anti-angiogenic activity of a small molecule stat3 inhibitor lll12抗血管生成活性的小分子stat3抑制剂lll12.pdfVIP

Anti-Angiogenic Activity of a Small Molecule STAT3 Inhibitor LLL12 1 1 2 3 1 1 Hemant K. Bid , Duane Oswald , Chenglong Li , Cheryl A. London , Jiayuh Lin , Peter J. Houghton * 1 Center for Childhood Cancer, Nationwide Children’s Hospital, Columbus, Ohio, United States of America, 2 College of Pharmacy, The Ohio State University, Columbus, Ohio, United States of America, 3 College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, United States of America Abstract Background: Recent data indicate the Signal Transducer and Activator of Transcription 3 (STAT3) pathway is required for VEGF production and angiogenesis in various types of cancers. STAT3 inhibitors have been shown to reduce tumor microvessel density in tumors but a direct anti-angiogenic activity has not been described. Methodology/Principal Findings: We investigated the direct action of a small molecule inhibitor of STAT3 (LLL12) in human umbilical cord vascular endothelial cells (HUVECs) in vitro, in a Matrigel model for angiogenesis in vivo, and its antitumor activity in a xenograft model of osteosarcoma. LLL12 (100 nM) significantly inhibited VEGF-stimulated STAT3 phosphorylation in HUVECs, reduced their proliferation/migration and inhibited VEGF-induced tube formation. Morphologic analysis of LLL12 treated HUVECs demonstrated marked changes in actin/tubulin distribution and bundling. In scid mice, LLL12 reduced microvessel invasion into VEGF-infused Matrigel plugs by ,90% at a dose of 5 mg/kg daily. Following a period of tumor progression (2 weeks), LLL12 completely suppressed further growth of established OS-1 osteosarcoma xenografts. Pharmacodynamic studies showed robust phos