通过抑制Aurora-B激酶抑制宫颈癌细胞的生长及对顺铂化疗敏感性影响的研究
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摘要
前言及目的
宫颈癌是女性最常见的恶性肿瘤之一,严重威胁妇女的身心健康。宫颈癌主要以手术和放射治疗为主,但许多患者就诊时已经失去手术机会。随着肿瘤化学治疗的基础和临床研究的迅速进展,子宫颈癌新辅助化疗(neoadjuvant chemotherapy, NACT)逐渐受到学者们的重视。以铂类为基础的联合化疗提高了宫颈癌患者的生存期’,但因其对正常组织的细胞毒性及获得性耐药严重地制约了总体的化疗效果,因此,寻找一些对肿瘤细胞有相对选择性、毒性小、却有一定疗效并能够增加已有化疗药物的敏感性,是提高宫颈癌尤其是晚期患者生存率的关键。
有丝分裂错误是基因组不稳定的重要原因,与肿瘤生成密切相关。许多有丝分裂调节蛋白在肿瘤细胞中表达紊乱,这些蛋白因此可成为有用的治疗靶点。Aurora激酶家族是一组调节中心体、微管功能的丝氨酸和苏氨酸激酶。在细胞有丝分裂的正常进行中发挥重要的作用。哺乳动物细胞Aurora激酶家族成员的结构和功能在进化上保守,根据该家族各成员在细胞内的定位可分为3种：Aurora-A、Aurora-B、Aurora-C2。Aurora-B是染色体的过客蛋白,定位于有丝分裂早期的染色体的着丝粒区域,分裂后期则从着丝粒移至嵌入纺锤体赤道板的微管。随着纺锤体的延伸,细胞开始胞质分裂,Aurora-B集聚至纺锤体中央和细胞皮层的裂沟内移部位,最终在中间体聚集,Aurora-B与另3个染色体过客蛋白一内着丝粒蛋白(INCENP)、survivin和borealin结合,该复合体的主要功能是保证Aurora-B在有丝分裂前和有丝分裂期间正确定位并激活,对于染色体正确排列和分离有着非常重要的作用。Aurora-B是有丝分裂中组蛋白H3的10位丝氨酸磷酸化所必需的激酶,组蛋白H3磷酸化主要由Aurora-B激酶控制,对于染色体浓缩非常重要,当组蛋白H3磷酸化被抑制时,染色体浓缩被抑制,阻碍细胞进入有丝分裂,组蛋白H3磷酸化可作为Aurora-B的直接的下游靶分子来衡量Aurora-B激酶抑制剂对细胞是否起作用的一个标准。
研究发现Aurora-A、Aurora-B在肺癌、前列腺癌、结直肠癌、卵巢癌、肝癌、膀胱癌、食管癌等许多恶性肿瘤中存在过表达,Aurora-A、Aurora-B的过表达可引起细胞基因组不稳定、有丝分裂错误、细胞恶性转变,抑制其表达可抑制细胞的增殖、促进细胞的凋亡。因此Aurora激酶家族已成为一个潜在的有价值的抗肿瘤治疗靶点。目前已有许多Aurora激酶抑制剂被报道,ZM447439 (C29H31N5O4x 3H20)就是其中之一,属ATP竞争型抑制剂,它可阻止染色体排列、纺锤体检查点功能和胞质分裂。ZM447439处理的细胞不分裂即退出有丝分裂,细胞周期阻滞,多倍体增加,细胞体积变大,增殖能力下降,凋亡增加等18-19。Fiona Girdler20等通过RNA干扰和诱导突变等技术研究证实ZM447439引起肿瘤细胞的形态和生物学行为的改变是通过抑制Aurora-B激酶所致。
因Aurora-B激酶只在分裂增殖的细胞中表达,而人类正常细胞多处于稳定状态,肿瘤细胞分裂增殖活跃,故其抑制剂对肿瘤细胞有很强的选择性。本文首先检测了Aurora-B激酶在宫颈癌组织中高表达,然后应用ZM447439抑制Aurora-B并联合顺铂(cisplatin cDDP)作用于宫颈癌细胞,研究其对细胞生物学功能的影响及与cDDP是否有协同效应。以上问题的研究目前在国内外少见报道。通过本研究可为宫颈癌的靶向治疗和临床化疗提供新的思路。
实验材料及方法
第一部分：应用免疫组织化学方法检测Aurora-B蛋白在不同宫颈组织中的表达,然后分析Aurora-B蛋白与宫颈癌各临床病理参数的关系。
第二部分：采用MTT方法检测ZM447439对SiHa细胞增殖能力的影响；流式细胞技术分别检测ZM447439对SiHa细胞周期及细胞凋亡的影响；显微镜和电镜观察SiHa细胞形态学改变；蛋白印迹技术检测Aurora-B和磷酸化组蛋白H3(H3-P)的表达变化。
第三部分：采用MTT、流式细胞技术检测ZM447439联合顺铂对SiHa细胞增殖能力、细胞周期及细胞凋亡的影响；蛋白印迹技术检测HPV16E6、P53、BCL-2、VEGF蛋白表达的改变。
结果
第一部分：Aurora-B蛋白在宫颈癌组织高表达,其次CIN，正常宫颈组织没有阳性表达。Aurora-B蛋白的表达与宫颈癌细胞的分化程度和病理类型有关(P<0.05),与年龄,临床分期,淋巴转移情况无关(P>0.05)。
第二部分：ZM447439以时间和剂量依赖的形式抑制SiHa细胞的增殖,引起细胞体积增大,数量减少,并出现凋亡改变。流式细胞技术显示ZM447439引起细胞G2/M期阻滞,及促进细胞早期凋亡。蛋白印迹技术显示ZM447439抑制了Aurora-B和H3-P蛋白的表达。
第三部分：MTT结果显示顺铂以时间和剂量依赖的形式抑制SiHa细胞的增殖,和ZM447439联用明显增强了顺铂的抑制增殖、促进凋亡的作用,引起S期明显抑制。抑制了HPV16E6、BCL-2、VEGF蛋白的表达,增强了P53蛋白的表达。
结论
第一部分：Aurora-B可作为宫颈癌治疗的潜在靶点。Aurora-B在宫颈鳞癌和腺癌的发病机制中所起的作用可能存在差异。Aurora-B的表达与宫颈癌细胞的成熟程度有关。
