DADS对人小细胞肺癌细胞株NCI-H446细胞及裸鼠移植瘤生长的影响
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摘要
目的:研究二烯丙基二硫(diallyl disulfide,DADS)体外抑制人小细胞肺癌细胞株H446细胞增殖作用及通过建立人小细胞肺癌细胞株H446细胞裸鼠移植瘤模型,研究DADS对裸鼠体内人小细胞肺癌H446细胞增殖、细胞成瘤性的影响及DADS在裸鼠小细胞肺癌移植瘤模型治疗小细胞肺癌的可行性,并初步探讨其作用机理。
方法:体外培养H446细胞,采用MTT、细胞计数检测DADS对体外培养的人肺癌H446细胞的抑制增殖作用;采用HE染色和AO-EB染色荧光观察DADS对体外培养的H446细胞的形态学改变;建立BALB/c人肺小细胞肺癌H446细胞裸鼠移植瘤模型,25只荷瘤实验裸鼠随机分为五组,即空白对照组,DADS低、中、高浓度剂量组,阳性对照组。采用皮下给药方法。DADS按三种浓度20μg/ml、60μg/ml、180μg/ml分组给药,阳性对照顺铂组按2mg/kg给药,空白对照组给等体积生理盐水,均隔日一次,共十次。观察裸鼠移植瘤的成瘤情况和DADS对肺癌移植瘤在BALB/c裸鼠体内生长情况的影响:定期观察肿瘤生长情况,测量肿瘤体积,绘制肿瘤生长曲线并计算抑瘤率;经HE染色光学显微镜观察移植瘤组织形态学特征;流式细胞术检测DADS对瘤组织细胞周期分布及凋亡率的影响;免疫组化检测各组瘤组织中增殖细胞核抗原(PCNA)蛋白的表达情况。
结果:MTT结果显示:DADS作用H446细胞后,明显抑制细胞增殖且抑制率呈现浓度和时间依赖性关系,H446细胞经DADS作用48小时,代谢MTT的能力明显降低,显示较强的细胞毒性反应。4,8,16,20,40,60μg/mlDADS作用于H446细胞48小时后,细胞存活率分别为98.8%,94.8%,79.2%,52.2%,27.6%,及22.6%,呈明显的剂量依赖性。IC_(50)值为介于20～40μg/ml之间。细胞计数结果表明:DADS作用H446细胞后呈浓度依赖性延长细胞群体倍增时间。常规培养的H446细胞群体倍增时间为25.40h,当DADS的浓度由4μg/ml增加到60μg/ml时,其细胞群体倍增时间由26.33h延长到145.64h(P＜0.05)。HE染色光学显微镜观察显示:DADS处理24h后的H446细胞,与对照组相比,细胞体积变小,胞浆丰富,细胞核变小,染色变淡,核仁数量明显减少。AO-EB染色荧光显微镜下表明,未处理H446细胞形态饱满,细胞质呈绿色,核染色为亮绿色,核形态规则,为圆形或椭圆形。DADS处理24h后,细胞皱缩或呈圆形,胞质呈黄色或橘红色,细胞核或细胞质内可见致密浓染的黄绿色或橘红色荧光,可见橘红色碎片。随DADS浓度增加,细胞渐稀疏。皮下注射DADS剂量为20mg·kg~(-1)、60mg·kg~(-1)和180mg·kg~(-1)时可明显抑制移植瘤的生长其抑瘤率分别为40.6%、53.1%和66.4%;五组H446裸鼠的移植瘤体积(处死后测量)测量,差异有显著性(P＜0.05),与空白对照组相比,低、中、高浓度组DADS均能抑制肿瘤生长,光学显微镜显示经DADS处理后瘤细胞密度及异型性明显减小。流式细胞术检测结果显示:DADS具有明显诱导人肺癌裸鼠移植瘤细胞的细胞周期阻滞作用和细胞凋亡率的影响,呈浓度依赖性并将移植瘤细胞阻滞在G_2/M期。PCNA免疫组化染色结果显示:DADS抑制移植瘤癌细胞PCNA的表达,PCNA标记指数NS组最高,均高于其他四组,差异比较有统计学意义(P＜0.05),其他四组之间差异无显著性意义(P＞0.05)
结论:
1.DADS对体外培养人小细胞肺癌H446细胞株具有抗增殖作用,且与药物浓度及作用时间相关。
2.DADS对裸鼠体内人小细胞肺癌H446细胞有较强的抗增殖作用,且呈剂量依赖性。
3.DADS通过将移植瘤细胞阻滞在G_2/M期来抑制肿瘤细胞增殖。
4.DADS抑制移植瘤细胞生长的作用可能与减少PCNA蛋白表达有关。
Objective:To observe the effects of DADS on the growth of human small cell lung cancer H446 cells in vivo and in vitro.
