IC162抑制CML细胞增殖、诱导CML细胞凋亡和化疗增敏作用及其机制研究
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摘要
研究背景:慢性粒细胞白血病(Chronic myeloid leukemia,CML)是以费城染色体(Philadephia,Ph)为特征的多潜能造血干细胞恶性克隆性疾病,其恶性克隆的持续扩充与细胞增殖和凋亡速率不平衡有关。CML具有特征性的染色体异位t(9,22)(q34,q11),产生Bcr/abl融合基因,编码蛋白质P210,后者在CML的发病过程中有重要作用。研究表明,P210可促进白血病细胞增殖,延缓其凋亡。对CML的治疗,传统方法包括羟基脲、a-干扰素、异基因造血干细胞移植及新近的酪氨酸激酶抑制剂,尽管治疗效果有很大改观,但仍有某些局限,特别是CML急变后治疗效果很差。因此,寻找CML急变后的新治疗方法仍是当前CML研究的目标。
近年来,采用传统中药提取物探讨对白血病治疗的新途径引起了人们的关注,从传统中药提取的抗白血病药物如苦参碱(Matrine)、姜黄素(Curcumin)和冬凌草甲素(Oridonin)的体外试验表明可抑制多种白血病细胞增殖和诱导细胞凋亡,动物实验显示该类药物几乎无不良反应。新近上海交通大学附属瑞金医院血研所的研究显示冬凌草甲素在体内外能诱导具有t(8,21)的急性粒细胞白血病M_2型(AML-M_2)细胞株和原代细胞凋亡,而且副作用小,是一种潜在的抗白血病药物。因此筛选新型抗白血病的中药有效成分,确定其抗白血病的作用并探讨其机制,已成为当今白血病研究领域的热点。
K562细胞株系人CML急性变细胞株,既具有急性白血病的细胞生物学行为,又具有CML细胞特有的本质,因此是体外研究筛选抗白血病药物疗效及机制的良好细胞模型。IC162是由单一中草药提纯出的单一化合物,分子量为368;具有类植物雌激素样作用(由于商业机密原因,其具体成份尚未解密),为了确定IC162是否有抗白血病效应,本研究用IC162作用于K562细胞株及来自CML急粒变病人新鲜骨髓白血病细胞,观察IC162对K562细胞和CML急粒变病人原代白血病细胞是否具有抑制增殖、诱导凋亡和化疗增敏作用;并对其分子机制进行探讨。
第一部分IC162对CML细胞的增殖抑制效应
目的:观察不同浓度IC162对K562细胞和CML急粒变病人原代白血病细胞增殖以及细胞分裂周期的影响。方法:用台盼蓝拒染试验、MTT试验、集落形成抑制试验和流式细胞仪分析K562细胞增殖能力及DNA含量,观察不同浓度的IC162对CML细胞(K562细胞或CML急粒变病人原代白血病细胞)增殖的抑制率、集落形成和对细胞周期的影响。结果:(1)IC162以浓度依赖性方式有效地抑制CML细胞增殖,IC162抑制K562细胞活力的IC50值为8.2μmol/L;IC162抑制CML急粒变病人原代白血病细胞活力的IC50值为12.5～16.3μmol/L;(2)IC162能显著抑制K562细胞集落形成,并呈量效关系;(3)IC162增加G0/G1期K562细胞百分率,降低S期K562细胞百分率。结论:IC162能够有效地抑制CML细胞增殖,并呈药物浓度和时间依赖性,IC162可阻滞CML细胞在G0/G1期从而抑制CML细胞增殖。
第二部分IC162对CML细胞的凋亡诱导效应
目的:确定IC162能否诱导CML细胞凋亡。方法:用不同浓度的IC162作用于K562和CML急粒变病人原代白血病细胞,采用Hochest33258染色和AnnexinV-FITC/PI染色检测凋亡细胞的百分率;用Western印迹检测IC162干预后的K562细胞Caspase-3蛋白质表达。结果:(1)两种检测方法均证明IC162能以浓度依赖性方式诱导CML细胞凋亡;(2)IC162诱导K562细胞凋亡伴有Caspase-3蛋白表达上调和裂解激活。结论:IC162能以浓度依赖性方式诱导CML细胞凋亡;其诱导K562细胞凋亡的分子机制与Caspase-3蛋白表达上调和裂解激活有关。
第三部分IC162对柔红霉素和高三尖杉酯碱抗K562细胞作用的化疗增敏效应
目的:确定IC162对柔红霉素或高三尖杉酯碱的抗K562细胞增殖作用和凋亡诱导效应是否存在增敏效应。方法:用低剂量IC162(2μmol/L)分别与柔红霉素或高三尖杉酯碱合用干预K562细胞48小时,用MTT试验、AnnexinV-FITC/PI染色流式分析单药或联合用药对K562细胞增殖、早期凋亡的影响。结果:2μmol/L IC162分别与320μg/L柔红霉素或40μg/L高三尖杉酯碱共同干预K562细胞,与单用低剂量的IC162、单用柔红霉素或高三尖杉酯碱比较,联合用药抑制K562细胞增殖活力和诱导细胞凋亡效应更明显。结论:IC162对柔红霉素或高三尖杉酯碱抗K562细胞增殖和凋亡诱导具有增敏效应。
第四部分IC162对K562细胞增殖抑制和凋亡诱导效应的分子机制
目的:观察IC162作用下K562细胞增殖抑制和凋亡诱导过程中COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9和VEGF mRNA表达变化以及COX-2蛋白表达的影响,以部分揭示IC162抗白血病作用的分子机制。方法:(1)用Western blot分析IC162作用下K562细胞COX-2蛋白质表达水平;(2) Real-time PCR定量检测COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9和VEGF mRNA的表达量。结果:(1) IC162能以浓度依赖性方式抑制K562细胞COX-2和SurvivinmRNA以及COX-2蛋白的表达水平;(2) IC162能抑制K562细胞CyclinD2和CyclinE mRNA的表达,而上调、p27mRNA表达;(3) IC162能抑制K562细胞MMP-2、MMP-9和VEGF mRNA的表达。结论:IC162的抗白血病作用与其抑制COX-2、细胞周期调节相关基因和血管生成调节相关基因信号转导途径有关。
