姜黄素逆转肺癌细胞对顺铂耐药性的FA/BRCA途径机制研究
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摘要
背景和目的：
研究已经证明FA/BRCA途径是修复细胞DNA交联损伤的重要组成部分,该途径的功能状态与细胞对致交联损伤药物如顺铂(DDP)的敏感性相关,正常的FA/BRCA途径被激活是细胞对DNA链间交联剂(DDP等)耐药的分子基础。但是肺癌细胞对DDP耐药现象与FA/BRCA途径功能状态的关系还不很清楚,迄今为止FA/BRCA途径在肺癌细胞对DDP耐药中的作用机制尚无研究报道,FA/BRCA途径抑制剂姜黄素是否可逆转DDP耐药肺癌细胞对DDP的耐药性亦未见文献报告。因此,本研究以体外培养肺癌细胞株为研究对象,通过检测对DDP具有不同敏感性的肺癌细胞株FA/BRCA途径相关基因FANCC、FANCF、 FANCL、FANCD2mRNA及蛋白表达和FANCD2单泛素化状态,探讨FA/BRCA途径参与肺癌细胞对交联剂DDP耐药的分子机制。通过应用姜黄素和DDP处理DDP耐药肺癌细胞,观察FA/BRCA途径功能状态和肺癌细胞对DDP敏感性的变化,研究FA/BRCA途径抑制剂姜黄素增加肺癌细胞对DDP敏感性的作用机制,探讨姜黄素作为DDP耐药逆转剂用于肺癌治疗的可行性。
方法：
1、体外培养肺癌细胞株A549、Calu-1,应用CCK-8法检测经不同浓度DDP处理后肺癌细胞株A549和Calu-1的细胞增殖抑制率,观察比较不同肺癌细胞株对DDP敏感性的差异。实时荧光定量RT-PCR法分别测定用不同浓度DDP处理前后A549、Calu-1的FANCC、FANCF、FANCL和FANCD2mRNA表达水平的变化,Western blotting法分别测定不同浓度DDP处理后A549、Calu-1细胞株FANCC、FANCF、FANCL和FANCD2蛋白的表达,测定以FANCD2-L和FANCD2-S比值所表示的FANCD2单泛素化程度。探讨FA/BRCA途径在肺癌细胞对DDP耐药中的作用机制。
2、体外培养DDP敏感肺癌细胞株A549和耐药肺癌细胞株A549/DDP,分别用不同浓度的姜黄素、DDP及姜黄素加DDP处理后,Western blotting法测定这两个肺癌细胞的FANCD2单泛素化程度,免疫荧光染色法观察胞核内FANCD2核聚小体的形成,CCK-8法测定细胞增殖抑制率,DAPI荧光染色检测细胞凋亡,Annexin V/PI流式细胞术测定细胞凋亡率。观察姜黄素、DDP及姜黄素加DDP分别对肺癌细胞的细胞增殖和凋亡的作用,以及与FA/BRCA途径激活状态之间的关系,探讨姜黄素增加耐DDP肺癌细胞对DDP敏感性的效应,以及其这一效应的FA/BRCA途径机制。
结果：
1、DDP对肺癌细胞A549、Calu-1的增殖抑制作用均呈剂量依赖性和时间依赖性关系。经过不同浓度DDP处理24H和48H后,细胞A549的IC50明显低于细胞Calu-1,表明细胞A549对DDP的敏感性高于细胞Calu-1,细胞Calu-1对DDP相对耐药。与此相对应的是,肺癌细胞A549的FANCF和FANCL mRNA的表达(主要在DDP浓度2.5-5μg/ml时和20μg/ml)低于细胞Calu-1, A549细胞FANCD2mRNA的表达在DDP处理24H有所增高,但在DDP处理48H后明显降低,而Calu-1细胞FANCD2mRNA的表达在DDP处理24H(除DDP浓度20μg/ml外)和48H后均明显升高(除DDP浓度20μg/ml外)。肺癌细胞A549中的FANCF. FANCL和]FANCD2蛋白表达水平随DDP浓度增高呈进行性降低,而肺癌细胞Calu-1的FANCF蛋白(在2.5-10μg/ml DDP浓度范围内)表达随DDP作用时间的延长和浓度的逐渐上升呈进行性增高。Calu-1细胞的FANCD2单泛素化程度明显高于A549细胞。
