浅蓝菌素联合吉西他滨抑制人胰腺癌细胞株BXPC-3生长及机制的实验研究
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摘要
第一部分浅蓝菌素对人胰腺癌细胞株BXPC-3的影响及机制
目的：研究脂肪酸合酶（fatty acid synthane，FAS）抑制剂浅蓝菌素（Cerulenin，Cer）对胰腺癌BXPC-3细胞体外生长和凋亡的影响，并初步探讨可能的作用机制。
方法：采用不同浓度（0、2.5、5、10、20、40μg/ml）Cer处理胰腺癌细胞BXPC-3，细胞增殖与毒性检测法（CCK8）检测OD值，计算对照组和各实验组BXPC-3细胞的抑制率，并计算最适宜的Cer IC50；取Cer浓度为0、5、10、20μg/ml处理胰腺癌BXPC-3细胞后进行流式细胞术及AnnexinV/PI早期凋亡检测细胞凋亡率和细胞周期的变化；反转录聚合酶链反应（Reverse Transcription Polymerase ChainReaction，RT-PCR）检测FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA表达水平的变化；免疫印迹法（Western Blot）检测细胞凋亡因子Bcl-2、Bax蛋白表达情况，酶测定法检测Caspase8、Caspase9、Caspase3活性。
结果：（1）CCK8法显示Cer可明显抑制BXPC-3细胞的生长，并随着浓度的增加和作用时间的延长而明显增强（P<0.05）。（2）流式细胞术及AnnexinV/PI早期凋亡检测出BXPC-3细胞经Cer作用48小时后，细胞周期S期比例上升，从（5.18±0.25）%上升到（25.15±1.15）%，G2期细胞比例下降（P<0.05）。细胞有明显凋亡，且以早期凋亡为主，在5μg/ml浓度下早期凋亡率为（11.67±0.65）%，10μg/ml浓度下为（29.1±1.31）%，而在20μg/ml浓度下为（48.8±1.23）%，与Cer浓度呈正相关。（3）RT-PCR检测FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA表明BXPC-3细胞经Cer作用48小时后，FASmRNA、 Bcl-2mRNA的表达呈浓度依赖性下降，Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA呈浓度依赖性上升，各浓度组与对照组比较差异有统计学意义（P<0.05）。（4） Western Blot结果显示Cer作用于BXPC-3细胞48h可使细胞中的Bcl-2蛋白表达下降，Bax蛋白表达升高，在Cer0μg/ml、5μg/ml、10μg/ml、20μg/ml浓度下Bcl-2/Bax比值分别为（4.29±0.15）、（1.82±0.02）、（1.01±0.08）、（0.38±0.05），差异具有统计学意义（P<0.05）。（5）酶测定法检测Cer作用于BXPC-3细胞48h可使Caspase8、Caspase9、Caspase3的活性增加，且呈浓度依赖性（P<0.05）。Cer5μg/ml、10μg/ml、20μg/ml浓度组Caspase3活性分别为对照组的（1.75±0.31）、（3.27±0.01）、（4.96±0.02）倍； Caspase9活性分别为对照组的（1.40±0.4）、（2.12±0.06）、（3.39±0.02）倍；Caspase8活性分别为对照组的（1.26±0.07）、（1.86±0.11）、（2.5±0.02）倍。
结论：Cer以时间、浓度依赖方式抑制胰腺癌BXPC-3细胞的生长，其机制可能是直接抑制肿瘤细胞增殖；阻滞细胞周期于S期；主要通过线粒体途径诱导细胞发生早期凋亡。
第二部分浅蓝菌素联合吉西他滨对胰腺癌细胞BXPC-3的影响
目的:探讨Cer联合吉西他滨（Gemcitabine，GEM）对胰腺癌细胞BXPC-3的协同抑制作用及机制。
方法:以浓度为10μg/ml的Cer联合20μmol/L的GEM处理对数生长期的人胰腺癌BXPC-3细胞，应用CCK8法检测OD值，计算对照组和各实验组BXPC-3细胞的抑制率；AnnexinV/PI双染法检测BXPC-3细胞早期凋亡情况；RT-PCR半定量检测Bcl-2mRNA、Bax mRNA表达水平的变化，Western Blot检测细胞凋亡因子蛋白Bcl-2、Bax表达情况。
结果: Cer和GEM都能有效地抑制人胰腺癌BXPC-3细胞增殖，二者联合作用后，具有协同效应；Cer组作用BXPC-3细胞48h时细胞早期凋亡为（31.37±1.04）%，GEM组为（38.33±0.75）%，联合组为（69.43±0.83）%，联合组晚期凋亡率也明显增加；细胞凋亡因子Bcl-2表达明显下降，促细胞凋亡因子Bax表达上升，各组与对照组及单药组与联合组相比均有统计学意义（P<0.05）。
结论：浅蓝菌素可以显著增强吉西他滨对人胰腺癌BXPC-3细胞的生长抑制作用，其机制可能是通过促进细胞凋亡而发挥作用。
Part I: Effect and mechanism of cerulenin on human pancreaticcarcinoma cell line BXPC-3
Objective: To study the effect of cerulenin on the growth and apoptosis of humanpancreatic cancer cell line BXPC-3in vitro，and to explore its possible mechanisms.
