Effects of tumor necrosis factor on sensitive and multidrug resistant human leukemia and myeloma cell lines

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Acquired multidrug resistance (MDR) in cancer cells often involves increased expression of cell surface glycoproteins like GP-170.
• Tumor necrosis factor (TNF) is a cytokine with known cytotoxic effects on cancer cells.

Purpose of the Study:

• To investigate the sensitivity of multidrug-resistant (MDR) human tumor cell lines to human recombinant tumor necrosis factor (rTNF).
• To explore the mechanisms underlying rTNF's effects on MDR cells, focusing on TNF receptor expression and intracellular responses.

Main Methods:

• Clonogenic assays were used to assess cell sensitivity to rTNF.
• Radioreceptor assays determined TNF receptor numbers.
• Intracellular ATP content was measured.
• RNA dot-blot analysis evaluated GP-170 expression.
• Doxorubicin accumulation was assessed in resistant cells.

Main Results:

• MDR cell lines (CEM/V, 8226/D) were significantly more sensitive to rTNF than their drug-sensitive parental lines (CEM, 8226).
• TNF receptor numbers were similar between resistant and sensitive cell lines.
• rTNF decreased intracellular ATP in CEM/V cells but not CEM cells; no differential ATP effect was seen in the 8226 lines.
• GP-170 RNA expression increased in 8226/D cells but was not altered by rTNF exposure.
• rTNF did not affect doxorubicin accumulation in 8226/D cells.

Conclusions:

• The enhanced sensitivity of MDR cells to rTNF is not mediated by increased TNF receptor expression.
• rTNF's effects are downstream of receptor binding and do not involve direct inhibition of GP-170 synthesis or efflux pump function.
• The mechanism of rTNF action in MDR cells involves post-binding cellular events, potentially affecting ATP metabolism in some resistant lines.