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目的 探讨全反式维甲酸 (ATRA)导致瘤细胞多药耐药 (MDR)的可能机制。方法 以ATRA和IL 4分别处理肝母细胞瘤系HepG2 细胞 ,观察瘤细胞增殖活性、甲胎蛋白分泌及细胞周期分布等生长特性改变 ;通过流式细胞仪检查p5 3、bcl 2及P 糖蛋白 (P gp)表达 ,用原位杂交观察c jun及c mycmRNA表达 ;以四氮甲基唑蓝 (MTT)生物活性检查药物敏感性。结果 ATRA及IL 4均能诱导HepG2 细胞分化 :ATRA处理可导致HepG2 细胞对多种化疗药物耐受 (耐药倍数 1.6～ 3.1倍 ) ,IL 4处理则增加瘤细胞对化疗药物的敏感性 (逆转倍数 4～ 17倍 )。ATRA处理使瘤细胞P gp表达从 (5 4.2±8.6 ) %增加到 (98.5± 1.4) % ,P <0 .0 1;IL 4降低P gp表达 (2 5 .4± 7.3) % ,P <0 .0 1。IL 4和ATRA处理均能降低瘤细胞c jun及c mycmRNA表达。IL 4处理增加瘤细胞p5 3表达 ,降低bcl 2表达 ,而ATRA处理对二者的表达无影响。结论 IL 4和ATRA诱导HepG2 细胞分化过程中 ,药物敏感性变化与分化程度、原癌基因c jun、c myc表达无关 ;ATRA所致的P gp表达增加可能为MDR的直接作用因素 ;p5 3(或bcl 2 )可以参与调节分化过程中药物敏感性变化。
Objective To investigate the possible mechanism of multidrug resistance (MDR) induced by all-trans retinoic acid (ATRA) in tumor cells. METHODS: Hepatoblastoma HepG2 cells were treated with ATRA and IL-4 to observe the growth characteristics of tumor cell proliferation, alpha-fetoprotein secretion, and cell cycle distribution. The p53, bcl-2 and P glycoproteins were examined by flow cytometry. (P gp) expression, in situ hybridization was used to observe the expression of c jun and c myc mRNA, and the bioactivity of tetramethyl thiazolyl blue (MTT) was used to examine the drug sensitivity. Results Both ATRA and IL 4 could induce differentiation of HepG2 cells: ATRA treatment could cause HepG2 cells to tolerate multiple chemotherapeutic agents (1.6- to 3.1-fold multiple drug resistance). IL 4 treatment increased the sensitivity of tumor cells to chemotherapy drugs (reversal Multiples 4 to 17 times). ATRA treatment increased the expression of P gp in the tumor cells from (5 4.2±8.6)% to (98.5±1.4) %, P <0.01; IL 4 decreased P gp expression (2 5 .4± 7.3) %, P < 0 .0 1. Both IL 4 and ATRA treatment reduced the expression of c jun and c myc mRNA in tumor cells. IL-4 treatment increased the expression of p53 in tumor cells and decreased the expression of bcl-2, but ATRA treatment had no effect on the expression of both. Conclusion During the differentiation of HepG2 cells induced by IL 4 and ATRA, the changes of drug sensitivity are not related to the degree of differentiation and the expression of proto-oncogenes c jun and c myc; the increase of P gp expression induced by ATRA may be a direct factor of MDR; p5 3 ( Or bcl 2) may be involved in regulating drug sensitivity changes during differentiation.