INDUCTION OF MULTIDRUG RESISTANCE IN HUMAN-CELLS BY TRANSIENT EXPOSURE TO DIFFERENT CHEMOTHERAPEUTIC DRUGS
INDUCTION OF MULTIDRUG RESISTANCE IN HUMAN-CELLS BY TRANSIENT EXPOSURE TO DIFFERENT CHEMOTHERAPEUTIC DRUGS
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DOI：
10.1093/jnci/85.8.632
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发表时间：
1993-04-21
期刊：
影响因子：
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通讯作者：
RONINSON, IB
中科院分区：
文献类型：
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作者：
CHAUDHARY, PM;RONINSON, IB
背景：MDR1(多药耐药)基因(又称PGY1)编码跨膜外排泵P-糖蛋白(Pgp)，在组织培养中对Pgp转运的细胞毒药物具有耐药性。化疗后肿瘤中MDR1表达的增加通常归因于Pgp转运的药物对原有的多药耐药细胞的选择。组织培养中MDR1的表达可以通过几种类型的应激诱导处理来增加，包括激活蛋白激酶C(PKC)的药物。然而，以前的研究未能证明短期接触任何化疗药物可以诱导药物敏感的人类细胞中常驻MDR1基因的表达。目的：本研究旨在利用高灵敏度的分析方法来确定短暂接触化疗药物是否会对人细胞中MDR1的表达产生影响，并评估PKC抑制剂是否会影响这一效应。方法：分析不同细胞毒药物处理后，在有或无PKC抑制剂存在的情况下，白血病或实体瘤细胞系MDR1基因的表达。用流式细胞仪检测Pgp的功能和表达，用聚合酶链式反应检测mdr1信使RNA(Mdr1)的表达。结果：化疗药物(包括不被Pgp转运的药物)可诱导大多数受试细胞亚群中Pgp和mdr1mRNA的表达。这种诱导与显微镜下可检测到的细胞损伤一起被观察到。药物诱导的MDR1表达和相关的长春花碱耐药性增加两到三倍在K562白血病细胞中持续了至少几周。药物介导的MDR1诱导可被对PKC有效的非特异性蛋白激酶抑制剂阻断，但不能被对PKC无效的蛋白激酶抑制剂阻断。结论：无论药物是否通过Pgp转运，细胞毒药物对细胞的损伤均可诱导MDR1mRNA和Pgp的表达。这种诱导可以被蛋白激酶抑制剂阻止。提示：细胞损伤诱导mdr1表达可能是治疗后人类肿瘤mdr1表达增加的原因。蛋白激酶抑制剂可能有助于预防癌症化疗过程中出现的多药耐药。
Background: The MDR1 (multidrug resistance) gene (also known as PGY1), which encodes the transmembrane efflux pump P-glycoprotein (Pgp), confers resistance to Pgp-transported cytotoxic drugs in tissue culture. The increase in MDR1 expression in tumors after chemotherapy is usually attributed to selection of pre-existing multidrug-resistant cells by Pgp-transported drugs. MDR1 expression in tissue culture can be increased by several types of stress-inducing treatment, including agents that activate protein kinase C (PKC). Previous studies, however, failed to demonstrate that short-term exposure to any chemotherapeutic drug can induce the expression of the resident MDR1 gene in drug-sensitive human cells. Purpose: This study was designed to utilize highly sensitive assays to determine if transient exposure to chemotherapeutic drugs would have an effect on MDR1 expression in human cells and to assess if PKC inhibitors would influence such an effect. Methods: We analyzed the MDR1 gene expression in several human cell lines derived from leukemias or solid tumors, after treatment with different cytotoxic drugs, in the presence or absence of PKC inhibitors. Pgp function and expression were studied by flow cytometric assays, and MDR1 messenger RNA (mRNA) was assayed by polymerase chain reaction. Results: Transient exposure to chemotherapeutic drugs, including agents that are not transported by Pgp, induced Pgp and MDR1 mRNA expression in subpopulations of treated cells in most of the tested cell lines. This induction was observed along with microscopically detectable cell damage. The drug-induced MDR1 expression and the associated twofold to threefold increase in resistance to vinblastine were sustained in K562 leukemia cells for at least several weeks after the removal of the drug. Drug-mediated MDR1 induction was blocked by nonspecific protein kinase inhibitors that are active against PKC, but not by a protein kinase inhibitor ineffective against PKC. Conclusions: Expression of the human MDR1 mRNA and Pgp can be induced in response to cellular damage by cytotoxic drugs regardless of whether the drugs are transported by Pgp. This induction can be prevented by protein kinase inhibitors. Implications: Induction of MDR1 expression in response to cellular damage may account for increased MDR1 expression in treated human tumors. Protein kinase inhibitors may be useful in preventing the emergence of multidrug resistance during cancer chemotherapy.