蜂斗菜素和查尔酮衍生物抑制人神经母细胞瘤细胞增殖作用及其机制研究
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摘要
背景与目的：神经母细胞瘤(Neuroblastoma, NB)是一种节后交感神经系统的胚胎性恶性肿瘤,为儿童最常见的颅外实体肿瘤之一。神经母细胞瘤在婴幼儿中的发病率及死亡率高,预后差。目前为止,尚未有十分行之有效的治疗方法。我们首次研究了蜂斗菜素(petasin)以及两种查尔酮类(Chal cones)新型化合物的抗人神经母细胞瘤细胞作用及其机制,为蜂斗菜素以及查尔酮类新型化合物开发用于神经母细胞瘤的预防和治疗提供初步的实验依据。
方法：本论文利用SRB法检测药物作用肿瘤细胞后的细胞活性；流式细胞术检测细胞周期和凋亡；Hoechst33258染色法检测细胞凋亡；细胞计数法检测蜂斗菜素连续作用7days对SK-N-SH和SH-SY5Y细胞生长的影响,以及蜂斗菜素处理SK-N-SH和SH-SY5Y细胞72h撤去药物后细胞的生长情况；β-半乳糖苷酶染色实验观察蜂斗菜素对SK-N-SH细胞衰老的影响；蛋白免疫印迹法(western blot)检测蜂斗菜素处理SK-N-SH细胞不同时间后,对ERK1/2和MEK蛋白磷酸化水平的影响。实验中以顺铂为阳性对照药物。
结果：蜂斗菜素对SK-N-SH, SH-SY5Y, SK-N-BE(2), SGC7901, SMMC7721,Ec9706和U251细胞均有不同程度的增殖抑制作用,其中对SK-N-SH细胞的增殖抑制作用最强,72h的IC50低至0.8μmol·L-1,并且这种抑制效应在一定范围内呈剂量和时间依赖性。蜂斗菜素使SK-N-SH细胞的周期阻滞于G1期,但不诱导其凋亡和衰老；蜂斗菜素处理SK-N-SH细胞72h后撤去药物,细胞的增殖能力和周期分布都恢复正常水平。而蜂斗菜素对SH-SY5Y细胞增殖抑制作用相对SK-N-SH细胞较弱(72h的IC50为25.5μmol·L-1),但可以诱导其发生凋亡,并且蜂斗菜素处理SH-SY5Y细胞72h后撤去药物,细胞的增殖能力没有恢复。进一步研究蜂斗菜素对SK-N-SH细胞的作用机制,我们还发现蜂斗菜素可以瞬时地下调SK-N-SH细胞的ERK1/2和MEK蛋白的磷酸化水平。同时,查尔酮类新型化合物A和B对SK-N-SH细胞均有不同程度的抑制作用,并且抑制效应在一定范围内呈剂量和时间依赖性。并且,化合物A使SK-N-SH细胞的周期阻滞于G1期,而化合物B则使SK-N-SH细胞的周期阻滞于G2M期。化合物A和B都可以诱导SK-N-SH细胞发生凋亡,并且两种化合物诱导SK-N-SH细胞凋亡后细胞核形态的变化不同。
结论：蜂斗菜素能够有效地抑制SK-N-SH增殖,其作用机制可能与其阻滞SK-N-SH细胞的周期和下调ERK1/2和MEK蛋白的磷酸化水平有关；而蜂斗菜素抑制SH-SY5Y细胞的增殖,可能与其诱导SH-SY5Y细胞的凋亡有关。查尔酮类新型化合物A和B都能抑制SK-N-SH细胞增殖,作用机制可能与其改变SK-N-SH细胞周期分布和诱导细胞凋亡相关。
BACKGROUND&OBJECTIVE:Neuroblastoma is an embryonal malignancy of postganglionic sympathetic nervous system, one of the most common extracranial solid tumors in children. There is high morbidity and mortality of the tumor in infants and young children, with poor prognosis. So far, there is no effective way to improve this situation. We studied the effects of petasin and two novel compounds of chalcones on anti-human neuroblastoma and its mechanism, and provided preliminary experimental evidence for petasin and two novel compounds of chalcones using on the prevention and treatment of neuroblastoma.
