肿瘤的多药耐药及新型耐药逆转剂的研究
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摘要
肿瘤的多药耐药(multidrug resistance, MDR)是在肿瘤病人接受化疗时常会发生的,经某一种药物诱发,同时对其他多种结构和作用机制完全不同的抗癌药物产生交叉耐药的一种现象。这主要是由于药物外排蛋白P-糖蛋白(P-gp)在肿瘤细胞中过表达导致的。针对P-gp靶点已经开发了很多抑制剂,但是由于诸多的副作用的存在,目前还有没有一个抑制剂能够成功上市。因此设计和开发新型的有选择性的高效低毒的抑制剂依然任重而道远。
小分子化合物抑制P-gp主要是通过配体受体的结合而产生作用。我们实验室的新型化合物1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride (phenoprolamine hydrochloride,1416)是P-gp经典抑制剂维拉帕米(verapamil, VER)的结构类似物,并且其钙拮抗的作用弱于VER。我们以VER为阳性对照,对1416的体内外逆转MDR活性进行了研究。MTT实验表明1416能够明显增强硫酸长春碱(vinblastin,VBL)在耐药细胞K562/ADM知KBV中的细胞毒性,而对相应的母本细胞没有影响。流式细胞术,激光共聚焦技术发现1416能增加细胞内P-gp的底物罗丹明123(Rh123)的含量,进一步验证了1416对MDR的调节。体内荷瘤裸鼠模型表明1416在体内对VBL抗肿瘤活性的增强。所以1416是很有应用前景的能够逆转MDR的小分子化合物。
表观遗传学是在不改变基因序列的前提下对基因表达的调节,并且该调节是可逆的。研究表明肿瘤的多药耐药表型的诱发与表观遗传学的调节有关,我们将白血病细胞株的母本型K562细胞经阿霉素诱导得到K562/ADM细胞,通过RT-PCR和流式细胞术检测了耐药诱导以后的K562/ADM的MDR1基因和P-gp的表达上调,并且MTT实验和Rh123的积累外排实验表明了K562/ADM对P-gp底物的外排增加,验证了MDR表型的成立。随后我们对耐药细胞的表观遗传改变进行了初步探索：发现DNA甲基化在基因组水平和MDR1基因的启动子部位都发生了下调,染色质结构更为松散,小RNA的表达谱也发生了改变,这些发现为肿瘤多药耐药的表观遗传学分子诊断和逆转策略提供了重要的信息。
随着非编码小RNA成为科学家们研究的热点,越来越多的关于microRNA对MDR1基因的表达调节被报道。我们运用先进的高通量测序(high-throughput sequencing)技术在全基因组(genome-wide)水平上比较了K562细胞和K562/ADM细胞的microRNA表达,结合计算机靶点预测,筛选了具有潜在调节MDR1表达的候选microRNAs,miR-381和miR-495。通过核转染进microRNA的类似物或者抑制剂,改变候选microRNAs的细胞内的水平,发现miR-381或者miR-495的类似物转染能够抑制MDR1/P-gp的表达并进而抑制其对底物的外排功能,证明了候选microRNAs对MDR1的负性调节功能,为逆转肿瘤多药耐药提供了新的思路和可能性。我们还发现了耐药细胞中位于14号染色体上一个microRNA簇全部发生了下调,提示这个染色体区域的不稳定可能与肿瘤多药耐药的形成有关。
Multidrug resistance (MDR) frequently develops in cancer patients exposed to chemotherapeutic agents and is usually accomplished by over-expression of P-glycoprotein (P-gp), a MDR1gene encoded protein. P-gp acts as a drug efflux pump to reduce the intracellular concentration of the drug(s). Inhibiting the transport function of P-gp is an effective way of reversing MDR, against this target, three generations of P-gp inhibitors has been developed but none of them has been successful on the market due to severe side effect. Therefore, it is necessary to develop some agents which can effectively reverse MDR with low or no pharmacology defects.
1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride (phenoprolamine hydrochloride,1416) is a new verapamil analogue with a higher IC50for blocking calcium channel currents than verapamil. We examined the inhibition effect of1416on P-gp both in vitro and in vivo.1416significantly enhanced cytotoxicity of vinblastine in P-gp overexpressed human multidrug-resistant K562/ADM and KBV cells, but had no such effect on the parent K562and KB cells. The MDR-modulating function of1416was further confirmed by increasing intracellular Rhodanmine123content in MDR cells. Human K562/ADM xenograft-nude mice model verified that1416potentiate the antitumor activity of vinblastine in vivo. RT-PCR and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by1416treatment. All these observations suggested that1416would be a promising agent for overcoming MDR in cancer chemotherapy.
Epigenetics is the study of epigenetic inheritance, a set of reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence (genotype). Many studies have shown that the MDR phenotype is associated with epigenetic regulation. We established a MDR cell line (K562/ADM) from human leukemia cell K562by stepwise increase adriamycine concentration in culture medium and then MDR phenotype (MDR1gene upregulation, P-gp overexpression and increased substrate efflux) was confirmed in K562/ADM as compared to parental K562cells. Thereafter, we investigated the epigenetic variation in K562/ADM cells: DNA methylation level was decreased in whole genome as well as in the promoter region of MDR1; Chromatin structure became more decompacting; Small RNA expression profiles were dysregulated. These findings may help us to discover epigenetic biomarkers for the molecular diagnosis of MDR and may constitute potentially novel targets for therapy.
