a novel inhibitor, called "C188", using MTT assay. The molecular formula of C188 is C21H15FN4O3 and the molecular weight is 390. Flow cytometry and Western blotting were employed to assess cell cycle arrest after treatment with C188. Wound-healing and transwell assays were applied to measure the cell migration and invasion viability. The regulatory effects of C188 on Wnt/ß­catenin signaling and localization of ß­catenin in the nucleus were investigated by Western blotting and immunofluorescence. RESULTS: We found that C188 significantly suppressed proliferation and growth in a dose- and time-dependent manner in breast cancer cells, but not in normal breast cells. The inhibitory effect was caused by cell cycle arrest at the G1-phase which is induced by C188 treatment. Additionally, C188 dramatically inhibited cell migration of breast cancer cells in a dose-dependent manner. The migration inhibition was attributed to the suppression of Wnt/ß­catenin signaling and localization of ß­catenin in the nucleus mediated by regulating phosphorylation of ß­catenin and its subsequent stability. Furthermore, the target genes, including Axin 2, c-JUN, and c-Myc, were downregulated due to the decrease of ß­catenin in the nucleus after exposure to C188. CONCLUSION: C188 treatment resulted in the downregulation of cyclin D which led to cell cycle arrest at the G1 phase, and the inhibition of cell migration, indicating that C188 may be an effective novel therapeutic candidate as a potential treatment for human breast cancer.

A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells.

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.

Diversity-Oriented Synthesis of Imidazo-Dipyridines with Anticancer Activity via the Groebke-Blackburn-Bienaymé and TBAB-Mediated Cascade Reaction in One Pot.

A facile and metal-free one-pot protocol for the synthesis of fused imidazopyridine scaffolds has been developed. This novel protocol combines the Groebke-Blackburn-Bienaymé reaction (GBBR) with a sequential TBAB-mediated cyclization cascade. Biological evaluation demonstrated that compound 6a inhibits human prostate cancer cell DU-145 proliferation with an IC50 of 1.6 µM. The molecular mechanism study indicates that 6a significantly suppresses the oncogenic Erk kinase phosphorylation at 3 µM.

Prediction of the risk of coronary arterial lesions in Kawasaki disease by serum 25-hydroxyvitamin D3.

UNLABELLED: Kawasaki disease (KD) is associated with the development of coronary arterial lesions (CALs) in children. We aimed to test the hypothesis that circulating 25-hydroxyvitamin D3 [25-(OH)D3] could be identified as a clinical parameter for predicting CALs secondary to KD in children. We enrolled 35 children with KD in the acute phase and measured serum 25-(OH)D3 levels in all of them, then followed up by echocardiography for CALs. Additionally, serum 25-(OH)D3 levels were obtained in 23 febrile children with respiratory tract infections and 30 healthy children. Of the 35 KD children, nine had CALs according to echocardiography and 26 did not (NCALs). Serum 25-(OH)D3 levels were not significantly different between NCALs and healthy children (49.2 ± 23.8 versus 44.1 ± 30.2 ng/ml; P = 0.49). Serum 25-(OH)D3 levels were significantly higher in children with CALs than those without CALs (83.9 ± 26.3 versus 49.2 ± 23.8 ng/ml; P = 0.001). The cutoff value of 65 ng/ml to predict subsequent CALs had a specificity of 0.73, sensitivity of 0.78, and diagnostic accuracy of 0.74. CONCLUSION: Serum 25-(OH)D3 levels were elevated dur-ing the acute phase in KD children who had subsequent CALs. Serum 25-(OH)D3 levels in the acute phase of KD may be used to predict subsequent CALs.