METHODS:The antiproliferation effects of the compounds on tumor cells were detected by SRB assay. Cell cycle distributions were measured by flow cytometry. Cellular apoptosis was detected by Hoechst33258staining assay and flow cytometry. The growth of SK-N-SH and SH-SY5Y cells were established by cell counting, and the proliferation of SK-N-SH and SH-SY5Y cells following removal of petasin were established by the same method. Cell senescence of SK-N-SH was observed by β-galactosidase staining assay. The phosphorylation of ERK1/2and MEK of SK-N-SH was determined by western blot. The positive control of experiment is cisplatin.
RESULTS:Petasin resulted in various degree inhibition of SK-N-SH, SH-SY5Y, SK-N-BE(2), SGC7901, SMMC7721, EC9706, and U251cells in a dose-and time-dependent manner within certain range. After treated with petasin, the cell cycle of SK-N-SH arrested in G1phase, and there was no apoptosis shown neither by Hoechst33258staining nor flow cytometry analysis. And petasin did not induce SK-N-SH cells senescence. The capacity of proliferation and cell cycle of SK-N-SH following removal of petasin had returned to normal levels. In correspond, there was apoptosis shown both by Hoechst33258staining and flow cytometry analysis in SH-SY5Y after treated with petasin. And the proliferation capacity of SH-SY5Y following removal of petasin had not returned to normal levels. In the end, western blot analysis observed that the phosphorylation of ERK1/2and MEK was decreased by pretreatment with petasin in transiently. At the same times, compound A and B resulted in various degree inhibitions of SK-N-SH cells in a dose-and time-dependent manner within certain range. After treated with compound A and B, the cell cycle of SK-N-SH were arrested in G1and G2M phase, respectively. And there was apoptosis shown both by Hoechst33258staining and flow cytometry analysis.
CONCLUSION:Petasin can inhibit the proliferation of SK-N-SH and SH-SY5Y. Petasin-treated SK-N-SH cells just were inhibited the cell proliferation, the mechanism may be associated with down-regulation the phosphorylation of ERK1/2and MEK protein. Novel compounds of chalcones can inhibit the proliferation of SK-N-SH, and the mechanism may be related with changing cell cycle distribution and inducing apoptosis.
方法：本论文利用SRB法检测药物作用肿瘤细胞后的细胞活性；流式细胞术检测细胞周期和凋亡；Hoechst33258染色法检测细胞凋亡；细胞计数法检测蜂斗菜素连续作用7days对SK-N-SH和SH-SY5Y细胞生长的影响,以及蜂斗菜素处理SK-N-SH和SH-SY5Y细胞72h撤去药物后细胞的生长情况；β-半乳糖苷酶染色实验观察蜂斗菜素对SK-N-SH细胞衰老的影响；蛋白免疫印迹法(western blot)检测蜂斗菜素处理SK-N-SH细胞不同时间后,对ERK1/2和MEK蛋白磷酸化水平的影响。实验中以顺铂为阳性对照药物。
结果：蜂斗菜素对SK-N-SH, SH-SY5Y, SK-N-BE(2), SGC7901, SMMC7721,Ec9706和U251细胞均有不同程度的增殖抑制作用,其中对SK-N-SH细胞的增殖抑制作用最强,72h的IC50低至0.8μmol·L-1,并且这种抑制效应在一定范围内呈剂量和时间依赖性。蜂斗菜素使SK-N-SH细胞的周期阻滞于G1期,但不诱导其凋亡和衰老；蜂斗菜素处理SK-N-SH细胞72h后撤去药物,细胞的增殖能力和周期分布都恢复正常水平。而蜂斗菜素对SH-SY5Y细胞增殖抑制作用相对SK-N-SH细胞较弱(72h的IC50为25.5μmol·L-1),但可以诱导其发生凋亡,并且蜂斗菜素处理SH-SY5Y细胞72h后撤去药物,细胞的增殖能力没有恢复。进一步研究蜂斗菜素对SK-N-SH细胞的作用机制,我们还发现蜂斗菜素可以瞬时地下调SK-N-SH细胞的ERK1/2和MEK蛋白的磷酸化水平。同时,查尔酮类新型化合物A和B对SK-N-SH细胞均有不同程度的抑制作用,并且抑制效应在一定范围内呈剂量和时间依赖性。并且,化合物A使SK-N-SH细胞的周期阻滞于G1期,而化合物B则使SK-N-SH细胞的周期阻滞于G2M期。化合物A和B都可以诱导SK-N-SH细胞发生凋亡,并且两种化合物诱导SK-N-SH细胞凋亡后细胞核形态的变化不同。