Background: Chronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease characterized with the Philadelphia chromosome, and over-proliferation and apoptosis tolerance of malignant clone. The characteristic chromosome t (9; 22) (q34; q11) of CML result in bcr/abl fusion gene and encode fusion protein P~(210), which plays an important role in the pathogenesis of CML by promoting leukemia cells proliferation and resisting apoptosis. Although the traditional therapic methods of CML, including hydroxyurea, interferon-a, allogeneic hematopoietic stem cell transplantation and newly tyrosine kinase inhibitors, have improved greatly patient's prognosis, there are still some limitations for the CML patients with blastic crisis. Therefore, searching for new drugs in CML therapy is the main objective. In recent years, the studies of traditional Chinese medicine extracts for the treatment of leukemia have been extensively investigated,such as Matrine, Curcumin and Oridonin are proved in vitro that these drugs can suppress leukemia cells proliferation and induce cells apoptosis, and no adverse reactions are found in animal model. Recent studies from Institute of Hematology,Shanghai Rui Jin Hospital show that Oridonin could induce apoptosis on acute myeloid leukemia M_2 (AML- M_2) cell line and primary leukemic cells with t (8; 21) positive both in vitro and in vivo with little side effects. The research on the anti-leukemia effect of Chinese medicine and their clinical application have become an important issue. K562 cell line originated from human CML cells with blastic transformation.. Because of the character of acute leukemia cells and the specific essence of CML cells, K562 cells are a good study model for researching anti-leukemia drug. IC162 is a pure compound extracted from a Chinese herb medicine, which has phytoestrogen-like effect and Wt is 368. In present study, we try to determine whether IC162 may inhibit CML cells proliferation, induce CML cells apoptosis and enhance the chemotherapic sensitivity to Daunomycin and Homoharringtonine and explore its molecular mechanisms.
