芹菜素通过抑制Nrf2-ARE通路逆转肝癌耐药的研究
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摘要
肝细胞癌（hepatocellular carcinoma, HCC,简称肝癌）是常见恶性肿瘤之一。化疗是肝癌治疗的重要手段。然而，化疗耐药的存在，特别是多药耐药现象（multidrug resistance, MDR）是导致肝癌化疗失败的主要原因。
核转录因子红细胞系相关因子-2（nuclear factor erythroid-2-related factor2,Nrf2）是细胞内重要的抗氧化应激调控因子，调控一系列细胞保护基因的表达。目前，Nrf2已成为逆转肿瘤耐药的重要靶点之一。因此，开发以Nrf2为靶点的小分子抑制剂与抗肿瘤药联用，增强肿瘤细胞对化疗药的敏感性，从而改善化疗药的治疗效果，为肿瘤协同治疗提供新途径。
已发现一些黄酮类化合物是有效的Nrf2抑制剂，如表没食子儿茶素3-没食子酸酯（epigallocatechin3-gallate, EGCG）、鸦胆子苦醇和木犀草素等。那么，芹菜素（4',5,7-trihydroxyflavone, apigenin, APG）作为一种与EGCG、鸦胆子苦醇和木犀草素等Nrf2抑制剂结构类似且同样具有抗癌潜力的天然黄酮类物质，是否也能有效抑制Nrf2通路，进而增敏肿瘤细胞逆转耐药呢？目前尚未见相关报道。为此，本研究将研究APG对肝癌耐药细胞的逆转作用，并从Nrf2通路探讨其逆转耐药的作用机制。
第一部分Nrf2与肝癌阿霉素耐药相关性的研究
目的：探讨肝癌中Nrf2的表达与阿霉素（doxorubicin,ADM）化疗耐药的关系。
方法：免疫组化法检测Nrf2、醛酮还原酶1B10（aldo-keto reductase1B10,AKR1B10）、多药耐药相关蛋白5（multidrug resistance-associated protein5, MRP5）在肝癌组织中的表达，分析Nrf2表达与AKR1B10、MRP5表达及与肝癌临床病理学特征之间的关系，免疫蛋白印迹法检测比较Nrf2在人肝癌亲本细胞株BEL-7402细胞和ADM选择性诱导的多药耐药细胞株BEL-7402/ADM细胞中的表达差异，通过siRNA干扰Nrf2表达后，MTT法检测细胞对ADM敏感性的变化。
结果：Nrf2、AKR1B10和MRP5在肝癌组织中表达水平明显高于癌周正常组织（P＜0.01；P＜0.01；P＜0.01），肝癌组织中AKR1B10和MRP5表达水平均与Nrf2表达水平呈显著正相关（P=0.009；P=0.016）。在肝癌中，Nrf2的表达与肿瘤分化程度（P=0.017）、TNM分期（P=0.028）、肝硬化病史（P=0.017），早期复发（P=0.016）密切相关。Nrf2在肝癌耐药细胞株BEL-7402/ADM较敏感细胞株BEL-7402中蛋白表达显著增加，且干扰Nrf2基因表达后，肝癌耐药细胞株BEL-7402/ADM对ADM的敏感性显著增强。
结论：本研究表明肝癌中Nrf2的高表达可能与ADM耐药相关。
第二部分芹菜素通过抑制PI3K/Akt/Nrf2通路逆转BEL-7402/ADM耐药
目的：Nrf2是细胞内重要的抗氧化应激调控因子，调控一系列细胞保护基因的表达。目前，Nrf2已成为逆转肿瘤耐药的重要靶点之一。在本实验中，我们将研究APG是否可以通过抑制Nrf2通路进而逆转BEL-7402/ADM细胞耐药。
方法：MTT实验检测APG对BEL-7402/ADM细胞耐药性的逆转情况。荧光显微镜和流式细胞仪检测APG对细胞内ADM浓度的影响。实时定量PCR和免疫蛋白印迹法分析APG对Nrf2通路的抑制作用。
结果：在本研究中，我们发现无毒剂量的APG可明显增强BEL-7402/ADM对抗癌药的敏感性，增加细胞内ADM蓄积。机制上，APG通过抑制PI3K/Akt信号通路，进而下调Nrf2mRNA和蛋白水平，并导致Nrf2下游基因HO-1、AKR1B10和MRP5表达减少，最终逆转细胞耐药。
结论：结果表明APG可通过下调PI3K/Akt/Nrf2信号通路，进而增强人肝癌耐药细胞BEL-7402/ADM对ADM的敏感性，逆转肿瘤耐药。
第三部分芹菜素联合阿霉素对人肝癌裸鼠皮下移植瘤的抑制作用
目的：探讨APG联合ADM对人肝癌裸鼠皮下移植瘤的抑制作用及其相关机制。
方法：建立BEL-7402裸鼠皮下移植瘤动物模型，32只BEL-7402细胞株移植成功的裸鼠随机分为四组：对照组、APG组（50mg/kg）、ADM组（3mg/kg）和联合用药组（APG50mg/kg+ADM3mg/kg），每组8只。上述药物每3d腹腔注射l次，共7次，观察各组药物对肿瘤的抑制作用。给药结束后处死裸鼠，切取移植瘤组织。免疫组化法检测Ki-67蛋白表达评价肿瘤细胞增殖。TUNEL染色评价肿瘤细胞凋亡情况。免疫蛋白印迹法检测肿瘤组织Nrf2蛋白的表达。
结果：与单药组相比，联合应用APG及ADM显著抑制肿瘤生长，诱导肿瘤细胞凋亡，抑制肿瘤细胞增殖。此外，联合用药还能下调肿瘤组织Nrf2蛋白的表达。
结论：本研究表明与APG或ADM单药组相比，联合用药组能更有效地抑制肝癌移植瘤生长，其机制可能与抑制肿瘤增殖活性，诱导肿瘤细胞凋亡和下调Nrf2表达有关。
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers.Chemotherapy is an important therapeutic strategy for HCC. Unfortunately, cancercells often develop chemoresistance, which presents a major obstacle contributing tothe failure of cancer therapy in HCC.
Nuclear factor erythroid-2-related factor2(Nrf2) is a redox-sensitivetranscription factor regulating expression of a number of cytoprotective genes.Recently, Nrf2is now viewed as a pharmacological target to overcomechemoresistance. Therefore, identification of small molecules inhibitors that potentlyinhibit the Nrf2-dependent response is desirable, and such compounds may be used asan adjuvant sensitizer to combat chemoresistance.
