Tumor necrosis factor α is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170 glycoprotein

Abstract

Multidrug resistance (MDR) is a phenomenon by which tumor cells exposed to a single anti-proliferative agent acquire resistance to other structurally 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-I 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 cytotoxicity mediated by tumor necrosis factor α(TNFα) in MDR variants of the human T- lymphoblastoid CEM cell line is associated with apoptosis (programmed cell death). Susceptibility of MDR cells to apoptosis was increased upon cycloheximide + TNFα 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 depletion of nutrients (i.e., serum starvation). In contrast, TNF-α exerted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226) drug-sensitive/-resistant cell pairs. However, the MDR variant of myeloma S8226 was more sensitive to the cytostatic effect of TNFα than the parental drug-sensitive cell line. These results suggest that the presence of the MDR phenotype may be associated with increased histotype-dependent cell susceptibility to specific, protein- synthesis-independent, apoptotic pathways.