PartⅠProliferation-inhibiting effect of IC162 on CML cells
Objective: To determine proliferation-inhibiting effect of IC162 on K562 and primary CML cells from CML patients with blast crisis. Methods: K562 cells and primary CML cells were treated with different concentrations of IC162, and then cells viability were analyzed with trypan blue exclusion test and MTT assay colony formation test. Cell cycle was checked by flow cytometry. Results: (1) IC162 effectively inhibited the proliferation of K562 and primary CML cells in a concentration-dependent way, and the IC50 was S.2μmol/L. (2) IC162 significantly inhibited colony formation of K562 cells in a dose-dependent way. (3) IC162 increased the percentage of G0/G1 phase K562 cells and decreased percentage of S phase K562 cells. Conclusion: IC162 can inhibit proliferation of K562 and primary CML cells by arresting cells in G0/G1 phase on a concentration-dependent manner.
PartⅡApoptosis-inducing effect of IC162 on CML cells
Objective: To ensure whether IC162 can induce the apoptosis of primary CML cells from CML patients with blast crisis. Methods: After CML cells were incubated with different concentrations of IC162, (1) morphologic character of apoptosis was evaluated by Hochest33258 staining; (2) the percentage of earlier apoptotic cells were analyzed by flow cytometry; (3) the molecular character of apoptosis was assayed by Western blot for detecting Caspase-3 expression. Results: (1) Hochest33258 staining and flow cytometry detection testify IC162 can induce the apoptosis of primary CML cells in a concentration-dependent way; (2) IC162-induced CML cells apoptosis is associated with up-regulation and cleavage of Caspase-3. Conclusion: IC162 can induce the apoptosis of primary CML cells with a concentration -dependent manner; The molecular mechanisms of apoptosis induction was related to up-regulated caspase-3 expression and activation.
PartⅢEffect of IC162 on enhancing the chemotherapic sensitivity of Daunomycin or Homoharringtonine on K562 cells
Objective: To determine whether IC162 can enhance the anti-proliferative effect and apoptosis-inducing effect on K562 cells to Daunomycin and Homoharringtonine. Methods: K562 cells were treated with low dose IC162 along,Daunomycin or Homoharringtonine along,and IC162 (2μmol/L) combined with Daunomycin or Homoharringtonine interfered with K562 cells for 48 h. The effects of the drugs on K562 cell growth inhibitation, apoptosis inducement were analyzed by MTT assay, AnnexinV-FITC/ PI assay. Results: The treatment of IC162 (2μmol/L) combined with Daunomycin(320μg/L) or Homoharringtonine (320μg/L) could significantly inhibit the K562 cell viability and induce the K562 cell apoptosis than those of treatments for IC162, Daunomycin or Homoharringtonine alone. Conclusion: IC162 can enhance the anti-proliferative effect and Apoptosis effect of Daunomycin or Homoharringtonine on K562 cells.
