TUMOR-NECROSIS-FACTOR-ALPHA IS A POWERFUL APOPTOTIC INDUCER IN LYMPHOID LEUKEMIC-CELLS EXPRESSING THE P-170 GLYCOPROTEIN

Multidrug resistance (MDR) is a phenomenon by which tumor cells expose d to a single anti-proliferative agent acquire resistance to other str ucturally and functionally unrelated drugs. The classical form of MDR is caused by a plasma-membrane protein currently named P-glycoprotein or P-170 encoded by the human mdr-1 gene in its functional isoform. In vitro cell lines expressing P-170 usually also present phenotypic and functional alterations. In the present study we report that the cytot oxicity mediated by tumor necrosis factor alpha (TNF alpha) in MDR var iants of the human T-lymphoblastoid CEM cell line is associated with a poptosis (programmed cell death), Susceptibility of MDR cells to apopt osis was increased upon cycloheximide + TNF alpha sequential treatment , whereby the impairment of protein synthesis due to the former agent was followed by the effect of cytokine exposure. Massive apoptosis of P-170-positive cells, but not of controls, was also obtained by deplet ion of nutrients (i.e., serum starvation). In contrast, TNF-alpha exer ted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226 ) drug-sensitive/-resistant cell pairs. However, the MDR variant of my eloma S8226 was more sensitive to the cytostatic effect of TNf alpha t han the parental drug-sensitive cell line. These results suggest that tire presence of the MDR phenotype may be associated with increased hi stotype-dependent cell susceptibility to specific, protein-synthesis-i ndependent, apoptotic pathways. (C) 1996 Wiley-Liss, Inc.