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Tumor necrosis factor alpha is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170
W Malorni1, G Rainaldi, E Tritarelli
1Department of Ultrastructures, Istituto Superiore di Sanità, Rome, Italy.
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-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 cytotoxicity mediated by tumor necrosis factor alpha (TNF alpha) 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 + 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 depletion of nutrients (i.e., serum starvation). In contrast, TNF-alpha 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 TNF alpha 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.
Insights
Multidrug resistance (MDR) in cancer cells can increase susceptibility to apoptosis, programmed cell death. This occurs via specific pathways, particularly when protein synthesis is impaired or nutrients are depleted, affecting P-glycoprotein-positive cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Multidrug resistance (MDR) is a critical challenge in cancer therapy, where tumor cells become resistant to multiple anti-cancer drugs.
- The P-glycoprotein (P-170) efflux pump, encoded by the mdr-1 gene, is a key mediator of classical MDR.
- MDR cells often exhibit altered phenotypes and functions, impacting their response to cytotoxic agents.
Purpose of the Study:
- To investigate the relationship between multidrug resistance (MDR) and apoptosis (programmed cell death) induced by tumor necrosis factor alpha (TNF-alpha).
- To explore how MDR affects the sensitivity of cancer cells to TNF-alpha-mediated apoptosis under different conditions, including impaired protein synthesis and nutrient deprivation.
Main Methods:
- Utilized MDR variants of human T-lymphoblastoid CEM cell lines, alongside epithelial (MCF-7) and myeloma (S8226) drug-sensitive/resistant cell pairs.
- Administered sequential treatment with cycloheximide and TNF-alpha to assess apoptosis induction.
- Induced apoptosis through nutrient depletion (serum starvation) in P-glycoprotein-positive cells.
Main Results:
- Cytotoxicity of TNF-alpha in MDR CEM cell variants was linked to apoptosis.
- Sequential treatment with cycloheximide and TNF-alpha enhanced apoptosis in MDR cells by impairing protein synthesis.
- Serum starvation induced massive apoptosis in P-glycoprotein-positive cells, but not controls.
- TNF-alpha induced similar apoptosis in drug-sensitive and resistant epithelial and myeloma cell pairs, though the MDR myeloma variant showed increased sensitivity to TNF-alpha's cytostatic effects.
Conclusions:
- The MDR phenotype may confer increased susceptibility to specific, protein-synthesis-independent apoptotic pathways.
- Histotype-dependent differences in apoptotic response are suggested in MDR cancer cells.
- These findings offer insights into novel therapeutic strategies targeting MDR tumors via apoptosis induction.