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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Aug 28;48(8):1128–1135. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.230061

Hsp90抑制剂白果酸与紫杉醇的协同抗鼻咽癌作用

Synergistic effect of Hsp90 inhibitor ginkgolic acids C15꞉1 combined with paclitaxel on nasopharyngeal carcinoma

MA Hui 1,2, HUANG Di 1, LI Bohan 1, DING Feng 1,2, LI Hongmei 1,2, WU Chengzhu 1,2,✉
Editor: 田 朴
PMCID: PMC10930849  PMID: 37875353

Abstract

Objective

Nasopharyngeal cracinoma is a kind of head and neck malignant tumor with high incidence and high mortality. Due to the characteristics of local recurrence, distant metastasis, and drug resistance, the survival rate of patients after treatment is not high. Paclitaxel (PTX) is used as a chemotherapy drug in treating nasopharyngeal carcinoma, but nasopharyngeal carcinoma cells are easy to develop resistance to PTX. Inhibition of heat shock protein 90 (Hsp90) can overcome common signal redundancy and resistance in many cancers. This study aims to investigate the anti-tumor effect of ginkgolic acids C15꞉1 (C15:1) combined with PTX on nasopharyngeal carcinoma CNE-2Z cells and the mechanisms.

Methods

This experiment was divided into a control group (without drug), a C15:1 group (10, 30, 50, 70 μmol/L), a PTX group (5, 10, 20, 40 nmol/L), and a combination group. CNE-2Z cells were treated with the corresponding drugs in each group. The proliferation of CNE-2Z cells was evaluated by methyl thiazolyl tetrazolium (MTT). Wound-healing assay and transwell chamber assay were used to determine the migration of CNE-2Z cells. Transwell chamber was applied to the impact of CNE-2Z cell invasion. Annexin V-FITC/PI staining was used to observe the effect on apoptosis of CNE-2Z cells. The changes of proteins involved in cell invasion, migration, and apoptosis after the combination of C15꞉1 and PTX treatment were analyzed by Western blotting.

Results

Compared with the control group, the C15꞉1 group and the PTX group could inhibit the proliferation of CNE-2Z cells (all P<0.05). The cell survival rates of the C15꞉1 50 μmol/L combined with 5, 10, 20, or 40 nmol/L PTX group were lower than those of the single PTX group (all P<0.05), the combination index (CI) value was less than 1, suggesting that the combined treatment group had a synergistic effect. Compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the combination group significantly inhibited the invasion and migration of CNE-2Z cells (all P<0.05). The results of Western blotting demonstrated that the combination group could significantly down-regulate Hsp90 client protein matrix metalloproteinase (MMP)-2 and MMP-9. The results of double staining showed that compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the apoptosis ratio of CNE-2Z cells in the combination group was higher (both P<0.05). The results of Western blotting suggested that the combination group could decrease the Hsp90 client proteins [Akt and B-cell lymphoma-2 (Bcl-2)] and increase the Bcl-2-associated X protein (Bax).

Conclusion

The combination of C15꞉1 and PTX has a synergistic effect which can inhibit cell proliferation, invasion, and migration, and induce cell apoptosis. This effect may be related to the inhibition of Hsp90 activity by C15꞉1.

Keywords: heat shock protein 90 inhibitor, ginkgolic acids C15꞉1, paclitaxel, nasopharyngeal carcinoma, synergistic effect, anti-tumor effect

鼻咽癌是一种头颈部恶性肿瘤，在东南亚、北非以及中国南方最为常见，具有高发病率和高病死率，在世界癌症排行榜上居于前列[1-3]。目前，临床上主要采用放射治疗(以下简称“放疗”)对鼻咽癌患者进行治疗，虽然早期鼻咽癌患者的预后及生存率有较大的改善和提高，但在治疗过程中存在局部复发和远处转移的风险，所以一般采用放疗联合化学治疗(以下简称“化疗”)的方式治疗鼻咽癌[4]。许多患者对放疗和化疗表现出一定的耐受性，治疗后患者的5年存活率约为70%[5]。紫杉醇是一种四环二萜类的天然产物，来源于红豆杉或者紫衫[6]，可用于治疗头颈部肿瘤，但鼻咽癌细胞易对紫杉醇产生耐药性，使得紫杉醇不能达到预期的抗肿瘤效果，导致中晚期的鼻咽癌患者治愈率低[7]。因此，亟需研制疗效更好的抗肿瘤药物，一方面降低癌细胞对药物的耐药性，另一方面增强其作用于肿瘤细胞的敏感性，从而提高鼻咽癌患者的治疗效果。