2. A549/DDP细胞株对DDP中度耐药。分别用不同浓度的姜黄素、DDP及姜黄素加DDP处理后,A549/DDP细胞FANCD2单泛素化程度明显高于A549细胞。当用姜黄素联合DDP处理A549/DDP细胞时,姜黄素的加入显著降低A549/DDP细胞的FANCD2单泛素化水平,且联合用药组的FANCD2单泛素化水平在0-20μg/ml DDP浓度范围内均低于单独用药组,显示出明显的抑制效应。当姜黄素和不同浓度DDP联合分别处理两个肺癌细胞时,A549/DDP细胞核聚小体的表达较A549细胞明显减弱,表明姜黄素能抑制以FANCD2单泛素化及核聚小体形成为激活特征的FA/BRCA途径功能,逆转肺癌细胞对DDP的耐药性。姜黄素联合DDP处理时A549细胞增殖抑制率均高于两药单用时的增殖抑制率,但并未观察到两个药物之间的协同作用,q值<1.15。姜黄素联合DDP处理时A549/DDP的细胞增殖抑制率亦高于两药单用时的增殖抑制率,但姜黄素和DDP显示出明显的协同效应,q值>1.15。姜黄素和DDP联用时DDP抑制A549/DDP细胞的IC50显著下降,逆转倍数显著增高,表明细胞对DDP的敏感性增加。同时DAPI法显示A549/DDP细胞经姜黄素联合DDP处理时,细胞核染色质固缩明显,形成很多颗粒物质,核内染色质由于浓集而呈亮蓝色,细胞核破裂形成碎片,核解体,可见凋亡小体。应用Annexin V/PI双染法结合流式细胞仪检测细胞凋亡率发现,单用姜黄素或DDP分别处理A549和A549/DDP细胞48H后,A549细胞凋亡率明显高于A549/DDP细胞。而与之相反的是,用姜黄素联合DDP处理A549/DDP细胞后,细胞凋亡率在DDP浓度10-20μg/ml范围明显高于A549细胞。表明姜黄素与DDP共同作用时,DDP介导的FA/BRCA途径DNA损伤修复功能的激活受到姜黄素抑制,从而增强DDP诱导耐药肺癌细胞A549/DDP凋亡的作用。结论：
1、FA/BRCA途径参与了肺癌细胞对DDP的耐药机制,其中蛋白FANCF、 FANCD2在肺癌Calu-1细胞对DDP的耐药中可能起了较大作用,FANCD2单泛素化程度与肺癌细胞对DDP的耐药性相关,DDP处理肺癌细胞后的FANCD2单泛素化状态有可能作为预测肺癌患者是否对铂类药物化疗敏感的候选指标。
2、姜黄素可抑制DDP耐药肺癌细胞株A549/DDP细胞的FANCD2单泛素化,减少核聚小体形成,增强DDP对耐药肺癌细胞的增殖抑制作用,并在诱导肺癌细胞凋亡时与DDP有协同作用,进而逆转了DDP耐药肺癌细胞对DDP的耐药性。因此我们的实验结果证明,姜黄素作为FA/BRCA途径抑制剂,可抑制肺癌细胞FA/BRCA途径的DNA损伤修复功能,逆转肺癌细胞对DDP的耐药性,有望在今后成为肺癌临床治疗中的重要成员。
Background and Objective
FA/BRCA pathway plays a pivotal role in repair of DNA cross-linking damage induced by DNA interstrand cross-link (ICL) agents and greatly influences drug response in cancer treatment. The studies have demonstrated that inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. But the mechanism for relationship between the FA/BRCA pathway function status and chemoresistance to cisplatin (DDP) in lung cancer cells is poorly understood. Also it is not clear whether FA/BRCA pathway inhibitor, such as curcumin, can enhance sensitivity to DDP in A549/DDP cell, a DDP-resistant lung cancer cell line. Thus, the purposes of this study are to explore the FA/BRCA pathway mechanism of resistance to DDP in lung cancer cells, and investigate the efficiency of curcumin in potentiating the cytotoxic effects of DDP in A549/DDP cells, and explore the feasibility of curcumin as DDP-resistant reversal agent in treatment of lung cancer.
