Development of resistance to glutathione depletion-induced cell death in CC531 colon carcinoma cells: Association with increased expression of Bcl-2

The glutathione (GSH) level of CC531 rat colorectal cancer cells is readily decreased by exposure to buthionine sulfoximine (BSO), an inhibitor of GSH synthesis; at 25 mu M BSO, these cells died in a non-apoptotic fashion. By continuous exposure of CC531 cells to increasing concentrations of BSO,we obtained a BSO-resistant cell line (CCBR25) that was 50 times more resistan t to BSO than the parental cell line. Whereas the GSH content of CCBR25 and CC531 cells was similar, the former contained a much higher level of the B cl-2 protein. After stable transfection of CC531 cells with the human bcl-2 gene, the resulting Bcl-2-overexpressing cell line appeared ro be 9 times more resistant to BSO than the parental cell line. These findings suggest t hat the Bcl-2 protein offers resistance against the cytotoxic effect of sev ere GSH depletion. (C) 2000 Elsevier Science Inc.