LBH589 Inhibits Glioblastoma Growth and Angiogenesis Through Suppression of HIF-1 alpha Expression
作者
Yao, ZG;Li, WH;Hua, F;Cheng, HX;Zhao, MQ;Sun, XC;Qin, YJ;Li, JM
作者单位
[Yao, Zhi-Gang; Cheng, Hong-Xia; Zhao, Miao-Qing; Sun, Xi-Chao; Qin, Ye-Jun; Li, Jia-Mei] Shandong Univ, Shandong Prov Hosp, Dept Pathol, 324 Jingwu Rd, Jinan 250021, Shandong, Peoples R China.;-;[Li, Wen-Huan] Shandong Univ, Shandong Prov Hosp, Dept Chemotherapy, Jinan, Shandong, Peoples R China.;-;[Hua, Fang] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing, Peoples R China.;-;[Hua, Fang] Peking Union Med Coll, Beijing, Peoples R China.
摘要
Glioblastoma (GBM) is an angiogenic malignancy with a highly unfavorable prognosis. Angiogenesis in GBM represents an adaptation to a hypoxic microenvironment and is correlated with tumor growth, invasion, clinical recurrence, and lethality. LBH589 (also called panobinostat) is a histone deacetylase (HDAC) inhibitor with potent antitumor activity. In the current study, we investigated the mechanism and effects of LBH589 on GBM growth and hypoxia-induced angiogenesis in vitro and in vivo. To determine the antitumor and angiogenesis activity and mechanism of LBH589, we used cell proliferations in vitro and GBM xenografts in vivo. To clarify mechanisms of LBH589 on angiogenesis, HDAC assay, RT-PCR, Western blot, and co-immunoprecipitation assays were performed. We found LBH589 displayed significant antitumor effects on GBM as demonstrated by inhibited cell proliferation, slower tumor growth, and decreased microvessel density of subcutaneous xenografts. These actions of LBH589 resulted from the disruption of heat shock protein 90/HDAC6 complex, increased HIF-1 alpha instability and degradation, and decreased VEGF expression. Our results indicate the potential antiangiogenic activity of LBH589 in human GBM and provide some preclinical data to warrant further exploration of HDAC inhibitors for the treatment of advanced glioma. Moreover, our study supports the role of HDAC inhibitors as a therapeutic strategy to target tumor angiogenesis.
关键词
HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; HISTONE DEACETYLASE INHIBITOR; PHASE-II; PANOBINOSTAT; ACETYLATION; TEMOZOLOMIDE; PROGRESSION; MECHANISMS; MULTIFORME; SURVIVAL
基本信息