Methods
1. The proliferation inhibition rates of lung cancer cell lines A549and Calu-1treated with variant concentration of DDP were measured using the CCK-8assay. The expression levels of FANCC, FANCF, FANCL and FANCD2mRNA were detected by real-time fluorescent quantitative PCR (RFQ-PCR). The expressions of FANCC, FANCF, FANCL and FANCD2proteins were determined by Western blotting. FANCD2monoubiquitination level was defined as the ratio of FANCD2-L and FANCD2-S (L/S).
2. After treatment with different concentrations of curcumin, DDP alone or combination of curcumin with DDP, the FANCD2monoubiquitination levels were measured by Western blotting in lung cancer cell lines A549and A549/DDP, respectivly. The formation of FANCD2nuclear foci were determined by immunofluorescence staining. The rate of cell proliferation inhibition was detected by CCK-8assay. Apoptosis was assessed by DAPI staining. Apoptosis rate was measured by flow cytometry using Annexin V/PI methods.
Results
1. After treatment with DDP, the rates of proliferation inhibiting of A549and Calu-1lung cancer cell lines were increased gradually with a dose-dependent manner (P<0.05) and a time-dependent manner (P<0.05). The50%inhibitory concentrations of DDP were significantly lower in A549cells than in Calu-1cells. FANCF and FANCL mRNA expression levels in A549cells were markedly lower than those in Calu-1cells. The FANCD2mRNA levels were increased in A549cells at24H after treatment of DDP (in2.5-5μg/ml and20μg/ml DDP respectively) and were decreased at48H after treatment of DDP, while the FANCD2mRNA expression were significantly increased in Calu-1cells at24H and48H after treatment of DDP (except for DDP concentration of20μg/ml at two time points). Meantime, the expressions of FANCC, FANCF and FANCL protein in A549cells were significantly decreased during the treatment of5-20μg/ml DDP as compared with control group. After treatment of5-10μg/ml and20μg/ml DDP, however, FANCC and FANCF mRNA levels in Calu-1cells were initially increased and then decreased after treatment of variant concentrations DDP. The FANCD2monoubiquitination levels in Calu-1cells were significantly higher than those in A549cells.
2. A549/DDP cell lines were moderately resistant to DDP. The FANCD2monoubiquitination levels in A549/DDP cells were significantly higher than those in A549cells following treatment with different concentrations of curcumin, DDP alone or combination of curcumin and DDP. In the concentration range of0-20μg/ml DDP, the addition of curcumin can significantly reduce FANCD2monoubiquitination levels in A549/DDP cells. FANCD2monoubiquitination levels in A549/DDP cells treated with combination of DDP and curcumin were significantly lower than those in these cells treated with curcumin or DDP alone. After treatment with combination of curcumin and DDP, the fluorescence nuclear foci expressions were significantly decreased in A549/DDP cells than in A549cells, implying that curcumin can inhibite FANCD2monoubiquitination levels and the formation of nuclear foci induced by DDP in these DDP-resistant lung caner cells. Proliferation inhibition rate in A549cells treated with curcumin puls DDP was significantly higher than that in these cells treated with curcumin or cisplatin alone, but synergism of curcumin and DDP on proliferation inhibition is not found in the DDP-sensitive cells (q value<1.15). Proliferation inhibition rate in A549/DDP cells treated with curcumin puls cisplatin was also significantly higher than that in these cells treated with single drug, moreover, there is a synergistic effect both curcumin and cisplatin on proliferation inhibition in the DDP-resistant cells(q values>1.15). The inhibitory concentrations of50%of DDP in A549/DDP cells were decreased significantly after treatment with cisplatin plus DDP. In addition, after treatment with curcumin plus DDP in A549/DDP cells, DAPI stained showed that their nuclear chromatin condensation which formed a lot of particulate matter, the nucleus breaks down into fragments, and apoptotic bodies can be seen. Apoptosis rate was markedly higher in A549cells than in A549/DDP cells after treatment with single drug. However, apoptosis rate in A549/DDP cells was significantly higher than that in A549when treatment with combination of curcumin and DDP of10-20μg/ml concentration. These results indicate that the activity of FA/BRCA pathway DNA damage repair function induced by DDP is inhibited effectively by curcumin.