化疗产生耐药性的情况尤其严重，解决这一问题的一种策略是确定影响多种致癌途径的靶点或癌细胞适应应激所需的基本机制[8]。热激蛋白90(heat shock protein 90，Hsp90)是一种伴侣蛋白，在多种细胞蛋白质的折叠和降解以及许多关键信号转导蛋白的功能调节中发挥关键作用[9]。研究[10-11]表明抑制Hsp90可以克服在许多癌症中常见的信号冗余和耐药机制。在本课题前期研究[12]中，Hsp90抑制剂检测试验结果显示银杏外种皮中银杏酸(ginkgolic acids，GAS)的单体白果酸对Hsp90 ATP酶活性具有抑制效果。白果酸(GAS C15꞉1)为银杏酸同系物之一，在银杏酸中含量最高，主要存在于银杏外种皮中，是银杏中一种有效成分，具有抗肿瘤、抗菌、抗病毒等多种药理活性。研究[13-15]表明：Hsp90抑制剂在与化疗药如紫杉醇类联合使用时，呈现协同的抗肿瘤效果，减轻化疗药物产生的不良反应，最终增强药物疗效。目前紫杉醇联合白果酸治疗鼻咽癌的研究鲜见报道。因此，本研究将白果酸与紫杉醇联用，探究Hsp90抑制剂白果酸联合紫杉醇对鼻咽癌细胞抗肿瘤活性的影响以及两药联用产生的作用机制，为临床上治疗鼻咽癌提供新的研究思路。

1. 材料与方法

1.1. 材料

白果酸从银杏外种皮中分离纯化而来，用高效液相色谱法(high-performance liquid chromatography，HPLC)测其纯度>95%；紫杉醇购自上海源叶生物科技有限公司；人鼻咽癌CNE-2Z细胞来源于中国科学院上海细胞库；RPMI 1640培养基购自美国Hyclone公司；胎牛血清购自杭州四季青公司；青霉素-链霉素溶液(100×)、结晶紫染液、二喹啉甲酸(bicinchoninic acid，BCA)蛋白浓度测定试剂盒、膜联蛋白V-异硫氰酸荧光素(Annexin V-fluoresceine isothiocyanate，Annexin V-FITC)细胞凋亡检测试剂盒购自上海碧云天生物技术有限公司；胰酶细胞消化液、二甲基亚砜(dimethyl sulfoxide，DMSO)、二抗羊抗兔IgG购自合肥白鲨生物科技有限公司；噻唑蓝(methyl thiazolyl tetrazolium，MTT)购自美国Sigma公司；Transwell小室购自美国Corning公司；基质胶购自美国BD公司；基质金属蛋白酶(matrix metalloproteinase，MMP)-2、MMP-9、B细胞淋巴瘤-2(B-cell lymphoma-2，Bcl-2)、Bcl-2关联X蛋白(Bcl-2-associated X protein，Bax)抗体购自美国Proteintech公司；Akt购自美国CST公司；β-actin购自武汉Abbkine公司。

1.2. 方法

1.2.1. 细胞培养及分组

将人鼻咽癌CNE-2Z细胞培养于RPMI 1640培养基(含10%胎牛血清和1%青霉素/链霉素)中，在温度为37 ℃、饱和湿度为5% CO2的培养箱中培养。

分组：对照组(不加药液)、白果酸组(用10、30、50、70 μmol/L处理CNE-2Z细胞)、紫杉醇组(5、10、20、40 nmol/L处理CNE-2Z细胞)和联合用药组。

1.2.2. MTT法

将CNE-2Z细胞接种于96孔板中(每孔5 000个)，除对照组外其他组分别处理细胞24、48 h。采用MTT比色法检测细胞存活率，按试剂说明书处理各组细胞，用酶标仪检测波长490 nm处吸光度值。用所测吸光度值和白果酸的浓度绘制曲线图，分析并计算白果酸的半数抑制浓度(half inhibitory concentration，IC50)值，然后选择低于IC50值的浓度。最终选择50 μmol/L浓度的白果酸与不同给药浓度的紫杉醇(5、10、20、40 nmol/L)联合作用于CNE-2Z细胞48 h(联合用药组)，研究白果酸与紫杉醇联用对CNE-2Z细胞增殖的效果。

