Hsp90抑制剂白果酸与紫杉醇的协同抗鼻咽癌作用

马慧; 黄滴; 李博涵; 丁凤; 李红梅; 吴成柱

doi:10.11817/j.issn.1672-7347.2023.230061

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论著 | 更新时间：2023-10-24

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
中南大学学报(医学版) 中南大学学报(医学版) 2023年48卷第8期页码：1128-1135
作者机构：

1.蚌埠医学院药学院，安徽蚌埠 233030
2.安徽省生化药物工程技术研究中心，安徽蚌埠 233030
作者简介：

马慧，Email: mahui9513@foxmail.com, ORCID: 0000-0002-3921-4466
吴成柱，Email: wuchengzhu0611@bbmc.edu.cn, ORCID: 0000-0003-1690-1930
基金信息：

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)
DOI：10.11817/j.issn.1672-7347.2023.230061
中图分类号：
CSTR：

马慧, 黄滴, 李博涵, 等. Hsp90抑制剂白果酸与紫杉醇的协同抗鼻咽癌作用[J]. 中南大学学报(医学版), 2023,48(8):1128-1135.

MA Hui, HUANG Di, LI Bohan, et al. Synergistic effect of Hsp90 inhibitor ginkgolic acids C15꞉1 combined with paclitaxel on nasopharyngeal carcinoma[J]. Journal of Central South University. Medical Science, 2023,48(8):1128-1135.
马慧, 黄滴, 李博涵, 等. Hsp90抑制剂白果酸与紫杉醇的协同抗鼻咽癌作用[J]. 中南大学学报(医学版), 2023,48(8):1128-1135. DOI： 10.11817/j.issn.1672-7347.2023.230061.

MA Hui, HUANG Di, LI Bohan, et al. Synergistic effect of Hsp90 inhibitor ginkgolic acids C15꞉1 combined with paclitaxel on nasopharyngeal carcinoma[J]. Journal of Central South University. Medical Science, 2023,48(8):1128-1135. DOI： 10.11817/j.issn.1672-7347.2023.230061.

摘要

目的,2,鼻咽癌是一种发病率高、病死率高的头颈部恶性肿瘤，易出现局部复发、远处转移以及耐药的情况，使得患者治疗后生存率并不高。紫杉醇作为化学治疗药物用于治疗鼻咽癌，但鼻咽癌细胞易对紫杉醇产生耐药性。而抑制热激蛋白90(heat shock protein 90，Hsp90)可以克服在许多癌症中常见的信号冗余和耐药机制。本研究旨在探究Hsp90抑制剂白果酸联合紫杉醇对鼻咽癌CNE-2Z细胞抗肿瘤活性的影响及其机制。,方法,2,本实验分为对照组(不加药液)、白果酸组(10、30、50、70 μmol/L)、紫杉醇组(5、10、20、40 nmol/L)和联用组，各组采用相应药物处理CNE-2Z细胞。采用噻唑蓝(methyl thiazolyl tetrazolium，MTT)比色法检测CNE-2Z细胞的存活率；划痕试验和Transwell迁移试验检测CNE-2Z细胞的迁移情况；Transwell侵袭试验检测CNE-2Z细胞的侵袭能力；Annexin V-FITC/PI双染检测CNE-2Z细胞的凋亡情况；蛋白质印迹法检测白果酸与紫杉醇联用后细胞侵袭迁移、凋亡相关蛋白表达的变化。,结果,2,与对照组相比，白果酸组和紫杉醇组均可抑制CNE-2Z细胞增殖(均,P,<,0.05)。50 μmol/L白果酸和5、10、20、40 nmol/L紫杉醇联用组细胞存活率均低于单用紫杉醇组(均,P,<,0.05)，药物联用指数(combination index，CI)小于1，具有协同作用。与单用50 μmol/L白果酸组和10 nmol/L紫杉醇组相比，联用组可明显抑制CNE-2Z细胞侵袭和迁移(均,P,<,0.05)，且下调Hsp90客户蛋白基质金属蛋白酶(matrix metalloproteinase，MMP)-2和MMP-9的表达水平。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，联用组的细胞凋亡率明显升高(均,P<,0.05)，且联用后下调Hsp90客户蛋白Akt和B细胞淋巴瘤-2(B-cell lymphoma-2，Bcl-2)的表达，上调Bcl-2关联X蛋白(Bcl-2-associated X protein，Bax)的表达。,结论,2,白果酸和紫杉醇联用后具有协同作用，可抑制CNE-2Z细胞增殖、侵袭及迁移，诱导细胞凋亡，这些作用可能与白果酸抑制Hsp90活性有关。

Abstract

Objective,2,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,2,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,2,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,2,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.

关键词

Hsp90抑制剂白果酸紫杉醇鼻咽癌协同作用抗肿瘤作用

Keywords

heat shock protein 90 inhibitorginkgolic acids C15꞉1paclitaxelnasopharyngeal carcinomasynergistic effectanti-tumor effect

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