Conclusions
FA/BRCA pathway is involved in the mechanism of resistant to DDP in lung cancer cells, FANCF and FANCC protein of this pathway may play important roles in DNA damage signaling and repair induced by DDP in Calu-1cells. A high level of FANCD2monoubiquitination in lung cancer cells is a feature of resistance to cisplatin. FANCD2L/S ratio may be a useful indicator to predict the sensitivity to platinum-based chemotherapy in patients with lung cancer. Curcumin inhibits FANCD2monoubiquitination induced by DDP in A549/DDP cells, reduces nuclear foci formation, increases cell proliferation inhibition rates, and induces cell apoptosis, thereby reverse resistance to DDP in the DDP resistant-drug lung cancer cells. As a FA/BRCA pathway inhibitor, curcumin can inhibit FA/BRCA pathway DNA damage repair function, reverse resistance to DDP in lung cancer cell, suggesting that curcumin may serve as a chemosensitizer to ICL-inducing anticancer drugs.
研究已经证明FA/BRCA途径是修复细胞DNA交联损伤的重要组成部分,该途径的功能状态与细胞对致交联损伤药物如顺铂(DDP)的敏感性相关,正常的FA/BRCA途径被激活是细胞对DNA链间交联剂(DDP等)耐药的分子基础。但是肺癌细胞对DDP耐药现象与FA/BRCA途径功能状态的关系还不很清楚,迄今为止FA/BRCA途径在肺癌细胞对DDP耐药中的作用机制尚无研究报道,FA/BRCA途径抑制剂姜黄素是否可逆转DDP耐药肺癌细胞对DDP的耐药性亦未见文献报告。因此,本研究以体外培养肺癌细胞株为研究对象,通过检测对DDP具有不同敏感性的肺癌细胞株FA/BRCA途径相关基因FANCC、FANCF、 FANCL、FANCD2mRNA及蛋白表达和FANCD2单泛素化状态,探讨FA/BRCA途径参与肺癌细胞对交联剂DDP耐药的分子机制。通过应用姜黄素和DDP处理DDP耐药肺癌细胞,观察FA/BRCA途径功能状态和肺癌细胞对DDP敏感性的变化,研究FA/BRCA途径抑制剂姜黄素增加肺癌细胞对DDP敏感性的作用机制,探讨姜黄素作为DDP耐药逆转剂用于肺癌治疗的可行性。
方法：
1、体外培养肺癌细胞株A549、Calu-1,应用CCK-8法检测经不同浓度DDP处理后肺癌细胞株A549和Calu-1的细胞增殖抑制率,观察比较不同肺癌细胞株对DDP敏感性的差异。实时荧光定量RT-PCR法分别测定用不同浓度DDP处理前后A549、Calu-1的FANCC、FANCF、FANCL和FANCD2mRNA表达水平的变化,Western blotting法分别测定不同浓度DDP处理后A549、Calu-1细胞株FANCC、FANCF、FANCL和FANCD2蛋白的表达,测定以FANCD2-L和FANCD2-S比值所表示的FANCD2单泛素化程度。探讨FA/BRCA途径在肺癌细胞对DDP耐药中的作用机制。
2、体外培养DDP敏感肺癌细胞株A549和耐药肺癌细胞株A549/DDP,分别用不同浓度的姜黄素、DDP及姜黄素加DDP处理后,Western blotting法测定这两个肺癌细胞的FANCD2单泛素化程度,免疫荧光染色法观察胞核内FANCD2核聚小体的形成,CCK-8法测定细胞增殖抑制率,DAPI荧光染色检测细胞凋亡,Annexin V/PI流式细胞术测定细胞凋亡率。观察姜黄素、DDP及姜黄素加DDP分别对肺癌细胞的细胞增殖和凋亡的作用,以及与FA/BRCA途径激活状态之间的关系,探讨姜黄素增加耐DDP肺癌细胞对DDP敏感性的效应,以及其这一效应的FA/BRCA途径机制。