第二部分：抑制Aurora-B的表达,进而抑制其重要的下游因子H3的磷酸化,可以抑制宫颈癌SiHa细胞的增殖,促进细胞凋亡,引起细胞阻滞于有丝分裂期。
第三部分：抑制Aurora-B的表达能显著增强顺铂对宫颈癌SiHa细胞的化疗敏感性,显著诱导凋亡,两者具有协同作用。其机制可能与抑制HPV16E6、BCL-2的表达、促进P53蛋白功能恢复有关。
Introduction and Objectives
Cervical cancer is one of the most common malignancies of women. It severely threatens women's health. Radiation and surgery therapy have been used for patients with advanced or recurrent cancer, but many patients have already lost the chance of operation in fact, with the basic and clinical research advances rapidly, platinum-based neoadjuvant chemotherapy (NACT) has greatly improved the prognosis of these patients,as well as the cases with larger lesions.But because of the toxicity to normal tissue and the acquired resistance, it severely restricts the effectiveness and application of platinum-chemotherapy. Therefore, looking for some drugs with low toxicity, relatively selective for tumor cells and synergistic effect for chemotherapy seems extremely important. It is the key to improve the survival of cervical cancer patients, especially for those advanced patients.
Aurora kinase family of mammalian proteins are evolutionarily conservative at the structure and function, they can be divided into three kinds:Aurora-A, Aurora-B, Aurora-C according to their location in cells.Aurora-B is primarily located in the centromere region of the chromosome in the early stage of mitosis, and then transferred to the microtubule of the spindle equatorial plane in the late stage of mitosis.When the spindle elongates and the cytokinesis occurs, Aurora-B will aggregate in the fissures of the cell cortex and the center of the spindle.In finally, the protein will concentrate in the intermediate filament, binding to another three chromosomal passenger proteins INCENP, survivin and borealin to form a complex. This complex, playing an important role in proper arrangement and separation of chromosomes, has the function to ensure Aurora-B can precisely locate and activate before and during the mitosis period.Aurora-B is essential for the phosphorylation of histone H3 serine-10 in mitosis, which is very important for chromosome condensation.When histone H3 phosphorylation is inhibited, the chromosome condensation is inhibited, and cell mitosis is impeded. So,histone H3 phosphorylation can be used as a direct downstream target of Aurora-B to measure the effect of Aurora-B kinase inhibition.
