Abstract
MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.
Highlights
The development of resistance of tumor cells to multiple anticancer drugs is one of the critical problems for successful chemotherapy (Beck, 1990; Roninson, 1992; Ling, 1993; Ling, 1997)
Since FM3A/M and P388/M multidrug resistance (MDR) cells showed a constitutive heat shock factor (HSF) DNA-binding activity under the non-stressed condition (Kim et al, 1997) and quercetin has been shown to interfere with the formation of the complex between the heat shock elements (HSE) and HSF, and to downregulate the level of HSF1 (Hosokawa et al, 1992; Nagai et al, 1995)
When the MDR cells were treated with the indicated concentrations of quercetin, which did not inhibit cell growth, HSF DNA-binding activity was inhibited in a dose-dependent manner in both MDR cells (Figure 1A)
Summary
The development of resistance of tumor cells to multiple anticancer drugs is one of the critical problems for successful chemotherapy (Beck, 1990; Roninson, 1992; Ling, 1993; Ling, 1997) This resistance can be due to different factors, including failure of drug uptake or activation, alteration in the level of target enzymes such as dihydrofolate reductase and topoisomerase II, activation of enzymatic systems involved in repair of damage to DNA, enhanced expression of detoxifying enzymes such as glutathione S-transferases, and increased anticancer drug efflux (Vendrik et al, 1992) This last mechanism of resistance appears to be a major one, as suggested by numerous in vitro and clinical studies, and it confers multidrug resistance (MDR) and is usually linked to the overexpression of P-glycoprotein (P-gp), a plasma transmembrane glycoprotein encoded by MDR1 genes and thought to act as an ATP-dependent drug efflux pump (Chen et al, 1990; Pastan and Gottesman, 1991; Gottesman and Pastan, 1993). It has been shown that heat shock or sodium arsenite increases the activity of MDR1 promoter via HSEs, and Raf-dependent signaling pathway controls the transcription of MDR1 gene via a mechanism involving the modulation of heat shock factors (HSF) activity (Miyazak et al, 1992; Kioka et al, 1992; Kim et al, 1996)
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