结果：
1、DDP对肺癌细胞A549、Calu-1的增殖抑制作用均呈剂量依赖性和时间依赖性关系。经过不同浓度DDP处理24H和48H后,细胞A549的IC50明显低于细胞Calu-1,表明细胞A549对DDP的敏感性高于细胞Calu-1,细胞Calu-1对DDP相对耐药。与此相对应的是,肺癌细胞A549的FANCF和FANCL mRNA的表达(主要在DDP浓度2.5-5μg/ml时和20μg/ml)低于细胞Calu-1, A549细胞FANCD2mRNA的表达在DDP处理24H有所增高,但在DDP处理48H后明显降低,而Calu-1细胞FANCD2mRNA的表达在DDP处理24H(除DDP浓度20μg/ml外)和48H后均明显升高(除DDP浓度20μg/ml外)。肺癌细胞A549中的FANCF. FANCL和]FANCD2蛋白表达水平随DDP浓度增高呈进行性降低,而肺癌细胞Calu-1的FANCF蛋白(在2.5-10μg/ml DDP浓度范围内)表达随DDP作用时间的延长和浓度的逐渐上升呈进行性增高。Calu-1细胞的FANCD2单泛素化程度明显高于A549细胞。
2. A549/DDP细胞株对DDP中度耐药。分别用不同浓度的姜黄素、DDP及姜黄素加DDP处理后,A549/DDP细胞FANCD2单泛素化程度明显高于A549细胞。当用姜黄素联合DDP处理A549/DDP细胞时,姜黄素的加入显著降低A549/DDP细胞的FANCD2单泛素化水平,且联合用药组的FANCD2单泛素化水平在0-20μg/ml DDP浓度范围内均低于单独用药组,显示出明显的抑制效应。当姜黄素和不同浓度DDP联合分别处理两个肺癌细胞时,A549/DDP细胞核聚小体的表达较A549细胞明显减弱,表明姜黄素能抑制以FANCD2单泛素化及核聚小体形成为激活特征的FA/BRCA途径功能,逆转肺癌细胞对DDP的耐药性。姜黄素联合DDP处理时A549细胞增殖抑制率均高于两药单用时的增殖抑制率,但并未观察到两个药物之间的协同作用,q值<1.15。姜黄素联合DDP处理时A549/DDP的细胞增殖抑制率亦高于两药单用时的增殖抑制率,但姜黄素和DDP显示出明显的协同效应,q值>1.15。姜黄素和DDP联用时DDP抑制A549/DDP细胞的IC50显著下降,逆转倍数显著增高,表明细胞对DDP的敏感性增加。同时DAPI法显示A549/DDP细胞经姜黄素联合DDP处理时,细胞核染色质固缩明显,形成很多颗粒物质,核内染色质由于浓集而呈亮蓝色,细胞核破裂形成碎片,核解体,可见凋亡小体。应用Annexin V/PI双染法结合流式细胞仪检测细胞凋亡率发现,单用姜黄素或DDP分别处理A549和A549/DDP细胞48H后,A549细胞凋亡率明显高于A549/DDP细胞。而与之相反的是,用姜黄素联合DDP处理A549/DDP细胞后,细胞凋亡率在DDP浓度10-20μg/ml范围明显高于A549细胞。表明姜黄素与DDP共同作用时,DDP介导的FA/BRCA途径DNA损伤修复功能的激活受到姜黄素抑制,从而增强DDP诱导耐药肺癌细胞A549/DDP凋亡的作用。结论：
1、FA/BRCA途径参与了肺癌细胞对DDP的耐药机制,其中蛋白FANCF、 FANCD2在肺癌Calu-1细胞对DDP的耐药中可能起了较大作用,FANCD2单泛素化程度与肺癌细胞对DDP的耐药性相关,DDP处理肺癌细胞后的FANCD2单泛素化状态有可能作为预测肺癌患者是否对铂类药物化疗敏感的候选指标。
2、姜黄素可抑制DDP耐药肺癌细胞株A549/DDP细胞的FANCD2单泛素化,减少核聚小体形成,增强DDP对耐药肺癌细胞的增殖抑制作用,并在诱导肺癌细胞凋亡时与DDP有协同作用,进而逆转了DDP耐药肺癌细胞对DDP的耐药性。因此我们的实验结果证明,姜黄素作为FA/BRCA途径抑制剂,可抑制肺癌细胞FA/BRCA途径的DNA损伤修复功能,逆转肺癌细胞对DDP的耐药性,有望在今后成为肺癌临床治疗中的重要成员。
Background and Objective