PartⅣMolecular mechanisms of the proliferation-inhibiting and apoptosis-inducing effects of IC162 on K562 cells
Objective: To explore the mechanism of proliferation-inhibiting and apoptosis-inducing effects of IC162 on K562 cells. Methods: After K562 cells were incubated with different concentrations of IC162, (1) The protein expression of COX-2 in K562 cells were detected by Western blot; (2) The mRNA expression levels of COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9 and VEGF were detected with Real-time PCR; Results: (1) IC162 could down-regulate the expression of COX-2 proteins and mRNA in a concentration- dependent way on K562 cells; (2) IC162 could down-regulate mRNA expression levels of Survivin,CyclinD2, and CyclinE,and up-regulate mRNA expression levels of p27 in a concentration-dependent way on K562 cells; (3) IC162 could down-regulate mRNA expression levels of MMP-2、MMP-9 and VEGF in a concentration-dependent way on K562 cells. Conclusion: The anti-leukemic effets of IC162 is related to inhibition of signal transduction pathway involved in Cyclins, COX-2 and MMPs family
近年来,采用传统中药提取物探讨对白血病治疗的新途径引起了人们的关注,从传统中药提取的抗白血病药物如苦参碱(Matrine)、姜黄素(Curcumin)和冬凌草甲素(Oridonin)的体外试验表明可抑制多种白血病细胞增殖和诱导细胞凋亡,动物实验显示该类药物几乎无不良反应。新近上海交通大学附属瑞金医院血研所的研究显示冬凌草甲素在体内外能诱导具有t(8,21)的急性粒细胞白血病M_2型(AML-M_2)细胞株和原代细胞凋亡,而且副作用小,是一种潜在的抗白血病药物。因此筛选新型抗白血病的中药有效成分,确定其抗白血病的作用并探讨其机制,已成为当今白血病研究领域的热点。
K562细胞株系人CML急性变细胞株,既具有急性白血病的细胞生物学行为,又具有CML细胞特有的本质,因此是体外研究筛选抗白血病药物疗效及机制的良好细胞模型。IC162是由单一中草药提纯出的单一化合物,分子量为368;具有类植物雌激素样作用(由于商业机密原因,其具体成份尚未解密),为了确定IC162是否有抗白血病效应,本研究用IC162作用于K562细胞株及来自CML急粒变病人新鲜骨髓白血病细胞,观察IC162对K562细胞和CML急粒变病人原代白血病细胞是否具有抑制增殖、诱导凋亡和化疗增敏作用;并对其分子机制进行探讨。
第一部分IC162对CML细胞的增殖抑制效应
目的:观察不同浓度IC162对K562细胞和CML急粒变病人原代白血病细胞增殖以及细胞分裂周期的影响。方法:用台盼蓝拒染试验、MTT试验、集落形成抑制试验和流式细胞仪分析K562细胞增殖能力及DNA含量,观察不同浓度的IC162对CML细胞(K562细胞或CML急粒变病人原代白血病细胞)增殖的抑制率、集落形成和对细胞周期的影响。结果:(1)IC162以浓度依赖性方式有效地抑制CML细胞增殖,IC162抑制K562细胞活力的IC50值为8.2μmol/L;IC162抑制CML急粒变病人原代白血病细胞活力的IC50值为12.5～16.3μmol/L;(2)IC162能显著抑制K562细胞集落形成,并呈量效关系;(3)IC162增加G0/G1期K562细胞百分率,降低S期K562细胞百分率。结论:IC162能够有效地抑制CML细胞增殖,并呈药物浓度和时间依赖性,IC162可阻滞CML细胞在G0/G1期从而抑制CML细胞增殖。
第二部分IC162对CML细胞的凋亡诱导效应
目的:确定IC162能否诱导CML细胞凋亡。方法:用不同浓度的IC162作用于K562和CML急粒变病人原代白血病细胞,采用Hochest33258染色和AnnexinV-FITC/PI染色检测凋亡细胞的百分率;用Western印迹检测IC162干预后的K562细胞Caspase-3蛋白质表达。结果:(1)两种检测方法均证明IC162能以浓度依赖性方式诱导CML细胞凋亡;(2)IC162诱导K562细胞凋亡伴有Caspase-3蛋白表达上调和裂解激活。结论:IC162能以浓度依赖性方式诱导CML细胞凋亡;其诱导K562细胞凋亡的分子机制与Caspase-3蛋白表达上调和裂解激活有关。
第三部分IC162对柔红霉素和高三尖杉酯碱抗K562细胞作用的化疗增敏效应
目的:确定IC162对柔红霉素或高三尖杉酯碱的抗K562细胞增殖作用和凋亡诱导效应是否存在增敏效应。方法:用低剂量IC162(2μmol/L)分别与柔红霉素或高三尖杉酯碱合用干预K562细胞48小时,用MTT试验、AnnexinV-FITC/PI染色流式分析单药或联合用药对K562细胞增殖、早期凋亡的影响。结果:2μmol/L IC162分别与320μg/L柔红霉素或40μg/L高三尖杉酯碱共同干预K562细胞,与单用低剂量的IC162、单用柔红霉素或高三尖杉酯碱比较,联合用药抑制K562细胞增殖活力和诱导细胞凋亡效应更明显。结论:IC162对柔红霉素或高三尖杉酯碱抗K562细胞增殖和凋亡诱导具有增敏效应。