Studies found that the Aurora-A and Aurora-B were over-expressed in lung cancer, prostate cancer, colorectal cancer, ovarian cancer, hepatocellular carcinoma, bladder cancer,carcinoma of esophagus.Enhancing their expression can cause cell genome instability, mitotic errors and cell malignant transformation; suppressing their expression can inhibit cell proliferation and promote apoptosis.Aurora kinase family therefore has become a potentially valuable anti-tumor therapeutic target.
There are a lot of Aurora kinase inhibitors previously reported, one of which is ZM447439.ZM447439 is an ATP competitive inhibitor, which can inhibit the microtubule inaction caused by the abnormal kinetochore separation,prevent chromosomes alignment and separation,inhibiting spindle checkpoint,inhibit cytokinesis.Cells treated with ZM447439 exit mitosis without dividing, the cell cycle is arrested, polyploidy increased, cell size increased, proliferation decreased, apoptosis increased, etc. Through RNA interference and induced mutation techniques, Girdler et al. proved that the inhibition of Aurora-B by ZM447439 can cause the changes of tumor cell morphology and biological behavior.
Aurora-B kinase is only expressed in the proliferating cells, most of human normal cells are in a steady state, so the inhibitor of Aurora-B kinase on the tumor cells have a strong selective. First, this paper tested the higher express of Aurora-B kinase in cervical cancer tissue, then combined ZM447439 with cisplatin in cervical cancer cells, investigated the effect of ZM447439 on cell and the synergy effect with cDDP. The study of these questions at home and abroad is now rarely reported. Through this study, we provide new ideas for target therapy and clinical chemotherapy for cervical cancer.
Materials and Methods
Part I:Detected Aurora-B protein in different tissues of the cervix by immunohistochemistry and then analyzed the relationship between Aurora B protein and clinical parameters of cervical cancer.
Part II:The effect of ZM447439 on proliferation of SiHa cells was tested by MTT; the changes of cell cycle and apoptosis were detected by flow cytometry; cell morphology was observed with microscope and electron microscope; Aurora B and H3-P protein was detected by Western blot.
Part III:The changes of cell proliferation and cell cycle and apoptosis under ZM447439 and cisplatin were respectively tested using MTT, flow cytometry. HPV16E6,P53,BCL-2, VEGF protein expression were detected by Western blot.
Results
Part I:The rate of Aurora-B expression is highest in cervical cancer and has no significant correlation to clinical stage, lymph node metastasis and age(P> 0.05). Aurora-B protein expression has significant correlation to cancer cell differentiation and pathological type (P<0.05).
Part II:ZM447439 can reduce the number of SiHa cell, increase the volume of cell, and lead to apoptosis in a dose-and time-dependent manner. The results of Flow cytometry showed G2/M arrest and the increase of early apoptosis by ZM447439. Protein blot investegated that ZM447439 inhibited Aurora B and H3-P expression.
Part III:MTT results showed that cisplatin inhibited the growth of SiHa cells in the form of time and dose-dependent. Combined with cisplatin, ZM447439 significantly enhanced the effect of inhibiting proliferation and promoting apoptosis of cisplatin, and caused significant arrest of S phase, and inhibited HPV16E6, BCL-2, VEGF protein expression, and enhanced the expression of P53 protein.
Conclusions
PartⅠ:Aurora B provides a new target for the treatment of cervical cancer. The role of Aurora B in the pathogenesis of cervical squamous cell carcinoma and adenocarcinoma may be different.Aurora B expression has relation to the degree of maturity of cervical cancer cells.
PartⅡ:Inhibiting the expression of Aurora B and H3 phosphorylation can inhibit the proliferation of cervical cancer SiHa cells, promote apoptosis,cause cell arrest at mitosis.
PartⅢ:The inhibition of Aurora B significantly enhanced the chemosensitivity of cisplatin for cervical cancer SiHa cells, significantly induced apoptosis,showed synergistic effect. The mechanism may be related to the inhibition HPV16E6,BCL-2 expression, and the recovering of P53 function.