1.2.3. 药物联用指数计算

采用药物联用指数(combination index，CI)评估白果酸和紫杉醇的联合作用。将白果酸、紫杉醇以及两者联用作用细胞后得到的细胞生长抑制率输入到CompuSyn软件中，分析白果酸与紫杉醇共同使用后产生的效果，计算CI。CI小于1代表两药联用具有协同作用，CI等于1代表两药联用具有相加作用，CI大于1代表两药联用具有拮抗作用[16]。

1.2.4. 划痕试验

采用划痕试验和Transwell小室检测CNE-2Z细胞的迁移情况。将CNE-2Z细胞在6孔板中进行种板(每孔6×105个)，培养过夜至细胞贴壁并长满，使用黄枪头缓慢垂直地划痕，用PBS洗掉已不贴壁的细胞，在显微镜下采集图像，分别用50 μmol/L白果酸、 10 nmol/L紫杉醇、50 μmol/L白果酸+10 nmol/L紫杉醇作用于细胞36 h，再进行图像采集，最后通过ImageJ软件对数据进行处理。

1.2.5. Transwell迁移试验

在24孔板中加入800 μL培养液(含胎牛血清)，小室上室加入200 μL细胞悬液(每孔5×104个)，且上室培养液不含胎牛血清，分别用50 μmol/L白果酸、10 nmol/L紫杉醇、50 μmol/L白果酸+10 nmol/L紫杉醇作用于细胞36 h，经PBS擦拭上室，4%多聚甲醛固定15 min，结晶紫染色15 min后，在显微镜下进行图像采集，并计算细胞迁移抑制率。

1.2.6. Transwell侵袭试验

采用Transwell侵袭试验检测CNE-2Z细胞的侵袭能力。将40 μL混合后的基质胶(基质胶与RPMI 1640培养基的比例为1꞉4)均匀铺在小室上室，放置培养箱30~60 min，至基质胶凝固不流动，进行细胞接种，用白果酸、紫杉醇处理细胞36 h，其他步骤同迁移试验。

1.2.7. Annexin V-FITC/PI双染

采用Annexin V-FITC/PI双染检测CNE-2Z细胞的凋亡情况。在12孔板上接种CNE-2Z细胞(每孔2.5×105个)，分别加入50 μmol/L白果酸、10 nmol/L紫杉醇、50 μmol/L白果酸+10 nmol/L紫杉醇作用细胞48 h后，收集细胞，加入提前预冷的Annexin V结合液，在避光状态下，加入5 μL Annexin V-FITC染液，5 min后再加3 μL PI染液染色15 min，通过滤网过滤到流式管中，放置于上流式细胞仪中进行检测。

1.2.8. 蛋白质印迹法

采用蛋白质印迹法检测相关蛋白质的表达变化。将CNE-2Z细胞以每孔5×105接种于6孔板中，分别加入50 μmol/L白果酸、10 nmol/L紫杉醇、50 μmol/L白果酸+10 nmol/L紫杉醇作用于细胞48 h，收集细胞，以2 500 r/min离心10 min，提取蛋白质，用BCA试剂盒进行蛋白质定量处理。每组取20 μg蛋白质进行聚丙烯酰胺电泳，转移至PVDF膜，用5%的脱脂牛奶封闭2 h，用TBST洗3次；加入相应一抗于4 ℃孵育过夜，用TBST洗3次；加入二抗在室温下孵育2 h，用TBST洗3次。采用Bio-Rad凝胶成像仪获取图像。

1.3. 统计学处理

使用SPSS 16.0软件进行数据分析，正态分布的计量资料用均数±标准差( x¯ ±s)表示。采用单因素方差分析进行多组间比较，LSD-t检验进行两两比较。P<0.05为差异具有统计学意义。

2. 结 果

2.1. 白果酸和紫杉醇均可抑制CNE-2Z细胞增殖

随着白果酸、紫杉醇给药浓度及处理时长的增加，CNE-2Z细胞的存活率呈下降的趋势。与对照组相比，30、50、70 μmol/L白果酸组和10、20、40 nmol/L紫杉醇组的细胞存活率明显降低；与同组同一浓度处理24 h时相比，处理48 h的细胞存活率均明显降低(均P<0.05，图1)，表明白果酸和紫杉醇对CNE-2Z细胞的增殖均有抑制效果。

图1.

