组蛋白去乙酰化酶抑制剂与顺铂联用对口腔鳞癌细胞作用的体外研究
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摘要
研究背景：以顺铂为代表的铂类化合物由于其显著的抗瘤效应，是治疗口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)最常用的一类化疗药物。为克服临床上越来越多的病人对顺铂产生的耐药性及减轻由于用药剂量所导致的毒副反应，以顺铂为核心的联合用药方案是目前口腔肿瘤防治领域的研究热点和难点。
研究目的：本课题首次尝试将新的抗瘤药物，即组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors,HDACIs)与顺铂进行联合配伍，探索二者联用应用于口腔鳞癌治疗的可能性，特别是观察HDACIs与顺铂联合应用作用于口腔鳞癌细胞后，是否能增强药物在体外的抗瘤效应，并初步探讨二者联用作用于口腔鳞癌细胞的分子机制。
研究方法：以口腔鳞癌细胞Tea8113及KB为研究对象：(1)采用MTS比色实验研究HDACIs及顺铂单独作用于口腔鳞癌细胞后，对其生长增殖的抑制作用，获得口腔鳞癌细胞对单独使用两种药物的剂量反应；(2)采用westem blotting的方法观察HDACIs作用于口腔鳞癌细胞后，对细胞组蛋白乙酰化水平的影响；(3)结合前面1，2所得实验结果，采用低剂量的HDACIs及顺铂进行联用，运用MTS及克隆形成实验检测药物对口腔鳞癌细胞的毒性作用；(4)采用流式细胞术(flow cytometry,FCM)及TUNEL(terminal deoxynucleotidyltransferase dUTP nick end labeling)检测低剂量的HDACIs与顺铂配伍后是否能诱导口腔鳞癌细胞发生凋亡，并与单独运用这两种药物的细胞相比较；(5)采用westem blotting的方法检测低剂量的HDACIs与顺铂联合应用对以p53为中心的细胞信号通路的影响。
研究结果：两株口腔鳞癌细胞都对HDACIs及顺铂呈现出较好的敏感性并且HDACIs可以迅速导致Tca8113及KB细胞组蛋白乙酰化水平的提高；与单独运用低剂量的两种药物比较，低剂量的HDACIs及顺铂联用可以使两种药物的细胞毒性作用显著增强(P＜0．05)，并明显诱导口腔鳞癌细胞发生凋亡(P＜0．05)；两种药物进行低剂量的联用后，可以诱导p53的表达，活化其下游信号分子BID，细胞色素C(Cytochrome C)从线粒体释放到胞浆中并导致凋亡效应分子Caspase 3发生裂解。
结论：HDACIs可以有效增强口腔鳞癌细胞对低剂量顺铂的敏感性，在体外实验中呈现了较好的抗癌效应；同时HDACIs对顺铂的协同作用可能是通过重建与顺铂耐药密切相关的p53内源性及外源性凋亡信号通路得以实现。本研究提示我们：HDACIs与顺铂的配伍可能成为口腔鳞癌治疗领域的新策略。
Background
Platinum-based chemotherapy drug, for example, cisplatin, has been used as the first -line single agent for its powerful therapeutic effects against oral squamous cell carcinoma(OSCC).However, both the resistance to cisplatin and dose-related toxicity remain two of the most crucial issues in the chemotherapy of clinical OSCC treatment. Researches have been seeking a combinative treatment regimen to improve the effect of chemotherapy. In our study, we evaluated the potential combinative effect of histone deacetylase inhibitors (HDACIs) and cisplatin on OSCC cell lines.
Purpose
To explore the possible synergistic anticancer efficiency of both HDACIs and cisplatin in OSCC cell line. Molecular mechanisms underlying drug induced apoptosis and activation of apoptosis related proteins in OSCC cell lines are also examined.
Methods
By using MTS methods, Tca8113 and KB cells were firstly treated with HDACIs and cisplatin alone and the dose response for single agent was obtained. Then, western blotting was performed to evaluate the acetylated histone level in Tca81113 and KB cells treated with HDACIs. Subsequently, a subtoxic dose of cisplatin and HDACIs was used in combination to compare their activities against OSCC cancer cells. Cell growth and viability were assessed using MTS and colony formation assay, and apoptosis was measured by flow cytometry and DeadEnd~(TM) Fluorometric TUNEL System. At last, to further explore the cellular basis of the synergistic response observed in OSCC cell lines, the analysis of selected p53 related apoptosis network was then performed by western blotting.
Results
Both Tca8113 and KB were sensitive to HDACIs and cisplatin alone. HDACIs could rapidly induce accumulation of acetylated histone in OSCC cell lines. Compared with either HDACIs or cisplatin treated alone, co-administration of subtoxic of both drugs synergistically induces cytotoxicity and apoptosis in both Tca8113 and KB cell lines (P<0.05).The increased drug sensitivity observed with co-treatment of the cells with HDACIs is mediated by p53 induction, increased activation of pro-apoptotic protein BID, released of cytochrome C to cytosol, and increased activation of caspase-3.