宫颈癌是女性最常见的恶性肿瘤之一,严重威胁妇女的身心健康。宫颈癌主要以手术和放射治疗为主,但许多患者就诊时已经失去手术机会。随着肿瘤化学治疗的基础和临床研究的迅速进展,子宫颈癌新辅助化疗(neoadjuvant chemotherapy, NACT)逐渐受到学者们的重视。以铂类为基础的联合化疗提高了宫颈癌患者的生存期’,但因其对正常组织的细胞毒性及获得性耐药严重地制约了总体的化疗效果,因此,寻找一些对肿瘤细胞有相对选择性、毒性小、却有一定疗效并能够增加已有化疗药物的敏感性,是提高宫颈癌尤其是晚期患者生存率的关键。
有丝分裂错误是基因组不稳定的重要原因,与肿瘤生成密切相关。许多有丝分裂调节蛋白在肿瘤细胞中表达紊乱,这些蛋白因此可成为有用的治疗靶点。Aurora激酶家族是一组调节中心体、微管功能的丝氨酸和苏氨酸激酶。在细胞有丝分裂的正常进行中发挥重要的作用。哺乳动物细胞Aurora激酶家族成员的结构和功能在进化上保守,根据该家族各成员在细胞内的定位可分为3种：Aurora-A、Aurora-B、Aurora-C2。Aurora-B是染色体的过客蛋白,定位于有丝分裂早期的染色体的着丝粒区域,分裂后期则从着丝粒移至嵌入纺锤体赤道板的微管。随着纺锤体的延伸,细胞开始胞质分裂,Aurora-B集聚至纺锤体中央和细胞皮层的裂沟内移部位,最终在中间体聚集,Aurora-B与另3个染色体过客蛋白一内着丝粒蛋白(INCENP)、survivin和borealin结合,该复合体的主要功能是保证Aurora-B在有丝分裂前和有丝分裂期间正确定位并激活,对于染色体正确排列和分离有着非常重要的作用。Aurora-B是有丝分裂中组蛋白H3的10位丝氨酸磷酸化所必需的激酶,组蛋白H3磷酸化主要由Aurora-B激酶控制,对于染色体浓缩非常重要,当组蛋白H3磷酸化被抑制时,染色体浓缩被抑制,阻碍细胞进入有丝分裂,组蛋白H3磷酸化可作为Aurora-B的直接的下游靶分子来衡量Aurora-B激酶抑制剂对细胞是否起作用的一个标准。
研究发现Aurora-A、Aurora-B在肺癌、前列腺癌、结直肠癌、卵巢癌、肝癌、膀胱癌、食管癌等许多恶性肿瘤中存在过表达,Aurora-A、Aurora-B的过表达可引起细胞基因组不稳定、有丝分裂错误、细胞恶性转变,抑制其表达可抑制细胞的增殖、促进细胞的凋亡。因此Aurora激酶家族已成为一个潜在的有价值的抗肿瘤治疗靶点。目前已有许多Aurora激酶抑制剂被报道,ZM447439 (C29H31N5O4x 3H20)就是其中之一,属ATP竞争型抑制剂,它可阻止染色体排列、纺锤体检查点功能和胞质分裂。ZM447439处理的细胞不分裂即退出有丝分裂,细胞周期阻滞,多倍体增加,细胞体积变大,增殖能力下降,凋亡增加等18-19。Fiona Girdler20等通过RNA干扰和诱导突变等技术研究证实ZM447439引起肿瘤细胞的形态和生物学行为的改变是通过抑制Aurora-B激酶所致。
因Aurora-B激酶只在分裂增殖的细胞中表达,而人类正常细胞多处于稳定状态,肿瘤细胞分裂增殖活跃,故其抑制剂对肿瘤细胞有很强的选择性。本文首先检测了Aurora-B激酶在宫颈癌组织中高表达,然后应用ZM447439抑制Aurora-B并联合顺铂(cisplatin cDDP)作用于宫颈癌细胞,研究其对细胞生物学功能的影响及与cDDP是否有协同效应。以上问题的研究目前在国内外少见报道。通过本研究可为宫颈癌的靶向治疗和临床化疗提供新的思路。
实验材料及方法
第一部分：应用免疫组织化学方法检测Aurora-B蛋白在不同宫颈组织中的表达,然后分析Aurora-B蛋白与宫颈癌各临床病理参数的关系。
第二部分：采用MTT方法检测ZM447439对SiHa细胞增殖能力的影响；流式细胞技术分别检测ZM447439对SiHa细胞周期及细胞凋亡的影响；显微镜和电镜观察SiHa细胞形态学改变；蛋白印迹技术检测Aurora-B和磷酸化组蛋白H3(H3-P)的表达变化。
第三部分：采用MTT、流式细胞技术检测ZM447439联合顺铂对SiHa细胞增殖能力、细胞周期及细胞凋亡的影响；蛋白印迹技术检测HPV16E6、P53、BCL-2、VEGF蛋白表达的改变。
结果
第一部分：Aurora-B蛋白在宫颈癌组织高表达,其次CIN，正常宫颈组织没有阳性表达。Aurora-B蛋白的表达与宫颈癌细胞的分化程度和病理类型有关(P<0.05),与年龄,临床分期,淋巴转移情况无关(P>0.05)。
第二部分：ZM447439以时间和剂量依赖的形式抑制SiHa细胞的增殖,引起细胞体积增大,数量减少,并出现凋亡改变。流式细胞技术显示ZM447439引起细胞G2/M期阻滞,及促进细胞早期凋亡。蛋白印迹技术显示ZM447439抑制了Aurora-B和H3-P蛋白的表达。
第三部分：MTT结果显示顺铂以时间和剂量依赖的形式抑制SiHa细胞的增殖,和ZM447439联用明显增强了顺铂的抑制增殖、促进凋亡的作用,引起S期明显抑制。抑制了HPV16E6、BCL-2、VEGF蛋白的表达,增强了P53蛋白的表达。
结论
第一部分：Aurora-B可作为宫颈癌治疗的潜在靶点。Aurora-B在宫颈鳞癌和腺癌的发病机制中所起的作用可能存在差异。Aurora-B的表达与宫颈癌细胞的成熟程度有关。
第二部分：抑制Aurora-B的表达,进而抑制其重要的下游因子H3的磷酸化,可以抑制宫颈癌SiHa细胞的增殖,促进细胞凋亡,引起细胞阻滞于有丝分裂期。