Methods: The growth of pancreatic cancer cell BXPC-3treated by differentconcentrations of cerulenin (0、2.5、5、10、20、40μg/ml) was evaluated by CCK8assay,and inhibition ratios were calculated in all groups and suitable IC50of cerulenin wereworked out by calculation；With using different concentrations cerulenin (0、5、10、20μg/ml)to deal with BXPC-3, the apoptosis ratioes and changes of cell cycle were detected by flowcytometry and AnnexinV/PI fluos stainging；and the expression of FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA and Caspase3mRNA weredetected by RT-PCR；Bcl-2、Bax proteinum were detected by Western Blot in vitro；Caspase3、Caspase8and Caspase9activation was measured using a caspase fluorometricassay kit.
Results：(1) Cerulenin could inhibit the growth of the human pancreatic cancer cellline BXPC-3, and the inhibitory effect had dose-and-time dependence (P<0.05).(2)Theearly stage apoptosis and cyclomorphosis of BXPC-3cells was detected by flow cytometryand AnnexinV/PI fluos stainging after they were incubated48hours with cerulenin.Withthe increase of Cer concentration, ratio of S phase increased from(5.18±0.25)to(25.15±1.15)and ratio of G2phase declined homologously（P<0.05）,The early stage apoptosis rate ofBXPC-3cells was (11.67±0.65)%when they were incubated with5μg/ml Cer and the rate was (48.8±1.23)%with20μg/ml Cer. Appearantly, apoptosis rate was positively correlatedto Cer concentration.(3)The expression of FAS mRNA and Bcl-2mRNA decreased withconcentration-dependence after BXPC-3cells were incubated48hours with Cer, whichwas detected by RT-PCR. Otherwise, The expression of Caspase8mRNA、Caspase9mRNA、Caspase3mRNA and Bax mRNA increased with concentration-dependence,Comparisons of all Cer groups and control group have significant difference（P<0.05）.(4)The expression of Bcl-2was downregulated and the expression of Bax wasupregulated significantly after BXPC-3cells were incubated48hours with Cer, which wasdetected by Western Blot. And the ratio of Bcl-2/Bax were (4.29±0.15)、(1.82±0.02)、(1.01±0.08)、(0.38±0.05) when BXPC-3were incubated with0、5、10、20μg/ml Cer(P<0.05).(5)With the increase of Cer concentration, the activity of Caspase8、Caspase9and Caspase3was increased gradually in all Cer groups, Comparisons all Cer groups andcontrol group have significant difference (P<0.05). At the5、10、20μg/ml Cerconcentration,the caspase3activity was increased as (1.75±0.31)、(3.27±0.01)、(4.96±0.02)times as control group, the caspase9activity was increased as (1.40±0.4)、(2.12±0.06)、(3.39±0.02)times as control group, the caspase8activity was increased as(1.26±0.07)、(1.86±0.11)、(2.5±0.02)times as control group.
