Oxidative upregulation of Bcl-2 in healthy lymphocytes.
In many cell systems, pharmacological glutathione (GSH) depletion with the GSH neosynthesis inhibitor buthionine sulfoximine (BSO) leads to cell death and highly sensitizes tumor cells to apoptosis induced by standard chemotherapeutic agents. However, some tumor cells upregulate Bcl-2 in response to BSO, thus surviving the treatment and failing to be chemosensitized. Cell lines of monocytic and lymphocytic origins respond to BSO treatment in an opposite way, lymphocytes being chemosensitized and unable to transactivate Bcl-2. In this article we investigate the response to BSO of lymphocytes freshly isolated from peripheral blood of healthy donors. After ensuring that standard separation procedures do not alter per se lymphocytes redox equilibrium nor Bcl-2 levels in the first 24 h of culture, we show that BSO treatment promotes the upregulation of Bcl-2, with a mechanism involving the increased radical production consequent to GSH depletion. Thus, BSO treatment may increase the differential cytocidal effect of cytotoxic drugs in tumor versus normal lymphocytes.
Cristofanon
Silvia
S
Fondation Recherche sur le Cancer et les Maladies du Sang, Laboratoire de Biologie Moleculaire, et Cellulaire du Cancer (LBMCC), Hopital Kirchberg, 9 rue Edward Steichen, L-2540 Luxembourg.
Nuccitelli
Silvia
S
D'Alessio
Maria
M
Radogna
Flavia
F
De Nicola
Milena
M
Bergamaschi
Antonio
A
Cerella
Claudia
C
Magrini
Andrea
A
Diederich
Marc
M
Ghibelli
Lina
L
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D019253:Proto-Oncogene Proteins c-bcl-2; D019328:Buthionine Sulfoximine