LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

被引：85

作者：

Fuh, B. ^{[1
]}

Sobo, M. ^{[2
]}

Cen, L. ^{[2
]}

Josiah, D. ^{[3
]}

Hutzen, B. ^{[2
]}

Cisek, K. ^{[4
]}

Bhasin, D. ^{[5
]}

Regan, N. ^{[5
]}

Lin, L. ^{[2
]}

Chan, C. ^{[2
]}

Caldas, H. ^{[3
]}

DeAngelis, S. ^{[2
]}

Li, C. ^{[4
,5
]}

Li, P-K ^{[5
]}

Lin, J. ^{[2
]}

机构：

[1] E Carolina Univ, Dept Pediat, BSOM, Greenville, NC 27834 USA

[2] Ohio State Univ, Dept Pediat, Nationwide Childrens Hosp, Res Inst,Coll Med, Columbus, OH 43205 USA

[3] Wake Forest Univ Hlth Sci, Dept Neurosurg, Brain Tumor Ctr Excellence, Winston Salem, NC 27157 USA

[4] Ohio State Univ, Biophys Grad Program, Columbus, OH 43210 USA

[5] Ohio State Univ, Div Med Chem & Pharmacol, Coll Pharm, Columbus, OH 43210 USA

来源：

BRITISH JOURNAL OF CANCER | 2009年 / 100卷 / 01期

关键词：

STAT3; apoptosis; glioblastoma; LLL-3; BREAST-CANCER CELLS; CONSTITUTIVELY-ACTIVATED STAT3; SMALL-MOLECULE INHIBITOR; MALIGNANT GLIOMA-CELLS; TYROSINE PHOSPHORYLATION; NUCLEAR TRANSLOCATION; SIGNAL TRANSDUCERS; ANTITUMOR-ACTIVITY; IN-VIVO; APOPTOSIS;

D O I：

10.1038/sj.bjc.6604793

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study, we investigated the inhibitory effects of a small molecule compound known as LLL-3, which is a structural analogue of the earlier reported STAT3 inhibitor, STA-21, on the cell viability of human glioblastoma cells, U87, U373, and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87, U373, and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines as evidenced by increased poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavages. Furthermore, the U87 glioblastoma tumour-bearing mice treated with LLL-3 exhibited prolonged survival relative to vehicle-treated mice (28.5 vs 16 days) and had smaller intracranial tumours and no evidence of contralateral invasion. These results suggest that LLL-3 may be a potential therapeutic agent in the treatment of glioblastoma with constitutive STAT3 activation.

引用

页码：106 / 112

页数：7