Methods:H446 cell lines were cultured in vitro.Cell proliferation inhibition was measured by MTT assay,growth curve analysis and average doubling time.Cell morphologic changes were observed by optics microscope(HE staining)and fluorescence microscope(AO-EB staining and Hoechst 33258 staining).Animal models were constructed on BALB/c nude mice with subcutaneously transplanted SCLC H446.The nude mice bearing with SCLC H446 were divided into 5 groups by random selection,which were treated with NS or DDP or with different doses of DADS(20μg/ml,60μg/ml,180μg/ml,im.Qod for ten times).The human SCLC H446 cells were implant into the right axial regions of nude mice.The dimensions of xenografts were measured and the living states of nude mice with SCLC H446 were observed.The xenograft tumor growth in mice was observed after treated with DADS in vitro and intraperitoneal injection of DADS.The morphological changes of the tumors were examined under light microscopy.Phase distribution of xenograft cell cycle was analyzed by flow cytometry(FCM).Expression of proliferating cell nuclear antigen (PCNA)in every group xenograft was determined by immunohistochemical staining.
Results:MTT assay showed that DADS from 4 to 60μg/ml significantly inhibited H446 cells and exhibited a dose-dependent and time-dependent model.After exposure to DADS, H446 cell average doubling time retarded from 25.40 hours in normal cultured cells to DADS experimented H446 cells 145.64 hours(P＜0.05).Under inverted microscope,optics microscope and fluorescence microscope,H446 cellular heteromorphism diminished, nucleocytoplasmic proportion was reliable to reasonableness,cellular apparatus was abundant in plasm,nuclear and partial cell organs manifest retrograde alters.All these showed above suggested that H446 cells malignancy and proliferation capacity was declined because of DADS treatment.DADS at every group could inhibit the growth of xenograft in nude mice with SCLC H446(P＜0.05).When the dose of DADS were 20 mg·kg~(-1)、60 mg·kg~(-1)and 180 mg·kg~(-1),the tumor growth was significant inhibition the inhibiting rates on tumor were 40.6%、53.1%and 66.4%,and inhibition expression of PCNA protein in implanted tumor.Flow cytometry analysis revealed that treating xenograft tumor cells with increasing quantities of DADS increased the percentage of cells in the G_2/M phase.The results of immunohistochemical staining of PCNA showed that PCNA label index of group NS was the highest.There was no significant difference among the rest groups.
Conclusion:
1.DADS could significantly inhibit the proliferation of human small cell lung cancer cell lines H446 and this effect presents a scene of dose-dependent and time-dependent,
2.DADS could obviously inhibit the growth of xenograft of H446 cells in nude mouse.
3.DADS inhibited proliferation and induce apoptosis of xenograft tumor cell by preventing the G_2/M phase arrest.
4.Anti-proliferation mechanism probably related to down regulated expression of PCNA protein in xenograft.
方法:体外培养H446细胞,采用MTT、细胞计数检测DADS对体外培养的人肺癌H446细胞的抑制增殖作用;采用HE染色和AO-EB染色荧光观察DADS对体外培养的H446细胞的形态学改变;建立BALB/c人肺小细胞肺癌H446细胞裸鼠移植瘤模型,25只荷瘤实验裸鼠随机分为五组,即空白对照组,DADS低、中、高浓度剂量组,阳性对照组。采用皮下给药方法。DADS按三种浓度20μg/ml、60μg/ml、180μg/ml分组给药,阳性对照顺铂组按2mg/kg给药,空白对照组给等体积生理盐水,均隔日一次,共十次。观察裸鼠移植瘤的成瘤情况和DADS对肺癌移植瘤在BALB/c裸鼠体内生长情况的影响:定期观察肿瘤生长情况,测量肿瘤体积,绘制肿瘤生长曲线并计算抑瘤率;经HE染色光学显微镜观察移植瘤组织形态学特征;流式细胞术检测DADS对瘤组织细胞周期分布及凋亡率的影响;免疫组化检测各组瘤组织中增殖细胞核抗原(PCNA)蛋白的表达情况。
