Improving fascin inhibitors to block tumor cell migration and metastasis.

Tumor metastasis is the major cause of mortality of cancer patients, being responsible for ∼90% of all cancer deaths. One of the key steps during tumor metastasis is tumor cell migration which requires actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are antenna-like filopodia. Fascin protein is the main actin-bundling protein in filopodia. Here we report the development of fascin-specific small-molecules that inhibit the interaction between fascin and actin. These inhibitors block the in vitro actin-binding and actin-bundling activities of fascin, tumor cell migration and tumor metastasis in mouse models. Mechanistically, these inhibitors likely occupy one of the actin-binding sites, reduce the binding of actin filaments, and thus lead to the inhibition of the bundling activity of fascin. At the cellular level, these inhibitors impair actin cytoskeletal reorganization. Our data indicate that target-specific anti-fascin agents will have great potential for treating metastatic tumors.

Effects of intraarticular (32)P colloid in the treatment of hemophilic synovitis of the knee: A short term clinical study.

BACKGROUND: Chronic synovitis is a consequence of recurrent intraarticular hemorrhage in patients with hemophilia. Eventually, synovitis leads to degeneration of the articular cartilage, with serious consequences that impact the quality-of-life in hemophiliacs. The aim of our study was to investigate the short term clinical effects of intraarticular injection of the radionuclide preparation(32)P colloid ((32)P-labelled colloidal chromic phosphate suspension) on recurrent intraarticular hemorrhages in patients with hemophilic synovitis of the knee. MATERIALS AND METHODS: Patients who met the inclusion criteria (n = 22) were enrolled in an open-label study between October 2011 and September 2012.(32)P colloid was injected into the knee joint and patients were followed up over 6 months after treatment. Hemorrhage frequency, visual analog scale pain score, hospital for special surgery knee score, knee circumference, upper knee circumference, knee diameter, and knee range of motion (ROM) were compared before and after treatment with intraarticular(32)P colloid injection. RESULTS: In 24 knees evaluated in 22 participating patients, there was a significant reduction in the number of hemorrhages after(32)P colloid treatment, along with significant pain relief. However, there were no statistically significant changes in the degree of joint swelling, degree of muscle atrophy and knee ROM between the pre and post treatment evaluations. CONCLUSION: The frequency of joint hemorrhage in patients with hemophilic knee synovitis can be significantly reduced and local symptoms can be improved in the short term by intraarticular injection of(32)P colloid.

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization.

One of the key steps during tumour metastasis is tumour cell migration and invasion, which require actin cytoskeletal reorganization. Among the critical actin cytoskeletal protrusion structures are the filopodia, which act like cell sensory organs to communicate with the extracellular microenvironment and participate in fundamental cell functions such as cell adhesion, spreading and migration in the three-dimensional environment. Fascin is the main actin-bundling protein in filopodia. Using high-throughput screening, here we identify and characterize small molecules that inhibit the actin-bundling activity of fascin. Focusing on one such inhibitor, we demonstrate that it specifically blocks filopodial formation, tumour cell migration and invasion in vitro, and metastasis in vivo. Hence, target-specific anti-fascin agents have a therapeutic potential for cancer treatment.