Several flavonoid compounds have been reported to be Nrf2inhibitor that canreverse drug resistance effectively, such as epigallocatechin3-gallate (EGCG),luteolin, brusatol. Similar to luteolin, brusatol, and EGCG, apigenin (APG) is anatural compound with anticancer potential. So APG structurally related to themwhether sensitizing cancer cells to anticancer drugs through antagonizing the Nrf2signaling pathway is not clear. We aim to study the effect of APG on reversing drugresistance in HCC cells, as well as to explore the molecular mechanism through theNrf2pathway.
PartⅠ Study of the correlation between Nrf2anddoxorubicin–resistance in hepatocellar carcinoma cells
Objects: To explore the correlation of doxorubicin-resistance with Nrf2expression inHCC.
Methods: The expression of Nrf2, aldo-keto reductase1B10(AKR1B10), multidrugresistance-associated protein5(MRP5) protein in HCC were analyzed byimmunostaining. And the relationship of Nrf2expression in these tissues withclinicopathologic characteristics and correlation of AKR1B10, MRP5expression with Nrf2expression in HCC were analyzed. Using Western blot, expressions of Nrf2in BEL-7402 cells and doxorubicin resistant BEL-7402(BEL-7402/ADM) cells were compared. Inaddition, using Nrf2siRNA was created to inhibit Nrf2expression in BEL-7402/ADM cells,and cell viabilities in response to ADM treatment were measured by MTT analysis.
Results: The expression of Nrf2, AKR1B10, and MRP5in HCC were higher than that inthe corresponding normal tissue (P＜0.01; P＜0.01; P＜0.01). The Nrf2protein level waspositively correlated with AKR1B10/MRP5protein in the HCC tissues (P=0.009; P=0.016),as assessed by Spearman's rank correlation coefficient test. Additionally, there was asignificant correlations between Nrf2expression and tumor degree of differentiation(P=0.017), and TNM stage (P=0.028). Patients with liver cirrhosis and early recurrence hadhigher Nrf2expression (P=0.017; P=0.016). The Nrf2protein level in BEL-7402/ADMcells was higher than that in BEL-7402cells. And suppression of Nrf2expression sensitizedBEL-7402/ADM cells to ADM.
Conlusion: These results suggest that the high expression level of Nrf2is probablycorrelated with doxorubicin-resistance in HCC.
PartⅡ Reversal of apigenin on chemoresistance inBEL-7402/ADM cells via inhibiting PI3K/Akt/Nrf2pathway
Objects: Nrf2is a redox-sensitive transcription factor regulating expression of anumber of cytoprotective genes. Recently, Nrf2has emerged as an importantcontributor to chemoresistance in cancer therapy. Here, we investigated whether APGcould reverse drug resistance in BEL-7402/ADM cells via inhibiting Nrf2pathway.