结果:MTT结果显示:DADS作用H446细胞后,明显抑制细胞增殖且抑制率呈现浓度和时间依赖性关系,H446细胞经DADS作用48小时,代谢MTT的能力明显降低,显示较强的细胞毒性反应。4,8,16,20,40,60μg/mlDADS作用于H446细胞48小时后,细胞存活率分别为98.8%,94.8%,79.2%,52.2%,27.6%,及22.6%,呈明显的剂量依赖性。IC_(50)值为介于20～40μg/ml之间。细胞计数结果表明:DADS作用H446细胞后呈浓度依赖性延长细胞群体倍增时间。常规培养的H446细胞群体倍增时间为25.40h,当DADS的浓度由4μg/ml增加到60μg/ml时,其细胞群体倍增时间由26.33h延长到145.64h(P＜0.05)。HE染色光学显微镜观察显示:DADS处理24h后的H446细胞,与对照组相比,细胞体积变小,胞浆丰富,细胞核变小,染色变淡,核仁数量明显减少。AO-EB染色荧光显微镜下表明,未处理H446细胞形态饱满,细胞质呈绿色,核染色为亮绿色,核形态规则,为圆形或椭圆形。DADS处理24h后,细胞皱缩或呈圆形,胞质呈黄色或橘红色,细胞核或细胞质内可见致密浓染的黄绿色或橘红色荧光,可见橘红色碎片。随DADS浓度增加,细胞渐稀疏。皮下注射DADS剂量为20mg·kg~(-1)、60mg·kg~(-1)和180mg·kg~(-1)时可明显抑制移植瘤的生长其抑瘤率分别为40.6%、53.1%和66.4%;五组H446裸鼠的移植瘤体积(处死后测量)测量,差异有显著性(P＜0.05),与空白对照组相比,低、中、高浓度组DADS均能抑制肿瘤生长,光学显微镜显示经DADS处理后瘤细胞密度及异型性明显减小。流式细胞术检测结果显示:DADS具有明显诱导人肺癌裸鼠移植瘤细胞的细胞周期阻滞作用和细胞凋亡率的影响,呈浓度依赖性并将移植瘤细胞阻滞在G_2/M期。PCNA免疫组化染色结果显示:DADS抑制移植瘤癌细胞PCNA的表达,PCNA标记指数NS组最高,均高于其他四组,差异比较有统计学意义(P＜0.05),其他四组之间差异无显著性意义(P＞0.05)
结论:
1.DADS对体外培养人小细胞肺癌H446细胞株具有抗增殖作用,且与药物浓度及作用时间相关。
2.DADS对裸鼠体内人小细胞肺癌H446细胞有较强的抗增殖作用,且呈剂量依赖性。
3.DADS通过将移植瘤细胞阻滞在G_2/M期来抑制肿瘤细胞增殖。
4.DADS抑制移植瘤细胞生长的作用可能与减少PCNA蛋白表达有关。
Objective:To observe the effects of DADS on the growth of human small cell lung cancer H446 cells in vivo and in vitro.
Methods:H446 cell lines were cultured in vitro.Cell proliferation inhibition was measured by MTT assay,growth curve analysis and average doubling time.Cell morphologic changes were observed by optics microscope(HE staining)and fluorescence microscope(AO-EB staining and Hoechst 33258 staining).Animal models were constructed on BALB/c nude mice with subcutaneously transplanted SCLC H446.The nude mice bearing with SCLC H446 were divided into 5 groups by random selection,which were treated with NS or DDP or with different doses of DADS(20μg/ml,60μg/ml,180μg/ml,im.Qod for ten times).The human SCLC H446 cells were implant into the right axial regions of nude mice.The dimensions of xenografts were measured and the living states of nude mice with SCLC H446 were observed.The xenograft tumor growth in mice was observed after treated with DADS in vitro and intraperitoneal injection of DADS.The morphological changes of the tumors were examined under light microscopy.Phase distribution of xenograft cell cycle was analyzed by flow cytometry(FCM).Expression of proliferating cell nuclear antigen (PCNA)in every group xenograft was determined by immunohistochemical staining.
Results:MTT assay showed that DADS from 4 to 60μg/ml significantly inhibited H446 cells and exhibited a dose-dependent and time-dependent model.After exposure to DADS, H446 cell average doubling time retarded from 25.40 hours in normal cultured cells to DADS experimented H446 cells 145.64 hours(P＜0.05).Under inverted microscope,optics microscope and fluorescence microscope,H446 cellular heteromorphism diminished, nucleocytoplasmic proportion was reliable to reasonableness,cellular apparatus was abundant in plasm,nuclear and partial cell organs manifest retrograde alters.All these showed above suggested that H446 cells malignancy and proliferation capacity was declined because of DADS treatment.DADS at every group could inhibit the growth of xenograft in nude mice with SCLC H446(P＜0.05).When the dose of DADS were 20 mg·kg~(-1)、60 mg·kg~(-1)and 180 mg·kg~(-1),the tumor growth was significant inhibition the inhibiting rates on tumor were 40.6%、53.1%and 66.4%,and inhibition expression of PCNA protein in implanted tumor.Flow cytometry analysis revealed that treating xenograft tumor cells with increasing quantities of DADS increased the percentage of cells in the G_2/M phase.The results of immunohistochemical staining of PCNA showed that PCNA label index of group NS was the highest.There was no significant difference among the rest groups.
Conclusion:
1.DADS could significantly inhibit the proliferation of human small cell lung cancer cell lines H446 and this effect presents a scene of dose-dependent and time-dependent,
2.DADS could obviously inhibit the growth of xenograft of H446 cells in nude mouse.
3.DADS inhibited proliferation and induce apoptosis of xenograft tumor cell by preventing the G_2/M phase arrest.
4.Anti-proliferation mechanism probably related to down regulated expression of PCNA protein in xenograft.
引文
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