第三部分：抑制Aurora-B的表达能显著增强顺铂对宫颈癌SiHa细胞的化疗敏感性,显著诱导凋亡,两者具有协同作用。其机制可能与抑制HPV16E6、BCL-2的表达、促进P53蛋白功能恢复有关。
Introduction and Objectives
Cervical cancer is one of the most common malignancies of women. It severely threatens women's health. Radiation and surgery therapy have been used for patients with advanced or recurrent cancer, but many patients have already lost the chance of operation in fact, with the basic and clinical research advances rapidly, platinum-based neoadjuvant chemotherapy (NACT) has greatly improved the prognosis of these patients,as well as the cases with larger lesions.But because of the toxicity to normal tissue and the acquired resistance, it severely restricts the effectiveness and application of platinum-chemotherapy. Therefore, looking for some drugs with low toxicity, relatively selective for tumor cells and synergistic effect for chemotherapy seems extremely important. It is the key to improve the survival of cervical cancer patients, especially for those advanced patients.
Aurora kinase family of mammalian proteins are evolutionarily conservative at the structure and function, they can be divided into three kinds:Aurora-A, Aurora-B, Aurora-C according to their location in cells.Aurora-B is primarily located in the centromere region of the chromosome in the early stage of mitosis, and then transferred to the microtubule of the spindle equatorial plane in the late stage of mitosis.When the spindle elongates and the cytokinesis occurs, Aurora-B will aggregate in the fissures of the cell cortex and the center of the spindle.In finally, the protein will concentrate in the intermediate filament, binding to another three chromosomal passenger proteins INCENP, survivin and borealin to form a complex. This complex, playing an important role in proper arrangement and separation of chromosomes, has the function to ensure Aurora-B can precisely locate and activate before and during the mitosis period.Aurora-B is essential for the phosphorylation of histone H3 serine-10 in mitosis, which is very important for chromosome condensation.When histone H3 phosphorylation is inhibited, the chromosome condensation is inhibited, and cell mitosis is impeded. So,histone H3 phosphorylation can be used as a direct downstream target of Aurora-B to measure the effect of Aurora-B kinase inhibition.