第四部分IC162对K562细胞增殖抑制和凋亡诱导效应的分子机制
目的:观察IC162作用下K562细胞增殖抑制和凋亡诱导过程中COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9和VEGF mRNA表达变化以及COX-2蛋白表达的影响,以部分揭示IC162抗白血病作用的分子机制。方法:(1)用Western blot分析IC162作用下K562细胞COX-2蛋白质表达水平;(2) Real-time PCR定量检测COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9和VEGF mRNA的表达量。结果:(1) IC162能以浓度依赖性方式抑制K562细胞COX-2和SurvivinmRNA以及COX-2蛋白的表达水平;(2) IC162能抑制K562细胞CyclinD2和CyclinE mRNA的表达,而上调、p27mRNA表达;(3) IC162能抑制K562细胞MMP-2、MMP-9和VEGF mRNA的表达。结论:IC162的抗白血病作用与其抑制COX-2、细胞周期调节相关基因和血管生成调节相关基因信号转导途径有关。
Background: Chronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease characterized with the Philadelphia chromosome, and over-proliferation and apoptosis tolerance of malignant clone. The characteristic chromosome t (9; 22) (q34; q11) of CML result in bcr/abl fusion gene and encode fusion protein P~(210), which plays an important role in the pathogenesis of CML by promoting leukemia cells proliferation and resisting apoptosis. Although the traditional therapic methods of CML, including hydroxyurea, interferon-a, allogeneic hematopoietic stem cell transplantation and newly tyrosine kinase inhibitors, have improved greatly patient's prognosis, there are still some limitations for the CML patients with blastic crisis. Therefore, searching for new drugs in CML therapy is the main objective. In recent years, the studies of traditional Chinese medicine extracts for the treatment of leukemia have been extensively investigated,such as Matrine, Curcumin and Oridonin are proved in vitro that these drugs can suppress leukemia cells proliferation and induce cells apoptosis, and no adverse reactions are found in animal model. Recent studies from Institute of Hematology,Shanghai Rui Jin Hospital show that Oridonin could induce apoptosis on acute myeloid leukemia M_2 (AML- M_2) cell line and primary leukemic cells with t (8; 21) positive both in vitro and in vivo with little side effects. The research on the anti-leukemia effect of Chinese medicine and their clinical application have become an important issue. K562 cell line originated from human CML cells with blastic transformation.. Because of the character of acute leukemia cells and the specific essence of CML cells, K562 cells are a good study model for researching anti-leukemia drug. IC162 is a pure compound extracted from a Chinese herb medicine, which has phytoestrogen-like effect and Wt is 368. In present study, we try to determine whether IC162 may inhibit CML cells proliferation, induce CML cells apoptosis and enhance the chemotherapic sensitivity to Daunomycin and Homoharringtonine and explore its molecular mechanisms.
