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Role of gamma-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis.
Anticancer Drugs. 2002 Mar; 13(3):281-91.AD

Abstract

Glutathione (GSH) is involved in many cellular functions, including cell growth and differentiation. GSH also plays an important role in the protection of cells against oxidative damage and hence in determining the sensitivity of cells to the cytotoxicity of anticancer agents. Because of this, induction of GSH depletion has been proposed as a good strategy for sensitizing tumor cells to antitumor agents. The aim of the present work is to study the effect of buthionine sulfoximine (BSO, a specific cellular GSH-depleting agent) in two rat tumor cell lines derived from the same rhabdomyosarcoma tumor model, the moderately differentiated and low metastatic F21 cell line, and the poorly differentiated and high metastatic S4MH cell line, to investigate the influence of the degree of differentiation in the induction of GSH depletion-based therapy. We observed that, whereas in the S4MH cell line BSO induced a dose-dependent inhibition of both cell growth in vitro and tumorigenic potential in vivo, in F21 cells the administration of moderate doses of BSO enhanced tumor growth and only at high doses was there a slight reduction of their tumorigenic potential. These effects were in consonance with the fact that the activity of gamma-glutamyltranspeptidase (gamma-GT) present in the F21 cells was 4 times higher than in the S4MH cells. Indeed, inhibition of gamma-GT activity by acivicin not only abrogated the BSO-induced increase of GSH content and of cell growth, but also the combination of acivicin + BSO significantly decreased intracellular GSH levels and cell proliferation, and induced F21 cells to apoptosis. These studies suggest that, as occurs in the rhabdomyosarcoma tumor model, gamma-GT levels and the degree of differentiation of tumor cells might influence the response of tumor cells to inducers of GSH depletion, and should be taken into account in therapies based on GSH metabolism.

Authors+Show Affiliations

Department of Cell Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Vizcaya, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11984072

Citation

Castro, Begoña, et al. "Role of Gamma-glutamyltranspeptidase On the Response of Poorly and Moderately Differentiated Rhabdomyosarcoma Cell Lines to Buthionine Sulfoximine-induced Inhibition of Glutathione Synthesis." Anti-cancer Drugs, vol. 13, no. 3, 2002, pp. 281-91.
Castro B, Alonso-Varona A, del Olmo M, et al. Role of gamma-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis. Anticancer Drugs. 2002;13(3):281-91.
Castro, B., Alonso-Varona, A., del Olmo, M., Bilbao, P., & Palomares, T. (2002). Role of gamma-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis. Anti-cancer Drugs, 13(3), 281-91.
Castro B, et al. Role of Gamma-glutamyltranspeptidase On the Response of Poorly and Moderately Differentiated Rhabdomyosarcoma Cell Lines to Buthionine Sulfoximine-induced Inhibition of Glutathione Synthesis. Anticancer Drugs. 2002;13(3):281-91. PubMed PMID: 11984072.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of gamma-glutamyltranspeptidase on the response of poorly and moderately differentiated rhabdomyosarcoma cell lines to buthionine sulfoximine-induced inhibition of glutathione synthesis. AU - Castro,Begoña, AU - Alonso-Varona,Ana, AU - del Olmo,Maite, AU - Bilbao,Pedro, AU - Palomares,Teodoro, PY - 2002/5/2/pubmed PY - 2002/9/20/medline PY - 2002/5/2/entrez SP - 281 EP - 91 JF - Anti-cancer drugs JO - Anticancer Drugs VL - 13 IS - 3 N2 - Glutathione (GSH) is involved in many cellular functions, including cell growth and differentiation. GSH also plays an important role in the protection of cells against oxidative damage and hence in determining the sensitivity of cells to the cytotoxicity of anticancer agents. Because of this, induction of GSH depletion has been proposed as a good strategy for sensitizing tumor cells to antitumor agents. The aim of the present work is to study the effect of buthionine sulfoximine (BSO, a specific cellular GSH-depleting agent) in two rat tumor cell lines derived from the same rhabdomyosarcoma tumor model, the moderately differentiated and low metastatic F21 cell line, and the poorly differentiated and high metastatic S4MH cell line, to investigate the influence of the degree of differentiation in the induction of GSH depletion-based therapy. We observed that, whereas in the S4MH cell line BSO induced a dose-dependent inhibition of both cell growth in vitro and tumorigenic potential in vivo, in F21 cells the administration of moderate doses of BSO enhanced tumor growth and only at high doses was there a slight reduction of their tumorigenic potential. These effects were in consonance with the fact that the activity of gamma-glutamyltranspeptidase (gamma-GT) present in the F21 cells was 4 times higher than in the S4MH cells. Indeed, inhibition of gamma-GT activity by acivicin not only abrogated the BSO-induced increase of GSH content and of cell growth, but also the combination of acivicin + BSO significantly decreased intracellular GSH levels and cell proliferation, and induced F21 cells to apoptosis. These studies suggest that, as occurs in the rhabdomyosarcoma tumor model, gamma-GT levels and the degree of differentiation of tumor cells might influence the response of tumor cells to inducers of GSH depletion, and should be taken into account in therapies based on GSH metabolism. SN - 0959-4973 UR - https://www.unboundmedicine.com/medline/citation/11984072/Role_of_gamma_glutamyltranspeptidase_on_the_response_of_poorly_and_moderately_differentiated_rhabdomyosarcoma_cell_lines_to_buthionine_sulfoximine_induced_inhibition_of_glutathione_synthesis_ L2 - http://dx.doi.org/10.1097/00001813-200203000-00010 DB - PRIME DP - Unbound Medicine ER -