Temozolomide-induced modification of the CXC chemokine network in experimental gliomas.

CXCL chemokines display important roles in glioblastoma (GBM) biology, including cell proliferation, death and migration features. While temozolomide (TMZ) represents the standard chemotherapeutic used to treat GBM patients, its role in CXCL networking in GBMs remains unexplored. The effects of short-term and long-term in vitro treatment with temozolomide on CXCL chemokine expression were characterized in human malignant glioma cell lines. U373 and T98G astroglioma and Hs683 oligodendroglioma cells were cultured for months in the presence of increasing concentrations of TMZ (up to 1 mM), and their whole genome profiles were analyzed along with a complete mapping of all CXCL chemokines and their respective receptor mRNAs. The study was extended to an additional established cell line and four primocultures. The in vitro results were compared with a clinical series of 156 human gliomas and 23 normal brain tissue samples. The expression and secretion of CXCL2, CXCL3 and CXCL8 following different TMZ treatments were determined in Hs683, U373 and T98G glioma cells. The long-term TMZ-treated astroglioma cells, but not the Hs683 oligodendroglioma cells, developed in vivo a certain level of resistance to TMZ, which correlated with the up- regulation of CXCL2, CXCL3 and CXCL8 expression in the U373 and T98G astroglioma cells. The transient down-regulation of CXCL2 in Hs683 glioma cells using siRNA markedly impaired their proliferation rate. In conclusion, TMZ affects the expression and secretion of CXCL2 (and, to a lesser extent, CXCL3 and CXCL8) in glioma cells, and CXCL2 directly impacts glioma cell biology.