期刊
MOLECULAR CANCER THERAPEUTICS
卷 13, 期 10, 页码 2303-2314出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-13-1005
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资金
- USHHS Ruth L. Kirschstein Institutional National Research Service Award (UCLA Tumor Biology Training Grant) [T32 CA009056]
- American Cancer Society Research Scholars Grant [RSG-12-083-01-TBG]
- NIH [P01 CA163200, CA-16042, AI-28697]
- Hirshberg Foundation for Pancreatic Cancer Research
- JCCC, UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/beta-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with beta-catenin and inhibit CBP function as a coactivator of Wnt/beta-catenin-mediated transcription. Given its ability to inhibit Wnt/beta-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G1 cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/beta-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer. (C) 2014 AACR.
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