Poster abstracts

Poster number 67 submitted by Brian Hutzen

Novel STAT3 phosphorylation inhibitors exhibit potent growth suppressive activity in breast and pancreatic cancer

Brian Hutzen (Molecular, Cellular, and Developmental Biology Program. The Ohio State University), Li Lin, Sarah Ball (Department of Pediatrics. Nationwide Childrens Hospital), Mingxin Zuo, Stephanie Deangelis, Elizabeth Foust (Department of Pediatrics. Nationwide Childrens Hospital), Bulbul Pandit, Pui-Kai Li, James Fuchs, Chenglong Li (Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University), Michael A. Ihnat, Satyendra S. Shenoy (Department of Cell Biology, University of Oklahoma Health Sciences Center), Jiayuh Lin (Experimental Therapeutics Program, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University)

Abstract:
The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in growth, survival, drug-resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small molecule STAT3 inhibitors known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds share many of the bioactive properties of curcumin, however they also bind selectively to Janus Kinase 2 (JAK2), an upstream kinase that phosphorylates and activates STAT3, and the STAT3 SH2 domain, which serves crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, dimerization and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in breast and pancreatic cancer cell lines. In addition, we show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenograft experiments. Our findings highlight the potential of these new compounds and their efficacy in targeting cancers that exhibit constitutive STAT3 signaling.

Keywords: STAT3, cancer, curcumin