FA/BRCA pathway plays a pivotal role in repair of DNA cross-linking damage induced by DNA interstrand cross-link (ICL) agents and greatly influences drug response in cancer treatment. The studies have demonstrated that inhibition of the FA/BRCA pathway can enhance the cytotoxic effects of ICL-inducing anticancer drugs and can reduce anticancer drug resistance. But the mechanism for relationship between the FA/BRCA pathway function status and chemoresistance to cisplatin (DDP) in lung cancer cells is poorly understood. Also it is not clear whether FA/BRCA pathway inhibitor, such as curcumin, can enhance sensitivity to DDP in A549/DDP cell, a DDP-resistant lung cancer cell line. Thus, the purposes of this study are to explore the FA/BRCA pathway mechanism of resistance to DDP in lung cancer cells, and investigate the efficiency of curcumin in potentiating the cytotoxic effects of DDP in A549/DDP cells, and explore the feasibility of curcumin as DDP-resistant reversal agent in treatment of lung cancer.
Methods
1. The proliferation inhibition rates of lung cancer cell lines A549and Calu-1treated with variant concentration of DDP were measured using the CCK-8assay. The expression levels of FANCC, FANCF, FANCL and FANCD2mRNA were detected by real-time fluorescent quantitative PCR (RFQ-PCR). The expressions of FANCC, FANCF, FANCL and FANCD2proteins were determined by Western blotting. FANCD2monoubiquitination level was defined as the ratio of FANCD2-L and FANCD2-S (L/S).
2. After treatment with different concentrations of curcumin, DDP alone or combination of curcumin with DDP, the FANCD2monoubiquitination levels were measured by Western blotting in lung cancer cell lines A549and A549/DDP, respectivly. The formation of FANCD2nuclear foci were determined by immunofluorescence staining. The rate of cell proliferation inhibition was detected by CCK-8assay. Apoptosis was assessed by DAPI staining. Apoptosis rate was measured by flow cytometry using Annexin V/PI methods.
