丙戊酸钠增强宫颈癌细胞Hela放射敏感性的实验性研究
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摘要
目的放射治疗作为一种传统治疗手段,在肿瘤的综合治疗中具有重要地位,在我国,大约70%的肿瘤需要放射治疗的参与。肿瘤对放射线敏感性差或瘤床周围正常组织对放射耐受性低往往导致放疗效果不理想。研制良好的放射增敏剂是提高放疗效果的一个重要途径,也成为肿瘤放射学的前沿课题。近年来,已有不少研究证明组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors,HDACIs)可通过抑制肿瘤细胞增殖、诱导凋亡、抑制肿瘤血管生成及转移、降低肿瘤侵袭力等机制发挥抗肿瘤作用,与放射联合还有放射增敏作用。HDACIs放射增敏的机制复杂,至今还未完全阐明。丙戊酸钠(valproic acid,VPA)一直以来用于癫痫的治疗,最近发现其具有抑制HDAC活性的作用,因其半衰期长、生物利用度高、有效血药浓度低、毒副作用小等优点,而显示出良好的临床应用前景。故本实验选择其作为HDACIs的代表,进一步阐明其放射增敏的机制,并为临床用药提供指导。
方法不同浓度VPA(0.25mmol/L、0.5 mmol/L、1 mmol/L、2 mmol/L、4 mmol/L)处理宫颈癌细胞系Hela不同时间(1d、2d、3d、4d、5d)后,通过MTT法检测VPA对Hela细胞的增殖抑制作用;倒置相差显微镜观察不同浓度VPA作用2d后细胞形态学变化;0.25mmol/L VPA作用Hela细胞24h后,克隆形成实验观察VPA的放射增敏作用;流式细胞仪检测不同浓度VPA作用后细胞周期分布及细胞凋亡率的变化;半定量RT-PCR测定Caspase-3及Bcl-2基因的表达;Western Blot检测caspase-3及Bcl-2蛋白的表达,了解VPA诱导细胞凋亡的具体途径。
结果HDAC抑制剂VPA对宫颈癌细胞系Hela有增殖抑制作用,且呈浓度、时间依赖性;经VPA处理2d后,Hela细胞逐渐缩小变成长梭形、胞膜皱缩、贴壁不良,有明显凋亡趋势;VPA在0.25mmol/L浓度时,对Hela细胞的毒性较低,但有放射增敏作用,克隆形成率明显减少(P＜0.05);VPA联合8Gy X线照射组细胞存活曲线与单纯照射组曲线相比,“肩”区减小,VPA抑制Hela细胞对放射致DNA亚致死损伤的修复能力。VPA能够诱导Hela细胞凋亡,阻滞细胞于G_2/M期,同时抑制细胞增殖;VPA无论在转录水平,还是翻译水平都上调caspase-3的表达,并可见蛋白裂解产物,表明VPA可以促进caspase-3的活化,同时下调bcl-2的表达。
结论HDAC抑制剂VPA对宫颈癌细胞系Hela有增殖抑制作用,呈浓度和作用时间依赖性。VPA在较低浓度0.25mmol/L对Hela细胞具有放射增敏作用,其放射增敏机制与直接抑制细胞增殖、增加细胞的凋亡及细胞周期阻滞有关。VPA增强Hela细胞放射诱导凋亡的机制主要是通过上调caspase-3表达,同时下调bcl-2的表达实现的。
Objective Radiotherapy conducting as a traditional therapy plays an important role in the treatment of malignancies,and it is involved in about 70%of total malignancies in our country.The outcome of radiation therapy depends on the radiosensitivity of tumor cells and the tolerance of the tissue bed to radiation.So developing satisfactory radiosensitizer is an important way to enhance the radiation effect,and it also becomes a front topic of radiation oncology.There are a lot of researches supporting that the histone deacetylase inhibitors(HDACIs)not only have antitumor effect through many ways,such as inhibiting tumor cell proliferation, inducing apoptosis,inhibiting tumor angiogenesis and metastasis,cutting down the tumor invasiveness and so on,but also enhance the radiosensitivity of tumor combined with radiation.The mechanisms of radiosensitivity enhancement of the histone deacetylase inhibitors are complicated and it is not very clear so far.Sodium valproate (VPA)has been used to treat epilepsy for many years.Recently it is found that it can inhibite the histone deacetylase,because it has many good qualities such as long half life、high bioavailability、low valid blood medicine level and few side effects,it shows good perspective.In this study,we choose VPA as the representative of HDACIs to illuminate the mechanisms of enhancing radiosensitivity futher,and to guide for the clinical medication.