Conclusion
These founding suggest us that concurrent treatment with HDACIs enhances tumor cell sensitivity to subtoxic doses of cisplatin through p53 intrinsic and extrinsic apoptosis pathway that has close relationship with drug resistance. This may be regarded as a novel strategy for treatment of OSCC.
研究目的：本课题首次尝试将新的抗瘤药物，即组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors,HDACIs)与顺铂进行联合配伍，探索二者联用应用于口腔鳞癌治疗的可能性，特别是观察HDACIs与顺铂联合应用作用于口腔鳞癌细胞后，是否能增强药物在体外的抗瘤效应，并初步探讨二者联用作用于口腔鳞癌细胞的分子机制。
研究方法：以口腔鳞癌细胞Tea8113及KB为研究对象：(1)采用MTS比色实验研究HDACIs及顺铂单独作用于口腔鳞癌细胞后，对其生长增殖的抑制作用，获得口腔鳞癌细胞对单独使用两种药物的剂量反应；(2)采用westem blotting的方法观察HDACIs作用于口腔鳞癌细胞后，对细胞组蛋白乙酰化水平的影响；(3)结合前面1，2所得实验结果，采用低剂量的HDACIs及顺铂进行联用，运用MTS及克隆形成实验检测药物对口腔鳞癌细胞的毒性作用；(4)采用流式细胞术(flow cytometry,FCM)及TUNEL(terminal deoxynucleotidyltransferase dUTP nick end labeling)检测低剂量的HDACIs与顺铂配伍后是否能诱导口腔鳞癌细胞发生凋亡，并与单独运用这两种药物的细胞相比较；(5)采用westem blotting的方法检测低剂量的HDACIs与顺铂联合应用对以p53为中心的细胞信号通路的影响。
研究结果：两株口腔鳞癌细胞都对HDACIs及顺铂呈现出较好的敏感性并且HDACIs可以迅速导致Tca8113及KB细胞组蛋白乙酰化水平的提高；与单独运用低剂量的两种药物比较，低剂量的HDACIs及顺铂联用可以使两种药物的细胞毒性作用显著增强(P＜0．05)，并明显诱导口腔鳞癌细胞发生凋亡(P＜0．05)；两种药物进行低剂量的联用后，可以诱导p53的表达，活化其下游信号分子BID，细胞色素C(Cytochrome C)从线粒体释放到胞浆中并导致凋亡效应分子Caspase 3发生裂解。
结论：HDACIs可以有效增强口腔鳞癌细胞对低剂量顺铂的敏感性，在体外实验中呈现了较好的抗癌效应；同时HDACIs对顺铂的协同作用可能是通过重建与顺铂耐药密切相关的p53内源性及外源性凋亡信号通路得以实现。本研究提示我们：HDACIs与顺铂的配伍可能成为口腔鳞癌治疗领域的新策略。
Background
Platinum-based chemotherapy drug, for example, cisplatin, has been used as the first -line single agent for its powerful therapeutic effects against oral squamous cell carcinoma(OSCC).However, both the resistance to cisplatin and dose-related toxicity remain two of the most crucial issues in the chemotherapy of clinical OSCC treatment. Researches have been seeking a combinative treatment regimen to improve the effect of chemotherapy. In our study, we evaluated the potential combinative effect of histone deacetylase inhibitors (HDACIs) and cisplatin on OSCC cell lines.
Purpose
To explore the possible synergistic anticancer efficiency of both HDACIs and cisplatin in OSCC cell line. Molecular mechanisms underlying drug induced apoptosis and activation of apoptosis related proteins in OSCC cell lines are also examined.
Methods
By using MTS methods, Tca8113 and KB cells were firstly treated with HDACIs and cisplatin alone and the dose response for single agent was obtained. Then, western blotting was performed to evaluate the acetylated histone level in Tca81113 and KB cells treated with HDACIs. Subsequently, a subtoxic dose of cisplatin and HDACIs was used in combination to compare their activities against OSCC cancer cells. Cell growth and viability were assessed using MTS and colony formation assay, and apoptosis was measured by flow cytometry and DeadEnd~(TM) Fluorometric TUNEL System. At last, to further explore the cellular basis of the synergistic response observed in OSCC cell lines, the analysis of selected p53 related apoptosis network was then performed by western blotting.
Results
Both Tca8113 and KB were sensitive to HDACIs and cisplatin alone. HDACIs could rapidly induce accumulation of acetylated histone in OSCC cell lines. Compared with either HDACIs or cisplatin treated alone, co-administration of subtoxic of both drugs synergistically induces cytotoxicity and apoptosis in both Tca8113 and KB cell lines (P<0.05).The increased drug sensitivity observed with co-treatment of the cells with HDACIs is mediated by p53 induction, increased activation of pro-apoptotic protein BID, released of cytochrome C to cytosol, and increased activation of caspase-3.
Conclusion
These founding suggest us that concurrent treatment with HDACIs enhances tumor cell sensitivity to subtoxic doses of cisplatin through p53 intrinsic and extrinsic apoptosis pathway that has close relationship with drug resistance. This may be regarded as a novel strategy for treatment of OSCC.
引文
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