图1

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白果酸、紫杉醇抑制CNE-2Z细胞增殖

Figure 1 GAS C15꞉1 and PTX inhibited the cell viability

A: After CNE-2Z cells were treated with GAS C15꞉1 (0, 10, 30, 50, 70 μmol/L) for 24 h and 48 h, cell survival rate was detected by MTT assay. B: After CNE-2Z cells were treated with PTX (0, 5, 10, 20, 40 nmol/L) for 24 h and 48 h, cell survival rate was detected by MTT assay. *P<0.05 vs the control group (0 μmol/L GAS C15꞉1 or 0 nmol/L PTX); †P<0.05 vs the 24 h at the same concentration. GAS: ginkgolic acids; MTT: Methyl thiazolyl tetrazolium; PTX: Paclitaxel.

2.2. 白果酸与紫杉醇联用具有协同作用

50 μmol/L白果酸和不同浓度的紫杉醇(5、10、20、40 nmol/L)联合作用CNE-2Z细胞48 h后，联用组细胞存活率均低于单用紫杉醇组(均P<0.05，图2)，CI依次为0.71、0.56、0.62、0.78，均小于1，表明白果酸与紫杉醇联用具有协同作用。

图2.

图2

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白果酸与紫杉醇联用具有协同作用

Figure 2 GAS C15꞉1 shows synergistic effect with PTX

Viability of CNE-2Z cells was detected by MTT assay after treated with GAS C15꞉1 and PTX at different concentrations for 48 h. *P<0.05 vs the PTX group. GAS: Ginkgolic acids; PTX: Paclitaxel; MTT: Methyl thiazolyl tetrazolium.

2.3. 白果酸与紫杉醇联用抑制CNE-2Z细胞侵袭 和转移

划痕试验和Transwell试验显示：与单用50 μmol/L白果酸组和10 nmol/L紫杉醇组相比，联用组CNE-2Z细胞的迁移率和侵袭率均明显降低(图3A~3D，均P<0.05)。表明白果酸与紫杉醇联用可显著抑制CNE-2Z细胞的侵袭和迁移。蛋白质印迹法结果显示：白果酸与紫杉醇联用可下调Hsp90客户蛋白MMP-2和MMP-9的表达(图3E)。

图3.

图3

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白果酸与紫杉醇联用抑制CNE-2Z细胞的侵袭和转移

Figure 3 Combination of GAS C15꞉1 (C15꞉1) and PTX inhibited the invasion and migration of CNE-2Z cells

A: Cell migration effect of CNE-2Z cells treated with 50 μmol/L C15꞉1, 10 nmol/L PTX, and the combination of 2 drugs for 36 h detected by wound-healing assay. B: Quantitative analysis of cell migration rate. C: Effects of cell invasion and migration were analyzed after CNE-2Z cells treated with 50 μmol/L C15꞉1, 10 nmol/L PTX, and the combination of 2 drugs for 36 h by transwell chamber experiment. D: Quantitative analysis of cell invasion and migration numbers. E: Levels of MMP-2 and MMP-9 in CNE-2Z cells analyzed by Western blotting. *P<0.05 vs the control group; †P<0.05 vs the C15꞉1+PTX group. GAS: Ginkgolic acids; PTX: Paclitaxel; MMP: Matrix metalloproteinase.

2.4. 白果酸与紫杉醇联用诱导细胞凋亡

双染结果显示：与单用50 μmol/L白果酸组和 10 nmol/L紫杉醇组相比，联合组作用CNE-2Z细胞48 h后，CNE-2Z细胞凋亡率显著升高(均P<0.05，图4A、4B)。蛋白质印迹法结果显示：白果酸和紫杉醇联用后可下调Hsp90客户蛋白Akt和Bcl-2的表达水平，上调Bax的表达水平(图4C)。

图4.

图4

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白果酸与紫杉醇联用诱导鼻咽癌CNE-2Z细胞凋亡

Figure 4 Apoptosis of CNE-2Z cells was induced by the combination of GAS C15:1 (C15:1) and PTX

A: Cells apoptosis rate analyzed by Annexin V-FITC/PI double staining after CNE-2Z cells were treated with 50 μmol/L C15:1, 10 nmol/L PTX, and the combination of 2 drugs for 48 h. B: Quantitative diagram of cells apoptosis rate. C: Levels of Akt, Bax and Bcl-2 in CNE-2Z cells analyzed by Western blotting. *P<0.05 vs the control group; †P<0.05 vs the C15꞉1+PTX group. GAS: Ginkgolic acids; PTX: Paclitaxel; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-associated X protein.

