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Cellosaurus publication CLPUB00268

Publication number CLPUB00268
Authors Servidei T., Meco D., Morosetti R., Riccardi A., Di Francesco A.M., Riccardi R., Dominici C.
Title Cisplatin-resistant U87-MG/Pt glioblastoma cell line shows higher sensitivity to STI-571 compared to its parental cell line.
Citation Proc. Am. Assoc. Cancer Res. 45:3876-3876(2004)
Web pages https://cancerres.aacrjournals.org/content/64/7_Supplement/894.1
Abstract STI-571 (Gleevec, imatinib mesylate) is a kinase inhibitor that specifically targets the activated Abl oncoprotein and several membrane tyrosine kinase receptors, including PDGF-R. Both PDGF ligands and receptors are often overexpressed in gliomas, suggesting the existence of an autocrine stimulatory loop. It is known that PDGF-R signals mainly through PI3K/Akt and Ras/MAPK pathways. PI3K/Akt is a major cell survival pathway and constitutively active AKT2 has been demonstrated to confer cisplatin resistance. In a previous study, it has been shown that STI-571 inhibits the growth of the human glioblastoma cell line U87-MG in nude mice. In the present study we compared STI-571 antiproliferative activity on U87-MG and on its cisplatin-resistant variant U87-MG/Pt. U87-MG/Pt was selected in our laboratory by culturing cells in stepwise increasing concentrations of cisplatin (resistance index ~ 10) and displays a lower level of PDGF-R protein expression than U87-MG. Unexpectedly, U87-MG/Pt cells were significantly more sensitive to STI-571 than U87-MG (IC50 values = 18.6 +- 3.9 muM vs. 32. 6 +- 3.9 muM, respectively; P<0.0005, two-tailed Student's t test) in a 3-day growth inhibition assay. Similar results were obtained in clonogenic survival assays. Treatment of both cell lines with STI-571 resulted in a dose-and time-dependent down- regulation of PDGF-R protein expression, starting as soon as 8 hrs from cell exposure. Interestingly, STI-571 (25 muM) increased p21 protein expression in a p53-independent manner and inhibited phosphorylation of Akt, without affecting Akt level of expression, only in U87-MG/Pt cells. By contrast, no inhibition of Akt phosphorylation was observed in U87-MG, not even when higher concentrations of STI-571 (up to 50 muM) were used. We are currently evaluating whether the inhibition of Akt phosphorylation results in a higher induction of apoptosis in U87-MG/Pt. In both cell lines, STI-571 increased the level of phosphorylation of p42/44 MAPK, thus suggesting that STI-571 efficacy may be potentiated by co-treatment with MEK 1/2 inhibitors. These findings confirm that STI-571 is active in glioblastoma cell lines. More interestingly a cisplatin-resistant variant shows a clear-cut higher sensitivity to STI-571, and the data available so far suggest that Akt might be involved in the mechanisms underlying this phenomenon. We are presently studying whether cisplatin-resistant cell lines from other tumors are also more sensitive to STI-571, and the resultant clinical implications.
Cell lines CVCL_4V16; U87-MG/Pt