Conclusion：Cerulenin could inhabit the growth of human pancreatic cancer cell lineBXPC-3in a dose-and-time dependent manner, and its mechanisms may directly inhibittummor cells to proliferate and arrest cell cycle in S stage. And it mainly induces apoptosisthrough mitochondrion pathways.
Part Ⅱ: Effect and mechanism of Cer in combination with GEM onpancreatic cancer cell BXPC-3
Objective: To investigate the effect and mechanism of action in pancreatic cancerBXPC-3cell treated by Cer in combination with GEM.
Methods: BXPC-3cells were cultivated with10μg/ml Cer and20μmol/L GEM. OD values were detected by CCK8assay and their inhibition ratios were calculated and earlyapoptosis of them were detected by AnnexinV/PI double staining method and theexpression of Bcl-2mRNA and Bax mRNA were detected by RT-PCR, Bcl-2、Baxproteinum were detected by Western Blot.
Result: Both Cer and GEM could inhibit effectivly BXPC-3cell’ proliferation.Cerulenin combinated with gemcitabine had synergistic effect and their combination couldincrease both early stage apoptosis obviously and advanced stage apoptosis, the early stageapoptosis was (31.37±1.04) when BXPC-3were cultivated with10μg/ml Cer,the ratewas(38.33±0.75)with20μmmol/L GEM and the rate was (69.43±0.83)%with10μg/ml Cercombined with20μg/ml Cer. And the expression of Bcl-2mRNA、Bcl-2protein weredownregulated, and the expression of Bax mRNA、 Bax protein were upregulated.Comparisons of treated groups and control group have significant difference (P<0.05) andcomparisons of single drug groups and combination group have also significant difference(P<0.05).
Conclusion： Cerulenin could obviously inhibit pancreatic cancer cell BXPC-3proliferation in a dose-and-time dependent manner in coordination with Gemcitabine.Itsmajor mechanisms maybe promote apoptosis of cells.
目的：研究脂肪酸合酶（fatty acid synthane，FAS）抑制剂浅蓝菌素（Cerulenin，Cer）对胰腺癌BXPC-3细胞体外生长和凋亡的影响，并初步探讨可能的作用机制。
方法：采用不同浓度（0、2.5、5、10、20、40μg/ml）Cer处理胰腺癌细胞BXPC-3，细胞增殖与毒性检测法（CCK8）检测OD值，计算对照组和各实验组BXPC-3细胞的抑制率，并计算最适宜的Cer IC50；取Cer浓度为0、5、10、20μg/ml处理胰腺癌BXPC-3细胞后进行流式细胞术及AnnexinV/PI早期凋亡检测细胞凋亡率和细胞周期的变化；反转录聚合酶链反应（Reverse Transcription Polymerase ChainReaction，RT-PCR）检测FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA表达水平的变化；免疫印迹法（Western Blot）检测细胞凋亡因子Bcl-2、Bax蛋白表达情况，酶测定法检测Caspase8、Caspase9、Caspase3活性。
