期刊
ONCOGENE
卷 25, 期 16, 页码 2304-2317出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209267
关键词
peroxisome proliferator-activated receptor gamma; paclitaxel; anaplastic thyroid carcinoma; RS5444; p21(WAF1/CIP1); combinatorial therapy; thiazolidinedione
资金
- NCI NIH HHS [CA100560, P30CA15083] Funding Source: Medline
Peroxisome proliferator-activated receptor gamma (PPARc) agonists demonstrate antitumor activity likely through transactivating genes that regulate cell proliferation, apoptosis, and differentiation. The PAX8/PPARc fusion oncogene, which is common in human follicular thyroid carcinomas appears to act via dominant negative suppression of wild-type PPARc, suggesting that it may be a tumor suppressor gene in thyroid cells. We have identified a novel high-affinity PPARc agonist (RS5444) that is dependent upon PPARc for its biological activity. This is the first report of this molecule and its antitumor activity. In vitro, the IC50 for growth inhibition is similar to 0.8 nM while anaplastic thyroid carcinoma (ATC) tumor growth was inhibited three-to fourfold in nude mice. siRNA against PPARc and a pharmacological antagonist demonstrated that functional PPARc was required for growth inhibitory activity of RS5444. RS5444 upregulated the cell cycle kinase inhibitor, p21(WAF1/CIP1). Silencing p21(WAF1CIP1) rendered cells insensitive to RS5444. RS5444 plus paclitaxel demonstrated additive antiproliferative activity in cell culture and minimal ATC tumor growth in vivo. RS5444 did not induce apoptosis but combined with paclitaxel, doubled the apoptotic index compared to that of paclitaxel. Our data indicate that functional PPARc is a molecular target for therapy in ATC. We demonstrated that RS5444, a thiazolidinedione (Tzd) derivative, alone or in combination with paclitaxel, may provide therapeutic benefit to patients diagnosed with ATC.
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