Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-VEGFR2-002 as a novel anti-angiogenesis agent.

Angiogenesis is an essential process in tumor growth, invasion and metastasis. VEGF receptor 2 (VEGFR2) inhibitors targeting tumor angiogenic pathway have been widely used in the clinical cancer treatment. However, most of currently used VEGFR2 kinase inhibitors are multi-target inhibitors which might result in target-associated side effects and therefore limited clinical toleration. Highly selective VEGFR inhibitors are still highly demanded from both basic research and clinical application point of view. Here we report the discovery and characterization of a novel VEGFR2 inhibitor (CHMFL-VEGFR2-002), which exhibited high selectivity among structurally closed kinases including PDGFRs, FGFRs, CSF1R, etc. CHMFL-VEGFR2-002 displayed potent inhibitory activity against VEGFR2 kinase in the biochemical assay (IC50 = 66 nmol/L) and VEGFR2 autophosphorylation in cells (EC50s ∼100 nmol/L) as well as potent anti-proliferation effect against VEGFR2 transformed BaF3 cells (GI50 = 150 nmol/L). In addition, CHMFL-VEGFR2-002 also displayed good anti-angiogenesis efficacy in vitro and exhibited good in vivo PK (pharmacokinetics) profile with bioavailability over 49% and anti-angiogenesis efficacy in both zebrafish and mouse models without apparent toxicity. These results suggest that CHMFL-VEGFR2-002 might be a useful research tool for dissecting new functions of VEGFR2 kinase as well as a potential anti-angiogenetic agent for the cancer therapy.

Propofol inhibits growth and invasion of pancreatic cancer cells through regulation of the miR-21/Slug signaling pathway.

AIM: Propofol, an intravenous anesthetic agent, has been found to inhibit invasion and growth of pancreatic cancer cells in vitro. However, the mechanisms underlying these tumor-promoting phenotypes are not known. The microRNA miR-21 has been reported to be overexpressed in pancreatic cancer, and overexpression of miR-21 confers a poor prognosis to patients with pancreatic cancer. Further studies have identified the E-cadherin transcription repressor Slug as a direct target of miR-21. In this study, we assessed whether propofol inhibits invasion and growth of pancreatic cancer cells by regulation of miR-21/Slug signaling. METHODS: PANC-1 pancreatic cancer cells were treated with different concentrations of propofol (1, 5 or 10 µg/mL) for 48 h, or 10 µg/mL propofol for 12, 24 or 36 h. Cell survival and apoptosis were detected by LDH release, BrdU cell proliferation and flow cytometry assays; cell invasion and migration were detected by transwell migration assays. miR-21 mimic (miR-21), Slug cDNA, PUMA siRNA and E-cadherin siRNA transfection was used to assess the signaling pathway in which propofol functions in PANC-1 cells. Protein and mRNA expression, respectively, were detected by western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. RESULTS: Propofol inhibited growth and invasion, and induced apoptosis, in a dose- and time-dependent manner in PANC-1 cells. Propofol inhibited miR-21 levels and decreased Slug expression, resulting in an increase in Slug-dependent PUMA and E-cadherin expression in PANC-1 cells. miR-21 overexpression or PUMA or E-cadherin silencing impaired propofol-induced cell apoptosis, growth and invasion. Re-expression of Slug attenuated the expression of PUMA and E-cadherin that was induced by propofol treatment, the reduction of growth and invasion, and the increase in cell apoptosis. CONCLUSIONS: Propofol can effectively inhibit invasion and induce apoptosis of PANC-1 cells by regulating miR-21/Slug signals.