Methods MTT assay was used to measure the proliferation inhibition of the histone deacetylase inhibitor(valproic acid,VPA)in different concentrations (0.25mmol/L、0.5 mmol/L、1 mmol/L、2 mmol/L、4 mmol/L)and durations(1d、2d、3d、4d、5d)on uterine cervix tumor cell line Hela.Morphologic changes of Hela were observed through inverted contrast microscope after it incubated with various concentration VPA for 2 days.Hela cells incubater with 0.25mmol/L VPA were exposed to different doses X-ray irradiation(IR)(0、2、4、6、8cGy).Then the cells were assayed for clonogenic survival to determine the radiosensitizing effect of VPA.Flow cytometry was used to determine the effects of various concentration VPA on apoptosis and cell cycle distribution.RT-PCR and Western Blot were used to detect the expression of caspase-3 and Bcl-2 to find the pathway of VPA to induce Hela to apoptosis.
Results The changes of the growth curve showed VPA inhibited the proliferation of Hela cells significantly with time and dose dependent;After a 2 days culture with various concentration VPA,the cells exhibited deflate,the cell membrane shrinkage and bad adherence.It showed obvious apoptosis tendency.The HDAC inhibitor VPA at the concentration of 0.25mmol/L enhanced the killing effect of IR on Hela cells,and the cloning efficiency decreased obviously(P＜0.05).The sensitization enhancement ratio(SER)was 1.35、1.29 according to D_q、D_0.VPA not only induced apoptosis and caused cell cycle arrest at G_2/M phase,but also inhibited the proliferation of Hela.The expression of caspase-3 mRNA and protein increased after treatment with VPA at a dose-dependent manner,and cleaved caspase-3 protein was also observed,whereas down regulation was detected with Bcl-2.
Conclusions These findings indicated that the histone deacetylase inhibitor VPA inhibited the growth of uterine cervix cancer cell line Hela at a dose-and time-dependent manner.VPA enhanced the radiosensitivity of Hela cells,and the mechanisms for this action might include inhibition of sublethal injury repair、direct cellular proliferation inhibition、increasing the sensitivity of Hela cell to X-ray irradiation-induced apoptosis and cell cycle arrest.Both of up-regulating the expression of caspase-3 and down-regulating the expression of Bcl-2 might play an imporment role in the sensitization enhancement of VPA to irradiation-induced apoptosis.
方法不同浓度VPA(0.25mmol/L、0.5 mmol/L、1 mmol/L、2 mmol/L、4 mmol/L)处理宫颈癌细胞系Hela不同时间(1d、2d、3d、4d、5d)后,通过MTT法检测VPA对Hela细胞的增殖抑制作用;倒置相差显微镜观察不同浓度VPA作用2d后细胞形态学变化;0.25mmol/L VPA作用Hela细胞24h后,克隆形成实验观察VPA的放射增敏作用;流式细胞仪检测不同浓度VPA作用后细胞周期分布及细胞凋亡率的变化;半定量RT-PCR测定Caspase-3及Bcl-2基因的表达;Western Blot检测caspase-3及Bcl-2蛋白的表达,了解VPA诱导细胞凋亡的具体途径。
结果HDAC抑制剂VPA对宫颈癌细胞系Hela有增殖抑制作用,且呈浓度、时间依赖性;经VPA处理2d后,Hela细胞逐渐缩小变成长梭形、胞膜皱缩、贴壁不良,有明显凋亡趋势;VPA在0.25mmol/L浓度时,对Hela细胞的毒性较低,但有放射增敏作用,克隆形成率明显减少(P＜0.05);VPA联合8Gy X线照射组细胞存活曲线与单纯照射组曲线相比,“肩”区减小,VPA抑制Hela细胞对放射致DNA亚致死损伤的修复能力。VPA能够诱导Hela细胞凋亡,阻滞细胞于G_2/M期,同时抑制细胞增殖;VPA无论在转录水平,还是翻译水平都上调caspase-3的表达,并可见蛋白裂解产物,表明VPA可以促进caspase-3的活化,同时下调bcl-2的表达。
结论HDAC抑制剂VPA对宫颈癌细胞系Hela有增殖抑制作用,呈浓度和作用时间依赖性。VPA在较低浓度0.25mmol/L对Hela细胞具有放射增敏作用,其放射增敏机制与直接抑制细胞增殖、增加细胞的凋亡及细胞周期阻滞有关。VPA增强Hela细胞放射诱导凋亡的机制主要是通过上调caspase-3表达,同时下调bcl-2的表达实现的。
