The small molecule curcumin analog FLLL32 induces apoptosis in melanoma cells via STAT3 inhibition and retains the cellular response to cytokines with anti-tumor activity

Molecular Cancer

Research

Gregory S Young¹  Jiayuh Lin²  Don M Benson³  Matthew A Bill³  Courtney Bakan³  Jennifer Yui³  Gregory B Lesinski⁴  William E Carson⁴  Stacey L Fossey⁵  James R Fuchs⁶  Chenglong Li⁶  Eric B Schwartz⁶  Pui-Kai Li⁶  Dale G Hoyt⁶  Dalia Abdelhamid⁶ 

[1] Center for Biostatistics, The Ohio State University, 2012 Kenny Rd, 43221, Columbus, OH, USA;Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, 700 Children's Dr, 43205, Columbus, OH, USA;Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, 400 W. 12th Ave, 43210, Columbus, OH, USA;Department of Surgery, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, 410 W. 10th Ave, 43210, Columbus, OH, USA;Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd, 43210, Columbus, OH, USA;Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 496 W. 12th Ave, 43210, Columbus, OH, USA;

关键词: Natural Killer Cell;    Curcumin;    Melanoma Cell;    STAT3 Pathway;    Human Melanoma Cell Line;   

DOI  :  10.1186/1476-4598-9-165

 received in 2010-05-17, accepted in 2010-06-25,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundWe characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells.ResultsFLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO).ConclusionsThese data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.

【 授权许可】

Unknown   
© Bill et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.