Influence of cytokines onmdr1 expression in human colon carcinoma cell lines: Increased cytoxicity of MDR relevant drugs

Abstract

We investigated the effects of tumor necrosis factor (TNF) α, interferon (IFN) ψ and interleukin-2 (IL-2) on themdr1 gene expression in four human colon carcinoma cell lines (LoVo, HT 115, SW 480, and LS 174T) at different times (8. 24, 48, and 72h). We found no significant changes inmdr1 expression after 8h and 24h of cytokine treatment in all four lines. After 48h and 72h, however, a marked reduction ofmdr1 expression in LoVo, HT 115, and SW 480 cells and an unaffected expression in LS 174T cells was observed. We examined whether the cytokine-mediated reduction ofmdr1 expression correlates to the multidrug resistance (MDR) phenotype. In those cell lines showing a decreasedmdr1 expression after a long-term cytokine pretreatment we found a dramatic enhancement of cytotoxicity of the MDR relevant drugs vincristine and doxorubicin, whereas LS 174T cells remained resistant. By contrast, the simultaneous application of cytokines and cytostatics caused no additive or synergistic effects. We conclude that in certain colon carcinoma cell lines a decreasedmdr1 expression caused by prolonged cytokine pretreatment correlates with an enhanced cytotoxicity of drugs susceptible to MDR as an MDR-overcoming effect.