Objective Radiotherapy conducting as a traditional therapy plays an important role in the treatment of malignancies,and it is involved in about 70%of total malignancies in our country.The outcome of radiation therapy depends on the radiosensitivity of tumor cells and the tolerance of the tissue bed to radiation.So developing satisfactory radiosensitizer is an important way to enhance the radiation effect,and it also becomes a front topic of radiation oncology.There are a lot of researches supporting that the histone deacetylase inhibitors(HDACIs)not only have antitumor effect through many ways,such as inhibiting tumor cell proliferation, inducing apoptosis,inhibiting tumor angiogenesis and metastasis,cutting down the tumor invasiveness and so on,but also enhance the radiosensitivity of tumor combined with radiation.The mechanisms of radiosensitivity enhancement of the histone deacetylase inhibitors are complicated and it is not very clear so far.Sodium valproate (VPA)has been used to treat epilepsy for many years.Recently it is found that it can inhibite the histone deacetylase,because it has many good qualities such as long half life、high bioavailability、low valid blood medicine level and few side effects,it shows good perspective.In this study,we choose VPA as the representative of HDACIs to illuminate the mechanisms of enhancing radiosensitivity futher,and to guide for the clinical medication.
Methods MTT assay was used to measure the proliferation inhibition of the histone deacetylase inhibitor(valproic acid,VPA)in different concentrations (0.25mmol/L、0.5 mmol/L、1 mmol/L、2 mmol/L、4 mmol/L)and durations(1d、2d、3d、4d、5d)on uterine cervix tumor cell line Hela.Morphologic changes of Hela were observed through inverted contrast microscope after it incubated with various concentration VPA for 2 days.Hela cells incubater with 0.25mmol/L VPA were exposed to different doses X-ray irradiation(IR)(0、2、4、6、8cGy).Then the cells were assayed for clonogenic survival to determine the radiosensitizing effect of VPA.Flow cytometry was used to determine the effects of various concentration VPA on apoptosis and cell cycle distribution.RT-PCR and Western Blot were used to detect the expression of caspase-3 and Bcl-2 to find the pathway of VPA to induce Hela to apoptosis.
Results The changes of the growth curve showed VPA inhibited the proliferation of Hela cells significantly with time and dose dependent;After a 2 days culture with various concentration VPA,the cells exhibited deflate,the cell membrane shrinkage and bad adherence.It showed obvious apoptosis tendency.The HDAC inhibitor VPA at the concentration of 0.25mmol/L enhanced the killing effect of IR on Hela cells,and the cloning efficiency decreased obviously(P＜0.05).The sensitization enhancement ratio(SER)was 1.35、1.29 according to D_q、D_0.VPA not only induced apoptosis and caused cell cycle arrest at G_2/M phase,but also inhibited the proliferation of Hela.The expression of caspase-3 mRNA and protein increased after treatment with VPA at a dose-dependent manner,and cleaved caspase-3 protein was also observed,whereas down regulation was detected with Bcl-2.
Conclusions These findings indicated that the histone deacetylase inhibitor VPA inhibited the growth of uterine cervix cancer cell line Hela at a dose-and time-dependent manner.VPA enhanced the radiosensitivity of Hela cells,and the mechanisms for this action might include inhibition of sublethal injury repair、direct cellular proliferation inhibition、increasing the sensitivity of Hela cell to X-ray irradiation-induced apoptosis and cell cycle arrest.Both of up-regulating the expression of caspase-3 and down-regulating the expression of Bcl-2 might play an imporment role in the sensitization enhancement of VPA to irradiation-induced apoptosis.
引文
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