结论：蜂斗菜素能够有效地抑制SK-N-SH增殖,其作用机制可能与其阻滞SK-N-SH细胞的周期和下调ERK1/2和MEK蛋白的磷酸化水平有关；而蜂斗菜素抑制SH-SY5Y细胞的增殖,可能与其诱导SH-SY5Y细胞的凋亡有关。查尔酮类新型化合物A和B都能抑制SK-N-SH细胞增殖,作用机制可能与其改变SK-N-SH细胞周期分布和诱导细胞凋亡相关。
BACKGROUND&OBJECTIVE:Neuroblastoma is an embryonal malignancy of postganglionic sympathetic nervous system, one of the most common extracranial solid tumors in children. There is high morbidity and mortality of the tumor in infants and young children, with poor prognosis. So far, there is no effective way to improve this situation. We studied the effects of petasin and two novel compounds of chalcones on anti-human neuroblastoma and its mechanism, and provided preliminary experimental evidence for petasin and two novel compounds of chalcones using on the prevention and treatment of neuroblastoma.
METHODS:The antiproliferation effects of the compounds on tumor cells were detected by SRB assay. Cell cycle distributions were measured by flow cytometry. Cellular apoptosis was detected by Hoechst33258staining assay and flow cytometry. The growth of SK-N-SH and SH-SY5Y cells were established by cell counting, and the proliferation of SK-N-SH and SH-SY5Y cells following removal of petasin were established by the same method. Cell senescence of SK-N-SH was observed by β-galactosidase staining assay. The phosphorylation of ERK1/2and MEK of SK-N-SH was determined by western blot. The positive control of experiment is cisplatin.
RESULTS:Petasin resulted in various degree inhibition of SK-N-SH, SH-SY5Y, SK-N-BE(2), SGC7901, SMMC7721, EC9706, and U251cells in a dose-and time-dependent manner within certain range. After treated with petasin, the cell cycle of SK-N-SH arrested in G1phase, and there was no apoptosis shown neither by Hoechst33258staining nor flow cytometry analysis. And petasin did not induce SK-N-SH cells senescence. The capacity of proliferation and cell cycle of SK-N-SH following removal of petasin had returned to normal levels. In correspond, there was apoptosis shown both by Hoechst33258staining and flow cytometry analysis in SH-SY5Y after treated with petasin. And the proliferation capacity of SH-SY5Y following removal of petasin had not returned to normal levels. In the end, western blot analysis observed that the phosphorylation of ERK1/2and MEK was decreased by pretreatment with petasin in transiently. At the same times, compound A and B resulted in various degree inhibitions of SK-N-SH cells in a dose-and time-dependent manner within certain range. After treated with compound A and B, the cell cycle of SK-N-SH were arrested in G1and G2M phase, respectively. And there was apoptosis shown both by Hoechst33258staining and flow cytometry analysis.
CONCLUSION:Petasin can inhibit the proliferation of SK-N-SH and SH-SY5Y. Petasin-treated SK-N-SH cells just were inhibited the cell proliferation, the mechanism may be associated with down-regulation the phosphorylation of ERK1/2and MEK protein. Novel compounds of chalcones can inhibit the proliferation of SK-N-SH, and the mechanism may be related with changing cell cycle distribution and inducing apoptosis.
引文
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