Results
1. After treatment with DDP, the rates of proliferation inhibiting of A549and Calu-1lung cancer cell lines were increased gradually with a dose-dependent manner (P<0.05) and a time-dependent manner (P<0.05). The50%inhibitory concentrations of DDP were significantly lower in A549cells than in Calu-1cells. FANCF and FANCL mRNA expression levels in A549cells were markedly lower than those in Calu-1cells. The FANCD2mRNA levels were increased in A549cells at24H after treatment of DDP (in2.5-5μg/ml and20μg/ml DDP respectively) and were decreased at48H after treatment of DDP, while the FANCD2mRNA expression were significantly increased in Calu-1cells at24H and48H after treatment of DDP (except for DDP concentration of20μg/ml at two time points). Meantime, the expressions of FANCC, FANCF and FANCL protein in A549cells were significantly decreased during the treatment of5-20μg/ml DDP as compared with control group. After treatment of5-10μg/ml and20μg/ml DDP, however, FANCC and FANCF mRNA levels in Calu-1cells were initially increased and then decreased after treatment of variant concentrations DDP. The FANCD2monoubiquitination levels in Calu-1cells were significantly higher than those in A549cells.
2. A549/DDP cell lines were moderately resistant to DDP. The FANCD2monoubiquitination levels in A549/DDP cells were significantly higher than those in A549cells following treatment with different concentrations of curcumin, DDP alone or combination of curcumin and DDP. In the concentration range of0-20μg/ml DDP, the addition of curcumin can significantly reduce FANCD2monoubiquitination levels in A549/DDP cells. FANCD2monoubiquitination levels in A549/DDP cells treated with combination of DDP and curcumin were significantly lower than those in these cells treated with curcumin or DDP alone. After treatment with combination of curcumin and DDP, the fluorescence nuclear foci expressions were significantly decreased in A549/DDP cells than in A549cells, implying that curcumin can inhibite FANCD2monoubiquitination levels and the formation of nuclear foci induced by DDP in these DDP-resistant lung caner cells. Proliferation inhibition rate in A549cells treated with curcumin puls DDP was significantly higher than that in these cells treated with curcumin or cisplatin alone, but synergism of curcumin and DDP on proliferation inhibition is not found in the DDP-sensitive cells (q value<1.15). Proliferation inhibition rate in A549/DDP cells treated with curcumin puls cisplatin was also significantly higher than that in these cells treated with single drug, moreover, there is a synergistic effect both curcumin and cisplatin on proliferation inhibition in the DDP-resistant cells(q values>1.15). The inhibitory concentrations of50%of DDP in A549/DDP cells were decreased significantly after treatment with cisplatin plus DDP. In addition, after treatment with curcumin plus DDP in A549/DDP cells, DAPI stained showed that their nuclear chromatin condensation which formed a lot of particulate matter, the nucleus breaks down into fragments, and apoptotic bodies can be seen. Apoptosis rate was markedly higher in A549cells than in A549/DDP cells after treatment with single drug. However, apoptosis rate in A549/DDP cells was significantly higher than that in A549when treatment with combination of curcumin and DDP of10-20μg/ml concentration. These results indicate that the activity of FA/BRCA pathway DNA damage repair function induced by DDP is inhibited effectively by curcumin.
Conclusions
FA/BRCA pathway is involved in the mechanism of resistant to DDP in lung cancer cells, FANCF and FANCC protein of this pathway may play important roles in DNA damage signaling and repair induced by DDP in Calu-1cells. A high level of FANCD2monoubiquitination in lung cancer cells is a feature of resistance to cisplatin. FANCD2L/S ratio may be a useful indicator to predict the sensitivity to platinum-based chemotherapy in patients with lung cancer. Curcumin inhibits FANCD2monoubiquitination induced by DDP in A549/DDP cells, reduces nuclear foci formation, increases cell proliferation inhibition rates, and induces cell apoptosis, thereby reverse resistance to DDP in the DDP resistant-drug lung cancer cells. As a FA/BRCA pathway inhibitor, curcumin can inhibit FA/BRCA pathway DNA damage repair function, reverse resistance to DDP in lung cancer cell, suggesting that curcumin may serve as a chemosensitizer to ICL-inducing anticancer drugs.
引文
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