Methods: Reverse of drug resistance was assayed by MTT analysis. IntracellularADM concentration was measured by Fluorometric and FCM analyses. Inhibition ofNrf2signaling pathway by APG was detected through real-time quantitative PCR andwestern blot analysis.
Results: In the present study, we found that non-toxic dose of APG significantlysensitizes BEL-7402/ADM cells to anticancer drugs and increases intracellularconcentration of ADM. Mechanistically, APG dramatically reduced Nrf2expressionat both the mRNA and protein levels through down-regulation of PI3K/Akt pathway,leading to a reduction of Nrf2-downstream genes HO-1, AKR1B10, and MRP5.
Conlusion: These results clearly demonstrate that APG can be used as an effectiveadjuvant sensitizer to prevent chemoresistance by down-regulating PI3K/Akt/Nrf2signaling pathway.
PartⅢ Synergisyic inhibitory effects by the combination ofapigenin and doxorubicin on human hepatocellar carcinomaxenografts in nude mice
Objects: In this study, we investigated the inhibitory effect of APG and ADM onhepatocellar carcinoma in vivo experiments using human hepatocellar carcinoma celllines, and we aimed to elucidate the possible molecular mechanism of their anticancereffect.
Methods: The animal model of BEL-7402transplantation tumor in nude mice wasconstructed.32nude mice were randomly assigned into four groups and treated i.p.with vehicle, ADM (3mg/kg), APG (50mg/kg), or in combination every three daysfor a total of seven times. The inhibitory effects of the drugs in each group wereobserved. The mice were sacrificed and their tumors were excised for further analysis,Tumor cell proliferation was analyzed by Ki-67immunostaining. Apoptosis wasdetermined by TUNEL assay. Nrf2protein levels were measured by Western blot.
Results: In vivo, combination treatment with APG and ADM resulted in enhancedtumor growth inhibition, apoptosis induction, inhibition of tumor cell proliferationand inhibition of Nrf2expression in tumor tissues.
Conlusion: These results suggest that the combination of APG and ADM would bemore efficacious for the treatment of HCC than either treatment alone. And inhibitionof Ki-67expression, induction of tumor cell apoptosis and down-regulation of Nrf2expression might be one of its possible mechanisms.
核转录因子红细胞系相关因子-2（nuclear factor erythroid-2-related factor2,Nrf2）是细胞内重要的抗氧化应激调控因子，调控一系列细胞保护基因的表达。目前，Nrf2已成为逆转肿瘤耐药的重要靶点之一。因此，开发以Nrf2为靶点的小分子抑制剂与抗肿瘤药联用，增强肿瘤细胞对化疗药的敏感性，从而改善化疗药的治疗效果，为肿瘤协同治疗提供新途径。
已发现一些黄酮类化合物是有效的Nrf2抑制剂，如表没食子儿茶素3-没食子酸酯（epigallocatechin3-gallate, EGCG）、鸦胆子苦醇和木犀草素等。那么，芹菜素（4',5,7-trihydroxyflavone, apigenin, APG）作为一种与EGCG、鸦胆子苦醇和木犀草素等Nrf2抑制剂结构类似且同样具有抗癌潜力的天然黄酮类物质，是否也能有效抑制Nrf2通路，进而增敏肿瘤细胞逆转耐药呢？目前尚未见相关报道。为此，本研究将研究APG对肝癌耐药细胞的逆转作用，并从Nrf2通路探讨其逆转耐药的作用机制。
第一部分Nrf2与肝癌阿霉素耐药相关性的研究
目的：探讨肝癌中Nrf2的表达与阿霉素（doxorubicin,ADM）化疗耐药的关系。
