Dobesilate inhibits the activation of signal transducer and activator of transcription 3, and the expression of cyclin D1 and bcl-XL in glioma cells.
OBJECTIVE
Because fibroblast growth factor (FGF) causes the intracellular accumulation of activated signal transducer and activator of transcription 3 (STAT3), we assessed whether dobesilate, a synthetic FGF inhibitor that has been reported to show antiproliferative and proapoptotic activities in glioma cell cultures, down-regulates the STAT3 signaling pathway in growing cultures of those cells. Because STAT3 signaling pathway plays pleiotropic roles in tumor proliferation, maintenance of STAT3 in its inactive state may prevent glioma growth and spreading.


METHODS
Rat glioma C6 cells were treated with dobesilate and cultures were evaluated immunocytochemically for STAT3 activation and enhancement of the expression rate of cyclin D1 and bcl-XL.


RESULTS
Dobesilate abrogates the accumulation of activated STAT3 in glioma cells. The decrease in the intracellular levels of activated STAT3 by the dobesilate treatment runs parallel with a significant attenuation of cyclin D1 and bcl-XL expression.


CONCLUSIONS
Treatment with inhibitors of FGF down-regulates the STAT3 signaling pathway. These alterations could be correlated to the already observed inhibition of cell proliferation and promotion of apoptosis in glioma cell cultures by dobesilate. The reported results may open new avenues for developing new treatments against these tumors.
Cuevas
P
P
Departamento de Investigación, Hospital Universitario Ramón y Cajal, Universidad de Alcalá de Henares, Madrid, Spain. pedro.cuevas@hrc.es
Díaz-González
D
D
Sánchez
I
I
Lozano
R M
RM
Giménez-Gallego
G
G
Dujovny
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002123:Calcium Dobesilate / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006131:Growth Inhibitors / Q000494:pharmacology; D006490:Hemostatics / Q000494:pharmacology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D051020:bcl-X Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
C494813:Bcl2l1 protein, rat; D006131:Growth Inhibitors; D006490:Hemostatics; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D051020:bcl-X Protein; D019938:Cyclin D1; D002123:Calcium Dobesilate; D005346:Fibroblast Growth Factors