Studies found that the Aurora-A and Aurora-B were over-expressed in lung cancer, prostate cancer, colorectal cancer, ovarian cancer, hepatocellular carcinoma, bladder cancer,carcinoma of esophagus.Enhancing their expression can cause cell genome instability, mitotic errors and cell malignant transformation; suppressing their expression can inhibit cell proliferation and promote apoptosis.Aurora kinase family therefore has become a potentially valuable anti-tumor therapeutic target.
There are a lot of Aurora kinase inhibitors previously reported, one of which is ZM447439.ZM447439 is an ATP competitive inhibitor, which can inhibit the microtubule inaction caused by the abnormal kinetochore separation,prevent chromosomes alignment and separation,inhibiting spindle checkpoint,inhibit cytokinesis.Cells treated with ZM447439 exit mitosis without dividing, the cell cycle is arrested, polyploidy increased, cell size increased, proliferation decreased, apoptosis increased, etc. Through RNA interference and induced mutation techniques, Girdler et al. proved that the inhibition of Aurora-B by ZM447439 can cause the changes of tumor cell morphology and biological behavior.
Aurora-B kinase is only expressed in the proliferating cells, most of human normal cells are in a steady state, so the inhibitor of Aurora-B kinase on the tumor cells have a strong selective. First, this paper tested the higher express of Aurora-B kinase in cervical cancer tissue, then combined ZM447439 with cisplatin in cervical cancer cells, investigated the effect of ZM447439 on cell and the synergy effect with cDDP. The study of these questions at home and abroad is now rarely reported. Through this study, we provide new ideas for target therapy and clinical chemotherapy for cervical cancer.
Materials and Methods
Part I:Detected Aurora-B protein in different tissues of the cervix by immunohistochemistry and then analyzed the relationship between Aurora B protein and clinical parameters of cervical cancer.
Part II:The effect of ZM447439 on proliferation of SiHa cells was tested by MTT; the changes of cell cycle and apoptosis were detected by flow cytometry; cell morphology was observed with microscope and electron microscope; Aurora B and H3-P protein was detected by Western blot.
Part III:The changes of cell proliferation and cell cycle and apoptosis under ZM447439 and cisplatin were respectively tested using MTT, flow cytometry. HPV16E6,P53,BCL-2, VEGF protein expression were detected by Western blot.
Results
Part I:The rate of Aurora-B expression is highest in cervical cancer and has no significant correlation to clinical stage, lymph node metastasis and age(P> 0.05). Aurora-B protein expression has significant correlation to cancer cell differentiation and pathological type (P<0.05).
Part II:ZM447439 can reduce the number of SiHa cell, increase the volume of cell, and lead to apoptosis in a dose-and time-dependent manner. The results of Flow cytometry showed G2/M arrest and the increase of early apoptosis by ZM447439. Protein blot investegated that ZM447439 inhibited Aurora B and H3-P expression.
Part III:MTT results showed that cisplatin inhibited the growth of SiHa cells in the form of time and dose-dependent. Combined with cisplatin, ZM447439 significantly enhanced the effect of inhibiting proliferation and promoting apoptosis of cisplatin, and caused significant arrest of S phase, and inhibited HPV16E6, BCL-2, VEGF protein expression, and enhanced the expression of P53 protein.
Conclusions
PartⅠ:Aurora B provides a new target for the treatment of cervical cancer. The role of Aurora B in the pathogenesis of cervical squamous cell carcinoma and adenocarcinoma may be different.Aurora B expression has relation to the degree of maturity of cervical cancer cells.
PartⅡ:Inhibiting the expression of Aurora B and H3 phosphorylation can inhibit the proliferation of cervical cancer SiHa cells, promote apoptosis,cause cell arrest at mitosis.
PartⅢ:The inhibition of Aurora B significantly enhanced the chemosensitivity of cisplatin for cervical cancer SiHa cells, significantly induced apoptosis,showed synergistic effect. The mechanism may be related to the inhibition HPV16E6,BCL-2 expression, and the recovering of P53 function.
引文
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4 Warner SL, Bearss DJ, Han H, Von Hoff DD.Targeting Aurora-2 kinase in cancer. Mol Cancer,Ther 2003;2:589-595.
5 Kimura M, Matsuda Y, Yoshioka T, et al.Identification and characterization of STK12/Aik2:a human gene related to aurora of Drosphila and yeast IPL1.Cytogenet Cell Genet 1998;82: 147-52.