3. 讨 论

降低鼻咽癌高复发率以及转移率，为鼻咽癌患者提供更好的治疗选择仍然是一项艰巨的挑战。研究[17]表明：一线化疗药在与分子靶向药联合使用时，由于不同的作用机制可产生相加或者协同的作用效果，对多种恶性肿瘤(包括鼻咽癌)的发展起抑制作用。此外，抑制Hsp90对多种致癌途径和过程具有协同影响，Hsp90抑制剂与其他治疗药物联合使用为研究新的组合策略提供理论基础[18]。

天然产物具有低毒、结构多样、多靶点等优势，在抗肿瘤药物研发方面扮演着重要角色[19]。前期研究[12]中发现银杏酸为新型Hsp90抑制剂，可抑制CNE-2Z细胞增殖、侵袭迁移，以及诱导其凋亡，可能通过抑制Hsp90 ATP酶活性发挥抗肿瘤作用。白果酸作为银杏酸中的主要成分[20]，同样具有抑制Hsp90 ATP酶活性的作用。本研究中白果酸与鼻咽癌一线化疗药物紫杉醇均可抑制鼻咽癌CNE-2Z细胞增殖，选用低于IC50浓度的白果酸与不同浓度的紫杉醇联用，结果发现，两药联用后可发挥协同的效果，这与之前的研究[21]结果一致，即紫杉醇与其他Hsp90抑制剂联用时，可产生协同的效果。

肿瘤复发和远处转移是鼻咽癌患者生存率低的主要原因[22]。肿瘤细胞通过接近并消化细胞基质进行转移，此过程受MMP-2和MMP-9调控，这2个因子在肿瘤细胞侵袭以及转移中发挥重要作用[23-24]。Hsp90伴侣复合物在肿瘤细胞中被高度上调以及广泛激活[25]。MMP-2和MMP-9作为Hsp90重要的客户蛋白，在肿瘤侵袭和转移的过程中扮演着非常重要的角色[26]。本研究结果显示：白果酸与紫杉醇联用可抑制CNE-2Z细胞侵袭迁移；白果酸与紫杉醇联用降低CNE-2Z细胞中MMP-2、MMP-9的表达。表明白果酸与紫杉醇联用后，产生的抑制CNE-2Z细胞侵袭迁移的作用，可能与下调Hsp90客户蛋白MMP-2和MMP-9表达有关。

为进一步研究白果酸与紫杉醇联用并作用于CNE-2Z细胞后对其凋亡的效果，本研究采用Annexin V-FITC/PI双染检测细胞凋亡，结果显示：与单用组相比，白果酸与紫杉醇联用可明显诱导CNE-2Z细胞凋亡。抗凋亡分子Bcl-2通过抑制Bax阻止凋亡，Bax是一种非常重要的促凋亡分子[27]。本研究的蛋白质印迹法结果显示：白果酸与紫杉醇联用后，可下调Hsp90客户蛋白Akt和Bcl-2表达，增加Bax表达。

以上结果表明，白果酸与紫杉醇联用后，可协同抑制CNE-2Z细胞增殖、侵袭迁移以及诱导细胞凋亡，这可能与白果酸抑制Hsp90 ATP酶活性有关。白果酸协同紫杉醇发挥抗肿瘤的作用，为鼻咽癌的临床策略提供了分子基础。本研究首次报道白果酸通过抑制Hsp90 ATP酶活性增强紫杉醇对体外鼻咽癌CNE-2Z细胞的抗肿瘤作用。但是，本研究未能探讨和阐明白果酸与紫杉醇在体内是否产生协同效果及其机制。紫杉醇可以对微管聚合产生抑制作用，然后通过抑制有丝分裂从而使细胞发生凋亡[28-29]，可能需要进一步的实验来阐明白果酸与紫杉醇联用后发挥协同作用的机制以及二者在体内联用的效果。

基金资助

安徽省自然科学基金(2008085MH284)；蚌埠医学院“512人才培育计划”(by51202202)；蚌埠医学院科技发展基金(BYKF1718)。

This work was supported by the National Natural Science Foundation of Anhui Province (2008085MH284), the “512 Talent Cultivation Program” of Bengbu Medical College (by51202202), and the Science and Technology Development Foundation of Bengbu Medical College (BYKF1718), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

马慧 实验操作，数据处理，论文撰写与修改；黄滴、李博涵 实验协助，数据处理；丁凤、李红梅 实验指导，论文修改；吴成柱 实验设计与指导，论文修改。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023081128.pdf

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