Small non-coding RNAs have now become the hot spot in medical research and were reported to paly critical roles in gene regulation. Here we present evidence that microRNAs can regulate the expression of the MDR1gene. Using high-throughput sequencing and bioinformatics prediction, we identified and validated two candidate microRNAs, miR-381and miR-495, that were strongly down-regulated in MDR cell lines. Functional analysis indicated that restoring expression of candidate miRNAs in K562/ADM cells led to reduced expression of MDR1/P-gp and increased drug uptake by the cells. We also discovered a microRNA cluster on a potentially unstable chromosomal region which may have a close relationship to the development of multidrug resistance.
小分子化合物抑制P-gp主要是通过配体受体的结合而产生作用。我们实验室的新型化合物1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride (phenoprolamine hydrochloride,1416)是P-gp经典抑制剂维拉帕米(verapamil, VER)的结构类似物,并且其钙拮抗的作用弱于VER。我们以VER为阳性对照,对1416的体内外逆转MDR活性进行了研究。MTT实验表明1416能够明显增强硫酸长春碱(vinblastin,VBL)在耐药细胞K562/ADM知KBV中的细胞毒性,而对相应的母本细胞没有影响。流式细胞术,激光共聚焦技术发现1416能增加细胞内P-gp的底物罗丹明123(Rh123)的含量,进一步验证了1416对MDR的调节。体内荷瘤裸鼠模型表明1416在体内对VBL抗肿瘤活性的增强。所以1416是很有应用前景的能够逆转MDR的小分子化合物。
表观遗传学是在不改变基因序列的前提下对基因表达的调节,并且该调节是可逆的。研究表明肿瘤的多药耐药表型的诱发与表观遗传学的调节有关,我们将白血病细胞株的母本型K562细胞经阿霉素诱导得到K562/ADM细胞,通过RT-PCR和流式细胞术检测了耐药诱导以后的K562/ADM的MDR1基因和P-gp的表达上调,并且MTT实验和Rh123的积累外排实验表明了K562/ADM对P-gp底物的外排增加,验证了MDR表型的成立。随后我们对耐药细胞的表观遗传改变进行了初步探索：发现DNA甲基化在基因组水平和MDR1基因的启动子部位都发生了下调,染色质结构更为松散,小RNA的表达谱也发生了改变,这些发现为肿瘤多药耐药的表观遗传学分子诊断和逆转策略提供了重要的信息。
随着非编码小RNA成为科学家们研究的热点,越来越多的关于microRNA对MDR1基因的表达调节被报道。我们运用先进的高通量测序(high-throughput sequencing)技术在全基因组(genome-wide)水平上比较了K562细胞和K562/ADM细胞的microRNA表达,结合计算机靶点预测,筛选了具有潜在调节MDR1表达的候选microRNAs,miR-381和miR-495。通过核转染进microRNA的类似物或者抑制剂,改变候选microRNAs的细胞内的水平,发现miR-381或者miR-495的类似物转染能够抑制MDR1/P-gp的表达并进而抑制其对底物的外排功能,证明了候选microRNAs对MDR1的负性调节功能,为逆转肿瘤多药耐药提供了新的思路和可能性。我们还发现了耐药细胞中位于14号染色体上一个microRNA簇全部发生了下调,提示这个染色体区域的不稳定可能与肿瘤多药耐药的形成有关。
Multidrug resistance (MDR) frequently develops in cancer patients exposed to chemotherapeutic agents and is usually accomplished by over-expression of P-glycoprotein (P-gp), a MDR1gene encoded protein. P-gp acts as a drug efflux pump to reduce the intracellular concentration of the drug(s). Inhibiting the transport function of P-gp is an effective way of reversing MDR, against this target, three generations of P-gp inhibitors has been developed but none of them has been successful on the market due to severe side effect. Therefore, it is necessary to develop some agents which can effectively reverse MDR with low or no pharmacology defects.
1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride (phenoprolamine hydrochloride,1416) is a new verapamil analogue with a higher IC50for blocking calcium channel currents than verapamil. We examined the inhibition effect of1416on P-gp both in vitro and in vivo.1416significantly enhanced cytotoxicity of vinblastine in P-gp overexpressed human multidrug-resistant K562/ADM and KBV cells, but had no such effect on the parent K562and KB cells. The MDR-modulating function of1416was further confirmed by increasing intracellular Rhodanmine123content in MDR cells. Human K562/ADM xenograft-nude mice model verified that1416potentiate the antitumor activity of vinblastine in vivo. RT-PCR and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by1416treatment. All these observations suggested that1416would be a promising agent for overcoming MDR in cancer chemotherapy.
Epigenetics is the study of epigenetic inheritance, a set of reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence (genotype). Many studies have shown that the MDR phenotype is associated with epigenetic regulation. We established a MDR cell line (K562/ADM) from human leukemia cell K562by stepwise increase adriamycine concentration in culture medium and then MDR phenotype (MDR1gene upregulation, P-gp overexpression and increased substrate efflux) was confirmed in K562/ADM as compared to parental K562cells. Thereafter, we investigated the epigenetic variation in K562/ADM cells: DNA methylation level was decreased in whole genome as well as in the promoter region of MDR1; Chromatin structure became more decompacting; Small RNA expression profiles were dysregulated. These findings may help us to discover epigenetic biomarkers for the molecular diagnosis of MDR and may constitute potentially novel targets for therapy.
Small non-coding RNAs have now become the hot spot in medical research and were reported to paly critical roles in gene regulation. Here we present evidence that microRNAs can regulate the expression of the MDR1gene. Using high-throughput sequencing and bioinformatics prediction, we identified and validated two candidate microRNAs, miR-381and miR-495, that were strongly down-regulated in MDR cell lines. Functional analysis indicated that restoring expression of candidate miRNAs in K562/ADM cells led to reduced expression of MDR1/P-gp and increased drug uptake by the cells. We also discovered a microRNA cluster on a potentially unstable chromosomal region which may have a close relationship to the development of multidrug resistance.
引文
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