结果：（1）CCK8法显示Cer可明显抑制BXPC-3细胞的生长，并随着浓度的增加和作用时间的延长而明显增强（P<0.05）。（2）流式细胞术及AnnexinV/PI早期凋亡检测出BXPC-3细胞经Cer作用48小时后，细胞周期S期比例上升，从（5.18±0.25）%上升到（25.15±1.15）%，G2期细胞比例下降（P<0.05）。细胞有明显凋亡，且以早期凋亡为主，在5μg/ml浓度下早期凋亡率为（11.67±0.65）%，10μg/ml浓度下为（29.1±1.31）%，而在20μg/ml浓度下为（48.8±1.23）%，与Cer浓度呈正相关。（3）RT-PCR检测FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA表明BXPC-3细胞经Cer作用48小时后，FASmRNA、 Bcl-2mRNA的表达呈浓度依赖性下降，Bax mRNA、Caspase8mRNA、Caspase9mRNA、Caspase3mRNA呈浓度依赖性上升，各浓度组与对照组比较差异有统计学意义（P<0.05）。（4） Western Blot结果显示Cer作用于BXPC-3细胞48h可使细胞中的Bcl-2蛋白表达下降，Bax蛋白表达升高，在Cer0μg/ml、5μg/ml、10μg/ml、20μg/ml浓度下Bcl-2/Bax比值分别为（4.29±0.15）、（1.82±0.02）、（1.01±0.08）、（0.38±0.05），差异具有统计学意义（P<0.05）。（5）酶测定法检测Cer作用于BXPC-3细胞48h可使Caspase8、Caspase9、Caspase3的活性增加，且呈浓度依赖性（P<0.05）。Cer5μg/ml、10μg/ml、20μg/ml浓度组Caspase3活性分别为对照组的（1.75±0.31）、（3.27±0.01）、（4.96±0.02）倍； Caspase9活性分别为对照组的（1.40±0.4）、（2.12±0.06）、（3.39±0.02）倍；Caspase8活性分别为对照组的（1.26±0.07）、（1.86±0.11）、（2.5±0.02）倍。
结论：Cer以时间、浓度依赖方式抑制胰腺癌BXPC-3细胞的生长，其机制可能是直接抑制肿瘤细胞增殖；阻滞细胞周期于S期；主要通过线粒体途径诱导细胞发生早期凋亡。
第二部分浅蓝菌素联合吉西他滨对胰腺癌细胞BXPC-3的影响
目的:探讨Cer联合吉西他滨（Gemcitabine，GEM）对胰腺癌细胞BXPC-3的协同抑制作用及机制。
方法:以浓度为10μg/ml的Cer联合20μmol/L的GEM处理对数生长期的人胰腺癌BXPC-3细胞，应用CCK8法检测OD值，计算对照组和各实验组BXPC-3细胞的抑制率；AnnexinV/PI双染法检测BXPC-3细胞早期凋亡情况；RT-PCR半定量检测Bcl-2mRNA、Bax mRNA表达水平的变化，Western Blot检测细胞凋亡因子蛋白Bcl-2、Bax表达情况。
结果: Cer和GEM都能有效地抑制人胰腺癌BXPC-3细胞增殖，二者联合作用后，具有协同效应；Cer组作用BXPC-3细胞48h时细胞早期凋亡为（31.37±1.04）%，GEM组为（38.33±0.75）%，联合组为（69.43±0.83）%，联合组晚期凋亡率也明显增加；细胞凋亡因子Bcl-2表达明显下降，促细胞凋亡因子Bax表达上升，各组与对照组及单药组与联合组相比均有统计学意义（P<0.05）。
结论：浅蓝菌素可以显著增强吉西他滨对人胰腺癌BXPC-3细胞的生长抑制作用，其机制可能是通过促进细胞凋亡而发挥作用。
Part I: Effect and mechanism of cerulenin on human pancreaticcarcinoma cell line BXPC-3
Objective: To study the effect of cerulenin on the growth and apoptosis of humanpancreatic cancer cell line BXPC-3in vitro，and to explore its possible mechanisms.
Methods: The growth of pancreatic cancer cell BXPC-3treated by differentconcentrations of cerulenin (0、2.5、5、10、20、40μg/ml) was evaluated by CCK8assay,and inhibition ratios were calculated in all groups and suitable IC50of cerulenin wereworked out by calculation；With using different concentrations cerulenin (0、5、10、20μg/ml)to deal with BXPC-3, the apoptosis ratioes and changes of cell cycle were detected by flowcytometry and AnnexinV/PI fluos stainging；and the expression of FAS mRNA、Bcl-2mRNA、Bax mRNA、Caspase8mRNA、Caspase9mRNA and Caspase3mRNA weredetected by RT-PCR；Bcl-2、Bax proteinum were detected by Western Blot in vitro；Caspase3、Caspase8and Caspase9activation was measured using a caspase fluorometricassay kit.