方法：免疫组化法检测Nrf2、醛酮还原酶1B10（aldo-keto reductase1B10,AKR1B10）、多药耐药相关蛋白5（multidrug resistance-associated protein5, MRP5）在肝癌组织中的表达，分析Nrf2表达与AKR1B10、MRP5表达及与肝癌临床病理学特征之间的关系，免疫蛋白印迹法检测比较Nrf2在人肝癌亲本细胞株BEL-7402细胞和ADM选择性诱导的多药耐药细胞株BEL-7402/ADM细胞中的表达差异，通过siRNA干扰Nrf2表达后，MTT法检测细胞对ADM敏感性的变化。
结果：Nrf2、AKR1B10和MRP5在肝癌组织中表达水平明显高于癌周正常组织（P＜0.01；P＜0.01；P＜0.01），肝癌组织中AKR1B10和MRP5表达水平均与Nrf2表达水平呈显著正相关（P=0.009；P=0.016）。在肝癌中，Nrf2的表达与肿瘤分化程度（P=0.017）、TNM分期（P=0.028）、肝硬化病史（P=0.017），早期复发（P=0.016）密切相关。Nrf2在肝癌耐药细胞株BEL-7402/ADM较敏感细胞株BEL-7402中蛋白表达显著增加，且干扰Nrf2基因表达后，肝癌耐药细胞株BEL-7402/ADM对ADM的敏感性显著增强。
结论：本研究表明肝癌中Nrf2的高表达可能与ADM耐药相关。
第二部分芹菜素通过抑制PI3K/Akt/Nrf2通路逆转BEL-7402/ADM耐药
目的：Nrf2是细胞内重要的抗氧化应激调控因子，调控一系列细胞保护基因的表达。目前，Nrf2已成为逆转肿瘤耐药的重要靶点之一。在本实验中，我们将研究APG是否可以通过抑制Nrf2通路进而逆转BEL-7402/ADM细胞耐药。
方法：MTT实验检测APG对BEL-7402/ADM细胞耐药性的逆转情况。荧光显微镜和流式细胞仪检测APG对细胞内ADM浓度的影响。实时定量PCR和免疫蛋白印迹法分析APG对Nrf2通路的抑制作用。
结果：在本研究中，我们发现无毒剂量的APG可明显增强BEL-7402/ADM对抗癌药的敏感性，增加细胞内ADM蓄积。机制上，APG通过抑制PI3K/Akt信号通路，进而下调Nrf2mRNA和蛋白水平，并导致Nrf2下游基因HO-1、AKR1B10和MRP5表达减少，最终逆转细胞耐药。
结论：结果表明APG可通过下调PI3K/Akt/Nrf2信号通路，进而增强人肝癌耐药细胞BEL-7402/ADM对ADM的敏感性，逆转肿瘤耐药。
第三部分芹菜素联合阿霉素对人肝癌裸鼠皮下移植瘤的抑制作用
目的：探讨APG联合ADM对人肝癌裸鼠皮下移植瘤的抑制作用及其相关机制。
方法：建立BEL-7402裸鼠皮下移植瘤动物模型，32只BEL-7402细胞株移植成功的裸鼠随机分为四组：对照组、APG组（50mg/kg）、ADM组（3mg/kg）和联合用药组（APG50mg/kg+ADM3mg/kg），每组8只。上述药物每3d腹腔注射l次，共7次，观察各组药物对肿瘤的抑制作用。给药结束后处死裸鼠，切取移植瘤组织。免疫组化法检测Ki-67蛋白表达评价肿瘤细胞增殖。TUNEL染色评价肿瘤细胞凋亡情况。免疫蛋白印迹法检测肿瘤组织Nrf2蛋白的表达。
结果：与单药组相比，联合应用APG及ADM显著抑制肿瘤生长，诱导肿瘤细胞凋亡，抑制肿瘤细胞增殖。此外，联合用药还能下调肿瘤组织Nrf2蛋白的表达。
结论：本研究表明与APG或ADM单药组相比，联合用药组能更有效地抑制肝癌移植瘤生长，其机制可能与抑制肿瘤增殖活性，诱导肿瘤细胞凋亡和下调Nrf2表达有关。
Hepatocellular carcinoma (HCC) is one of the most common malignant cancers.Chemotherapy is an important therapeutic strategy for HCC. Unfortunately, cancercells often develop chemoresistance, which presents a major obstacle contributing tothe failure of cancer therapy in HCC.
Nuclear factor erythroid-2-related factor2(Nrf2) is a redox-sensitivetranscription factor regulating expression of a number of cytoprotective genes.Recently, Nrf2is now viewed as a pharmacological target to overcomechemoresistance. Therefore, identification of small molecules inhibitors that potentlyinhibit the Nrf2-dependent response is desirable, and such compounds may be used asan adjuvant sensitizer to combat chemoresistance.
Several flavonoid compounds have been reported to be Nrf2inhibitor that canreverse drug resistance effectively, such as epigallocatechin3-gallate (EGCG),luteolin, brusatol. Similar to luteolin, brusatol, and EGCG, apigenin (APG) is anatural compound with anticancer potential. So APG structurally related to themwhether sensitizing cancer cells to anticancer drugs through antagonizing the Nrf2signaling pathway is not clear. We aim to study the effect of APG on reversing drugresistance in HCC cells, as well as to explore the molecular mechanism through theNrf2pathway.
