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) alpha, interferon (IFN) gamma and interleukin-2 (IL-2) on the mdr1 gene expression in four human colon carcinoma cell lines (Lo Vo, HT 115, SW 480, and LS 174T) at different times (8, 24, 48, and 72 h). We found no significant changes in mdr1 expression after 8 h and 24 h of cytokine treatment in all four lines. After 48 h and 72 h, however, a marked reduction of mdr1 expression in Lo Vo, HT 115, and SW 480 cells and an unaffected expression in LS 174T cells was observed. We examined whether the cytokine-mediated reduction of mdr1 expression correlates to the multidrug resistance (MDR) phenotype. In those cell lines showing a decreased mdr1 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 decreased mdr1 expression caused by prolonged cytokine pretreatment correlates with an enhanced cytotoxicity of drugs susceptible to MDR as an MDR-overcoming effect.

Decreased expression of P-glycoprotein in interleukin-1β and interleukin-6 treated rat hepatocytes

“…Moreover, it is possible that the cytochrome P450 and mdr gene families may have similarities in their regulation particularly as many similarities in substrates, inducers, and inhibitors are found between these families [37]. Furthermore, other pro-inflammatory cytokines, namely tumor necrosis factor and interferon, have been reported to downregulate both mdr1 [38,39] and cytochrome P450 gene transcription [28], supporting potential parallelism in their regulation. Interestingly, IL-6 mediated a significant suppression of PGP over the range of 1 -10 ng/ml (20 -200 Units/ml), bioactive concentrations comparable to those observed in patients with severe inflammatory states [40].…”

Enhancement of mdr1 gene expression by transforming growth factor-β1 in the new adriamycin-resistant human leukemia cell line ME-F2/ADM

“…The duct, P-glycoprotein (P-gp), which functions as an efflux pump preventing the intracellular accumulation of structurally unrecells (1 × 10 6 ) were incubated with the following cytokines at optimal concentration: IL-3 (100 U/ml), IL-4 (100 U/ml), IL-6 lated drugs. [1][2][3][4] The levels of mdr1 mRNA and P-gp have been reported to be regulated by cytokines 5,6 and various other (100 ng/ml), granulocyte colony-stimulating factor (100 U/ml), stem cell factor (100 ng/ml), erythropoietin (100 U/ml), interagents such as steroid hormone 7 and differentiating agents. 8 In the present study, we established adriamycin (ADM)-resistant feron-␥ (100 U/ml), leukemia inhibitory factor (1000 U/ml) and TGF-␤1 (10 U/ml) in 2 ml of medium for 24 h. TGF-␤1 sublines which expressed highly the mdr1 gene and P-gp, and demonstrated for the first time that this expression was increased markedly the P-gp expression on ME-F 2 /ADM100 and ME-F 2 /ADM200 cells, although none of the cytokines, increased by transforming growth factor (TGF)-␤1.…”

Interleukin-1 beta and tumor necrosis factor-alpha increase ABCG2 expression in MCF-7 breast carcinoma cell line and its mitoxantrone-resistant derivative, MCF-7/MX

“…These modulations appeared to happen at various levels of expression including transcriptional, posttranscriptional, translational, and/or post-translational levels [15][16][17][18][19][20][21][22][23][24]. So far the results of these studies are somewhat controversial and difficult to compare; the effects are highly dependent on the cytokine, the transporter and the cell type in which transporter regulation has been studied.…”