Results：(1) Cerulenin could inhibit the growth of the human pancreatic cancer cellline BXPC-3, and the inhibitory effect had dose-and-time dependence (P<0.05).(2)Theearly stage apoptosis and cyclomorphosis of BXPC-3cells was detected by flow cytometryand AnnexinV/PI fluos stainging after they were incubated48hours with cerulenin.Withthe increase of Cer concentration, ratio of S phase increased from(5.18±0.25)to(25.15±1.15)and ratio of G2phase declined homologously（P<0.05）,The early stage apoptosis rate ofBXPC-3cells was (11.67±0.65)%when they were incubated with5μg/ml Cer and the rate was (48.8±1.23)%with20μg/ml Cer. Appearantly, apoptosis rate was positively correlatedto Cer concentration.(3)The expression of FAS mRNA and Bcl-2mRNA decreased withconcentration-dependence after BXPC-3cells were incubated48hours with Cer, whichwas detected by RT-PCR. Otherwise, The expression of Caspase8mRNA、Caspase9mRNA、Caspase3mRNA and Bax mRNA increased with concentration-dependence,Comparisons of all Cer groups and control group have significant difference（P<0.05）.(4)The expression of Bcl-2was downregulated and the expression of Bax wasupregulated significantly after BXPC-3cells were incubated48hours with Cer, which wasdetected by Western Blot. And the ratio of Bcl-2/Bax were (4.29±0.15)、(1.82±0.02)、(1.01±0.08)、(0.38±0.05) when BXPC-3were incubated with0、5、10、20μg/ml Cer(P<0.05).(5)With the increase of Cer concentration, the activity of Caspase8、Caspase9and Caspase3was increased gradually in all Cer groups, Comparisons all Cer groups andcontrol group have significant difference (P<0.05). At the5、10、20μg/ml Cerconcentration,the caspase3activity was increased as (1.75±0.31)、(3.27±0.01)、(4.96±0.02)times as control group, the caspase9activity was increased as (1.40±0.4)、(2.12±0.06)、(3.39±0.02)times as control group, the caspase8activity was increased as(1.26±0.07)、(1.86±0.11)、(2.5±0.02)times as control group.
Conclusion：Cerulenin could inhabit the growth of human pancreatic cancer cell lineBXPC-3in a dose-and-time dependent manner, and its mechanisms may directly inhibittummor cells to proliferate and arrest cell cycle in S stage. And it mainly induces apoptosisthrough mitochondrion pathways.
Part Ⅱ: Effect and mechanism of Cer in combination with GEM onpancreatic cancer cell BXPC-3
Objective: To investigate the effect and mechanism of action in pancreatic cancerBXPC-3cell treated by Cer in combination with GEM.
Methods: BXPC-3cells were cultivated with10μg/ml Cer and20μmol/L GEM. OD values were detected by CCK8assay and their inhibition ratios were calculated and earlyapoptosis of them were detected by AnnexinV/PI double staining method and theexpression of Bcl-2mRNA and Bax mRNA were detected by RT-PCR, Bcl-2、Baxproteinum were detected by Western Blot.
Result: Both Cer and GEM could inhibit effectivly BXPC-3cell’ proliferation.Cerulenin combinated with gemcitabine had synergistic effect and their combination couldincrease both early stage apoptosis obviously and advanced stage apoptosis, the early stageapoptosis was (31.37±1.04) when BXPC-3were cultivated with10μg/ml Cer,the ratewas(38.33±0.75)with20μmmol/L GEM and the rate was (69.43±0.83)%with10μg/ml Cercombined with20μg/ml Cer. And the expression of Bcl-2mRNA、Bcl-2protein weredownregulated, and the expression of Bax mRNA、 Bax protein were upregulated.Comparisons of treated groups and control group have significant difference (P<0.05) andcomparisons of single drug groups and combination group have also significant difference(P<0.05).
Conclusion： Cerulenin could obviously inhibit pancreatic cancer cell BXPC-3proliferation in a dose-and-time dependent manner in coordination with Gemcitabine.Itsmajor mechanisms maybe promote apoptosis of cells.
引文
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