PartⅠ Study of the correlation between Nrf2anddoxorubicin–resistance in hepatocellar carcinoma cells
Objects: To explore the correlation of doxorubicin-resistance with Nrf2expression inHCC.
Methods: The expression of Nrf2, aldo-keto reductase1B10(AKR1B10), multidrugresistance-associated protein5(MRP5) protein in HCC were analyzed byimmunostaining. And the relationship of Nrf2expression in these tissues withclinicopathologic characteristics and correlation of AKR1B10, MRP5expression with Nrf2expression in HCC were analyzed. Using Western blot, expressions of Nrf2in BEL-7402 cells and doxorubicin resistant BEL-7402(BEL-7402/ADM) cells were compared. Inaddition, using Nrf2siRNA was created to inhibit Nrf2expression in BEL-7402/ADM cells,and cell viabilities in response to ADM treatment were measured by MTT analysis.
Results: The expression of Nrf2, AKR1B10, and MRP5in HCC were higher than that inthe corresponding normal tissue (P＜0.01; P＜0.01; P＜0.01). The Nrf2protein level waspositively correlated with AKR1B10/MRP5protein in the HCC tissues (P=0.009; P=0.016),as assessed by Spearman's rank correlation coefficient test. Additionally, there was asignificant correlations between Nrf2expression and tumor degree of differentiation(P=0.017), and TNM stage (P=0.028). Patients with liver cirrhosis and early recurrence hadhigher Nrf2expression (P=0.017; P=0.016). The Nrf2protein level in BEL-7402/ADMcells was higher than that in BEL-7402cells. And suppression of Nrf2expression sensitizedBEL-7402/ADM cells to ADM.
Conlusion: These results suggest that the high expression level of Nrf2is probablycorrelated with doxorubicin-resistance in HCC.
PartⅡ Reversal of apigenin on chemoresistance inBEL-7402/ADM cells via inhibiting PI3K/Akt/Nrf2pathway
Objects: Nrf2is a redox-sensitive transcription factor regulating expression of anumber of cytoprotective genes. Recently, Nrf2has emerged as an importantcontributor to chemoresistance in cancer therapy. Here, we investigated whether APGcould reverse drug resistance in BEL-7402/ADM cells via inhibiting Nrf2pathway.
Methods: Reverse of drug resistance was assayed by MTT analysis. IntracellularADM concentration was measured by Fluorometric and FCM analyses. Inhibition ofNrf2signaling pathway by APG was detected through real-time quantitative PCR andwestern blot analysis.
Results: In the present study, we found that non-toxic dose of APG significantlysensitizes BEL-7402/ADM cells to anticancer drugs and increases intracellularconcentration of ADM. Mechanistically, APG dramatically reduced Nrf2expressionat both the mRNA and protein levels through down-regulation of PI3K/Akt pathway,leading to a reduction of Nrf2-downstream genes HO-1, AKR1B10, and MRP5.
Conlusion: These results clearly demonstrate that APG can be used as an effectiveadjuvant sensitizer to prevent chemoresistance by down-regulating PI3K/Akt/Nrf2signaling pathway.
PartⅢ Synergisyic inhibitory effects by the combination ofapigenin and doxorubicin on human hepatocellar carcinomaxenografts in nude mice
Objects: In this study, we investigated the inhibitory effect of APG and ADM onhepatocellar carcinoma in vivo experiments using human hepatocellar carcinoma celllines, and we aimed to elucidate the possible molecular mechanism of their anticancereffect.
Methods: The animal model of BEL-7402transplantation tumor in nude mice wasconstructed.32nude mice were randomly assigned into four groups and treated i.p.with vehicle, ADM (3mg/kg), APG (50mg/kg), or in combination every three daysfor a total of seven times. The inhibitory effects of the drugs in each group wereobserved. The mice were sacrificed and their tumors were excised for further analysis,Tumor cell proliferation was analyzed by Ki-67immunostaining. Apoptosis wasdetermined by TUNEL assay. Nrf2protein levels were measured by Western blot.
Results: In vivo, combination treatment with APG and ADM resulted in enhancedtumor growth inhibition, apoptosis induction, inhibition of tumor cell proliferationand inhibition of Nrf2expression in tumor tissues.
Conlusion: These results suggest that the combination of APG and ADM would bemore efficacious for the treatment of HCC than either treatment alone. And inhibitionof Ki-67expression, induction of tumor cell apoptosis and down-regulation of Nrf2expression might be one of its possible mechanisms.
引文
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