6 Walsby E, Walsh V, Pepper C, Burnett A, Mills K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.Haematologica 2008;93:662-9.
7 Lee EC, Frolov A, Li R, Ayala G, Greenberg NM. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006;66:4996-5002.
8 Lam AK, Ong K, Ho YH.Aurora kinase expression in colorectal adenocarcinoma:correlations with clinicopathological features,p16 expression, and telomerase activity. Hum Pathol 2008;39: 599-604.
9 Scharer CD, Laycock N, Osunkoya AO, Logani S, McDonald JF, Benigno BB,Moreno CS.Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells. J Transl Med 2008;6:79.
10 Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, Imoto I, Eishi Y, Inazawa J, Miki Y, Tanaka H. Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. B J Surg 2008;95:611-9.
11 Park HS, Park WS, Bondaruk J, Tanaka N, Katayama H, Lee S,Spiess PE, Steinberg JR, Wang Z, Katz RL, Dinney C, Elias KJ, Lotan Y, Naeem RC, Baggerly K, Sen S,Grossman HB, Czerniak B.Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. J Natl Cancer Inst 2008;100:1401-11.
12 Zhang XH, Rao M, Loprieato JA, Hong JA, Zhao M, Chen GZ, Humphries AE, Nguyen DM, Trepel JB, Yu X, Schrump DS.Aurora A, Aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer Biol Ther 2008;7:388-97.
13 EijiTanaka,1 Yosuke Hashimoto,1 Tetsuo Ito,1Kan Kondo,1Motoshige Higashiyam-a,1ShigeruTsunoda,1.Cristian Ortiz,1 Yoshiharu Sakai.1 Johji Inazawa,2 andYutaka Shimadal.The Suppression of Aurora-A/STK15/BTAK Expression Enhances Chemosensitivity to Docetaxel in Human Esophageal Squamous Cell Carcinoma.Clin Cancer Res 2007;1331-1340.
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11 Qi G, Ogawa 1, Kudo Y, Miyauchi M et al. Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 2007 Mar;450(3):297-302.
12 Satoshi Hayama, Yataro Daigo, Takumi Yamabuki, et al. Phosphorylation and Activation of Cell Division Cycle Associated 8 by Aurora Kinase B Plays a Significant Role in Human Lung Carcinogenesis.Cancer Research 2007 May; 67(1),4113-4122.
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22 Modugno M, Casale E, Soncini C,et al.Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358.Cancer Res.2007 Sep 1;67(17):7987-90.
23 Tao Y, Zhang P, Girdler F,et al. Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152.Oncogene.2008 May 22;27(23):3244-55.
2 Carmena M, Earnshaw WC.The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003;4:842-54.
3 MURATA-HORI M, TATSUKA M, WANG Y L. Probing the dynamics and function of aurora B kinase in living cells du-ring mitosis and cytokinesis[J].Mol Biol Cell, 2002,13(4):1099-1108.
4 Warner SL, Bearss DJ, Han H, Von Hoff DD.Targeting Aurora-2 kinase in cancer. Mol Cancer,Ther 2003;2:589-595.
5 Kimura M, Matsuda Y, Yoshioka T, et al.Identification and characterization of STK12/Aik2:a human gene related to aurora of Drosphila and yeast IPL1.Cytogenet Cell Genet 1998;82: 147-52.
6 Walsby E, Walsh V, Pepper C, Burnett A, Mills K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.Haematologica 2008;93:662-9.
7 Lee EC, Frolov A, Li R, Ayala G, Greenberg NM. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006;66:4996-5002.
8 Lam AK, Ong K, Ho YH.Aurora kinase expression in colorectal adenocarcinoma:correlations with clinicopathological features,p16 expression, and telomerase activity. Hum Pathol 2008;39: 599-604.
9 Scharer CD, Laycock N, Osunkoya AO, Logani S, McDonald JF, Benigno BB,Moreno CS.Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian cancer cells. J Transl Med 2008;6:79.
10 Tanaka S, Arii S, Yasen M, Mogushi K, Su NT, Zhao C, Imoto I, Eishi Y, Inazawa J, Miki Y, Tanaka H. Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. B J Surg 2008;95:611-9.
