氧化砷对MR2细胞耐药转运分子作用的研究

目的探讨三氧化二砷(As2O3)对肿瘤耐药转运分子的作用。方法以耐全反式维甲酸(ATRA)早幼粒白血病细胞株MR2为研究对象,以非耐药早幼粒白血病细胞株NB4为对照组,用免疫组化法观察P糖蛋白(Pgp)、多药耐药相关蛋白(MRP)和肺耐药相关蛋白(LRP)的表达。结果MR2细胞Pgp表达为30%～40%,NB4细胞为10%～20%,二者差异有极显著性(P<0.001)。MR2细胞MRP表达为56.9±3.4～21.2±1.1,NB4细胞为20.6±5.3～16.7±1.2,二者差异有极显著性(P<0.001)。0.5～2.0μmol/LAs2O3能显著降低MR2细胞中Pgp和MRP的表达,而对LRP的表达无影响。MR2细胞中Pgp和MRP表达的降低与As2O3作用浓度和作用时间呈负相关。结论MR2细胞耐药转运分子Pgp和MRP表达的下调,可能是As2O3克服耐药的敏感靶分子,而LRP则否。ATRA可能是Pgp和MRP的转运底物

Effect of arsenic trioxide on drug transporting molecules in acute promyelocytic leukemia cell line

OBJECTIVE: To study the effect of arsenic trioxide (As2O3) on expression of drug transporting molecules in APL MR2 cell line. METHODS: MR2 resistant to all-trans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 was used in this in vitro study. Expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) was detected by immunocytochemical assay. RESULTS: The expression of Pgp was significantly higher in MR2 (30%-40%) than in NB4 (10%-20%) (P < 0.001), and that of MRP was also higher in MR2 (56.9 +/- 3.4-21.2 +/- 1.1) than in NB4 (20.6 +/- 5.3-16.7 +/- 1.2) (P < 0.001). As2O3 at concentrations ranging from 0.5 approximately 2.0 micromol/L could significantly decrease the expression of Pgp and MRP, but not that of LRP. The decrease in the expression of Pgp and MRP in MR2 cell line was negatively correlated with the dose and duration of action of As2O3. CONCLUSION: Pgp and MRP, but not LRP, may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.