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Abstract
Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand-triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues.
Highlights
Ovarian cancer is the fourth-leading cause of death in women with gynecologic diseases in the United States
We compared the abilities of SC144 to induce apoptosis and cell death in human ovarian cancer cells (OVCAR-8 and Caov-3) with human normal epithelial cells
IL-6 and Stat3 are involved in cancer progression and drug resistance in a variety of human cancers including ovarian cancer
Summary
Prolonged use of paclitaxel and carboplatin in the standard treatment often induces drug resistance, causes ovarian cancer relapse, and eventually the death of patients [2]. In this context, there is an urgent need for breakthrough drugs with effective therapeutic impact on ovarian cancer. Gp130 is part of the receptor signaling complexes for at least 8 cytokines [interleukin (IL)-6, IL-11, IL-27, LIF, CNTF, OSM, CT-1, and CLC; ref. Ligand binding induces the association of gp130 with a cytokine-specific receptor-a chain, followed by the activation of downstream signaling cascades including JAK/STAT, RAS/ RAF/MAPK, and PI3K/AKT pathways [4]. As a ubiquitously expressed receptor, gp130 is involved in a Authors' Affiliations: 1Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California; and 2Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Universita della Calabria, Arcavacata di Rende, Italy
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