11 Park HS, Park WS, Bondaruk J, Tanaka N, Katayama H, Lee S,Spiess PE, Steinberg JR, Wang Z, Katz RL, Dinney C, Elias KJ, Lotan Y, Naeem RC, Baggerly K, Sen S,Grossman HB, Czerniak B.Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. J Natl Cancer Inst 2008;100:1401-11.
12 Zhang XH, Rao M, Loprieato JA, Hong JA, Zhao M, Chen GZ, Humphries AE, Nguyen DM, Trepel JB, Yu X, Schrump DS.Aurora A, Aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer. Cancer Biol Ther 2008;7:388-97.
13 EijiTanaka,1 Yosuke Hashimoto,1 Tetsuo Ito,1Kan Kondo,1Motoshige Higashiyam-a,1ShigeruTsunoda,1.Cristian Ortiz,1 Yoshiharu Sakai.1 Johji Inazawa,2 andYutaka Shimadal.The Suppression of Aurora-A/STK15/BTAK Expression Enhances Chemosensitivity to Docetaxel in Human Esophageal Squamous Cell Carcinoma.Clin Cancer Res 2007;1331-1340.
14 Rawson TE, Ruth M, Blackwood E, Burdick D, Corson L, Dotson J, Drummond J, Fields C, Georges GJ, Goller B,Halladay J, Hunsaker T, Kleinheinz T,Krell HW, Li J, Liang J, Limberg A, McNutt A, Moffat J, Phillips G, Ran Y, Safina B,Ultsch M, Walker L, Wiesmann C, Zhang B, Zhou A, Zhu BY, Riiger P, Cochran AG. A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability. J Med Chem 2008;51:4465-75.
15 DeMoe JH, Santaguida S, Daum JR, Musacchio A, Gorbsky GJ.A high throughput, whole cell screen for small molecule inhibitors of the mitotic spindle checkpoint identifies OM137, a novel Aurora kinase inhibitor. Cancer Res 2009;69:1509-16.
16 Guo J, Anderson MG, Tapang P, Palma JP, Rodriguez LE, Niquette A, Li J, Bouska JJ, Wang G, Semizarov D, Albert DH, Donawho CK, Glaser KB,Shah OJ.Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152.Pharmacogenomics J 2009;9:90-102.
17 Hong YB,Kang HJ, Kim HJ, Rosen EM, Dakshanamurthy S, Rondanin R, Baruchello R, Grisolia G, Daniele S,Bae I.Inhibition of cell proliferation by a resveratrol analog in human pancreatic and breast cancer cells. Exp Mol Med 2009; 41:151-60.
18 Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther 2007; 6:1851-7.
19 Claire Ditchfield,1 Victoria L. Johnson,1 Anthony Tighe,1 Rebecca Ellston,2 Carolyn Haworth,2 Trevor Johnson,2 Andrew Mortlock,2 Nicholas Keen,2 and Stephen S. TaylorlAurora B couples chromosome alignment with anaphase by targeting BubRl,Mad2, and Cenp-E to kinetochores.J Cell Biol.2003 April 28;161(2):267-280.
20 Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM,Keen NJ, Taylor SS. Validating Aurora B as an anti-cancer drug target. J Cell Sci 2006; 119:3664-75.
21 黄文林,朱孝峰等。信号转导.北京：人民卫生出版社,2005.
22 Reiter R, Gais P, Jutting U, Steuer-Vogt MK, Pickhard A, Bink K, Rauser S,Lassmann S, Hofler H, Werner M, Walch A. Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma.Clin Cancer Res 2006;12:5136-5141.
23 Twu NF, Yuan CC, Yen MS, Lai CR, Chao KC, Wang PH, Wu HH, Chen YJ. Expression of Aurora kinase A and B in normal and malignant cervical tissue:high Aurora A kinase expression in squamous cervical cancer. Eur J Obstet Gynecol Reprod Biol 2009;142:57-63.
24 Qi G, Ogawa I. Kudo Y. Miyauchi M et al.Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch.2007 Mar;450(3):297-302.
25 Satoshi Hayama, Yataro Daigo, Takumi Yamabuki et al.Phosphorylation and Activation of Cell Division Cycle Associated 8 by Aurora Kinase B Plays a Significant Role in Human Lung Carcinogenesis.Cancer Research.2007 May 67(1),4113-4122.
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