The inhibition of glutamine synthetase sensitizes human sarcoma cells to l-asparaginase

Tardito, S. , Uggeri, J., Bozzetti, C., Bianchi, M.G., Rotoli, B.M., Franchi-Gazzola, R., Gazzola, G.C., Gatti, R. and Bussolati, O. (2007) The inhibition of glutamine synthetase sensitizes human sarcoma cells to l-asparaginase. Cancer Chemotherapy and Pharmacology, 60(5), pp. 751-758. (doi: 10.1007/s00280-007-0421-z) (PMID:17256128)

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Abstract

Purpose: To evaluate the activity of the antitumor enzyme l-asparaginase (ASNase) on tumor cells of mesenchymal origin and the contribution of glutamine synthetase (GS) to the adaptation to the metabolic stress caused by the anti-tumor enzyme. Methods: We studied the effects of ASNase in six human sarcoma cell lines: HT1080 (fibrosarcoma); RD (rhabdomyosarcoma); SW872 (liposarcoma); HOS, SAOS-2, and U2OS (osteosarcoma) in the absence or in the presence of the GS inhibitor methionine l-sulfoximine (MSO). Results: HT1080 and SW872 cells were highly sensitive to ASNase-dependent cytotoxicity. In contrast, RD, SAOS-2, HOS, and U2OS cells exhibited only a partial growth suppression upon treatment with the anti-tumor enzyme. In these cell lines ASNase treatment was associated with increased levels of GS. When ASNase was used together with MSO, the proliferation of the poorly sensitive cell lines was completely blocked and a significant decrease in the IC50 for ASNase was observed. Moreover, when ASNase treatment was carried on in the presence of MSO, HOS and U2OS osteosarcoma cells exhibited a marked cytotoxicity, with increased apoptosis. Conclusions: In human sarcoma cells (1) GS markedly contributes to the metabolic adaptation of tumor cells to ASNase and (2) the inhibition of GS activity enhances the antiproliferative and cytotoxic effects of ASNase. The two-step interference with glutamine metabolism, obtained through the combined treatment with ASNase and MSO, may provide a novel therapeutic approach that should be further investigated in human tumors of mesenchymal origin.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio
Authors: Tardito, S., Uggeri, J., Bozzetti, C., Bianchi, M.G., Rotoli, B.M., Franchi-Gazzola, R., Gazzola, G.C., Gatti, R., and Bussolati, O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Chemotherapy and Pharmacology
Publisher:Springer
ISSN:0344-5704
ISSN (Online):1432-0843
Published Online:26 January 2007

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