PartⅠProliferation-inhibiting effect of IC162 on CML cells
Objective: To determine proliferation-inhibiting effect of IC162 on K562 and primary CML cells from CML patients with blast crisis. Methods: K562 cells and primary CML cells were treated with different concentrations of IC162, and then cells viability were analyzed with trypan blue exclusion test and MTT assay colony formation test. Cell cycle was checked by flow cytometry. Results: (1) IC162 effectively inhibited the proliferation of K562 and primary CML cells in a concentration-dependent way, and the IC50 was S.2μmol/L. (2) IC162 significantly inhibited colony formation of K562 cells in a dose-dependent way. (3) IC162 increased the percentage of G0/G1 phase K562 cells and decreased percentage of S phase K562 cells. Conclusion: IC162 can inhibit proliferation of K562 and primary CML cells by arresting cells in G0/G1 phase on a concentration-dependent manner.
PartⅡApoptosis-inducing effect of IC162 on CML cells
Objective: To ensure whether IC162 can induce the apoptosis of primary CML cells from CML patients with blast crisis. Methods: After CML cells were incubated with different concentrations of IC162, (1) morphologic character of apoptosis was evaluated by Hochest33258 staining; (2) the percentage of earlier apoptotic cells were analyzed by flow cytometry; (3) the molecular character of apoptosis was assayed by Western blot for detecting Caspase-3 expression. Results: (1) Hochest33258 staining and flow cytometry detection testify IC162 can induce the apoptosis of primary CML cells in a concentration-dependent way; (2) IC162-induced CML cells apoptosis is associated with up-regulation and cleavage of Caspase-3. Conclusion: IC162 can induce the apoptosis of primary CML cells with a concentration -dependent manner; The molecular mechanisms of apoptosis induction was related to up-regulated caspase-3 expression and activation.
PartⅢEffect of IC162 on enhancing the chemotherapic sensitivity of Daunomycin or Homoharringtonine on K562 cells
Objective: To determine whether IC162 can enhance the anti-proliferative effect and apoptosis-inducing effect on K562 cells to Daunomycin and Homoharringtonine. Methods: K562 cells were treated with low dose IC162 along,Daunomycin or Homoharringtonine along,and IC162 (2μmol/L) combined with Daunomycin or Homoharringtonine interfered with K562 cells for 48 h. The effects of the drugs on K562 cell growth inhibitation, apoptosis inducement were analyzed by MTT assay, AnnexinV-FITC/ PI assay. Results: The treatment of IC162 (2μmol/L) combined with Daunomycin(320μg/L) or Homoharringtonine (320μg/L) could significantly inhibit the K562 cell viability and induce the K562 cell apoptosis than those of treatments for IC162, Daunomycin or Homoharringtonine alone. Conclusion: IC162 can enhance the anti-proliferative effect and Apoptosis effect of Daunomycin or Homoharringtonine on K562 cells.
PartⅣMolecular mechanisms of the proliferation-inhibiting and apoptosis-inducing effects of IC162 on K562 cells
Objective: To explore the mechanism of proliferation-inhibiting and apoptosis-inducing effects of IC162 on K562 cells. Methods: After K562 cells were incubated with different concentrations of IC162, (1) The protein expression of COX-2 in K562 cells were detected by Western blot; (2) The mRNA expression levels of COX-2、Survivin、CyclinD2、CyclinE、p27、MMP-2、MMP-9 and VEGF were detected with Real-time PCR; Results: (1) IC162 could down-regulate the expression of COX-2 proteins and mRNA in a concentration- dependent way on K562 cells; (2) IC162 could down-regulate mRNA expression levels of Survivin,CyclinD2, and CyclinE,and up-regulate mRNA expression levels of p27 in a concentration-dependent way on K562 cells; (3) IC162 could down-regulate mRNA expression levels of MMP-2、MMP-9 and VEGF in a concentration-dependent way on K562 cells. Conclusion: The anti-leukemic effets of IC162 is related to inhibition of signal transduction pathway involved in Cyclins, COX-2 and MMPs family
引文
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