阿帕替尼与白蛋白结合型紫杉醇在MDA- MB-231乳腺癌细胞系中的协同抗癌作用

doi:10.3877/cma.j.issn.2095-1221.2021.02.004

目的

阐明阿帕替尼（apatinib）和白蛋白结合型紫杉醇（nab-Paclitaxel）诱导MDA-MB-231乳腺癌细胞凋亡的分子机制。

方法

本研究以MDA-MB-231乳腺癌细胞为研究对象，并以apatinib和nab-Paclitaxel处理细胞后分组：0.1 ﹪DMSO处理为阴性对照组；10 μmol/L apatinib处理组（APA组）；经5、10、15、20 nmol/L nab-Paclitaxel处理组（Nab-p 5组、Nab-p 10组、Nab-p 15组和Nab-p 20组）；以及10 μmol/L apatinib分别与5、10、15、20 nmol/L nab-Paclitaxel联合处理组（APA+Nab-p 5组、APA+Nab-p 10组、APA+Nab-p 15组和APA+Nab-p 20组）。使用乳酸脱氢酶释放测定法测定apatinib和nab-Paclitaxel对MDA-MB-231细胞诱导的细胞毒活性，结合流式细胞术分析不同处理组细胞凋亡情况，通过JC-1染色法测定不同干预方式对MDA-MB-231细胞线粒体膜电位变化（ΔΨ_m）的影响，借助FAM-FLICA荧光成像检测caspase-8和caspase-9活性，通过彗星试验评估apatinib和nab-Paclitaxel对非致瘤上皮细胞株MCF-10A细胞DNA损伤的影响。两组之间独立样本t检验或单向ANOVA进行比较，多组之间使用Tukey事后检验。

结果

细胞毒性检测结果显示，与阴性对照组相比，Nab-p 20组MDA-MB-231细胞杀伤率在24 h时接近90 ﹪；与单药处理组（Nab-p 5组和Nab-p 10组）相比，APA+Nab-p 5组和APA+Nab-p 10组联合处理24 h和48 h后，分别检测到约85 ﹪和95 ﹪细胞死亡，差异均具有统计学意义（P均< 0.001）。流式细胞术统计结果显示，与Nab-p5组和Nab-p10组相比，APA+Nab-p 5组和APA+Nab-p 10组24 h时MDA-MB-231细胞凋亡率（31.8 ﹪ ± 1.48 ﹪、33.25 ﹪±1.77 ﹪比76.11 ﹪±1.14 ﹪、89.4 ﹪± 1.07﹪）升高（P均< 0.05）。线粒体膜电位检测结果表明，与对照组相比，在单药处理组中，仅APA组和Nab-p 10组24 h时去极化细胞（12.35 ﹪ ± 1.05﹪比78.33﹪± 1.11﹪、46.74﹪± 1.75﹪）增多；在联用处理组中，APA+Nab-p 5组和APA+Nab-p 10组24 h时去极化细胞（68.47﹪± 1.94﹪比90.03﹪± 1.79﹪）增多，差异均有统计学意义（P均< 0.05）。FAM-FLICA荧光成像结果显示，相较于单一处理组，apatinib和nab-Paclitaxel联用处理组的caspase-8和caspase-9蛋白高度活化。结合彗星试验分析，apatinib和nab-Paclitaxel干预对MCF-10A非致瘤上皮细胞株DNA完整性没有显著影响。

结论

apatinib/nab-Paclitaxel联用通过内源性的线粒体功能扰动和外源性的caspase激活诱导三阴性乳腺癌细胞MDA-MB-231凋亡，发挥协同抗癌作用。

关键词: 阿帕替尼, 白蛋白结合型紫杉醇, 协同作用, 乳腺癌, 细胞凋亡

Objective

To elucidate the molecular mechanisms of apatinib and nab-Paclitaxel in inducing apoptosis of MDA-MB-231 breast cancer cells.

Methods

MDA-MB-231 cells were treated with apatinib and nab-Paclitaxel alone or together and named: control group (0.1 ﹪ DMSO treatment) ; 10 μmol/L apatinib treatment group (APA group) ; 5, 10, 15, 20 nmol/L nab-Paclitaxel treatment group (Nab-p 5 groups, Nab-p 10 groups, Nab-p 15 groups and Nab-p 20 groups) and 10 μmol/L apatinib combined with 5, 10, 15, 20 nmol/L nab-Paclitaxel treatment group (APA Nab-p 5 groups, APA Nab-p 10 groups, APA Nab-p 15 groups and APA Nab-p 20 groups) . The cytotoxic activity induced by apatinib and albumin-bound paclitaxel on MDA-MB-231 cells was determined by a lactate dehydrogenase release assay. Flow cytometry was used to quantify apoptosis in different treatment groups. Effects of different intervention methods on mitochondrial membrane potential change (ΔΨ_m) of MDA-MB-231 cells were examined by JC-1 staining. Caspase-8 and Caspase-9 activities were detected by FAM-FLICA fluorescence imaging. The effects of apatinib and albumin-bound paclitaxel on DNA damage in non-tumorigenic epithelial cell line MCF-10A were evaluated by comet assay. Student's t test or one-way ANOVA was used for comparison between two groups, and Tukey post-test was used for comparison within multiple groups.

Results

Cytotoxicity test results showed that the MDA-MB-231 cell death rate in the Nab-p 20 group was close to 90 ﹪ at 24 h, and the difference was extremely significant compared with the control group (P < 0.001) . After treatment for 24 h and 48 h, about 85 ﹪ and 95 ﹪ of cell deaths were detected in the APA+Nab-p 5 group and APA+Nab-p 10 group respectively, which showed a significantly difference compared with the single-drug treatment group (Nab-p 5 group and Nab-p 10 group) (P < 0.001) . The results of flow cytometry showed that the apoptotic rate of APA+Nab-p5 (76.11±1.14) and APA+Nab-p10 (89.4±1.07) groups were significantly increased (P < 0.05) compared with the Nab-p5 (31.8±1.48) and Nab-p10 (33.25±1.77) groups. The results of mitochondrial membrane potential test showed that only depolarized cells in APA group (78.33±1.11) and Nab-p 10 group (46.74±1.75) was increased significantly at 24 h (all P < 0.01) compared with the control group (12.35±1.05) , in the single-drug treatment group, while in the combined treatment group, the depolarised cells in the APA+Nab-p 5 (68.47±1.94) and APA+Nab-p 10 group (90.03±1.79) also increased significantly (P < 0.05) . FAM-FLICA fluorescence imaging results showed that compared with the single treatment group, the caspase-8 and caspase-9 proteins in the combination group of apatinib and nab-Paclitaxel were highly activated. Comet assay analysis showed that the intervention of apatinib and nab-Paclitaxel did not significantly affect the DNA integrity of MCF-10A non-tumorigenic epithelial cell line.

Conclusion

Combined apatinib with nab-paclitaxel induces apoptosis through intrinsic mitochondrial function perturbation and extrinsic caspase activation in triple-negative breast cancer cells MDA-MB-231, and may exhibit a synergistic anticancer effect.

Key words: Apatinib, Albumin-bound paclitaxel, Synergistic effect, Breast cancer, Apoptosis

表1 apatinib和nab-Paclitaxel诱导MDA-MB-231细胞杀伤率比较（﹪，±s）

分组	实验次数	6 h	12 h	24 h	48 h
阴性对照	3	2.31±1.83	2.16±0.99	3.74±1.67	3.97±2.31
APA	3	2.24±0.86^a	27.43±1.52^a	55.72±2.13^a	86.05±2.61^a
Nab-p 5	3	2.45±1.58	1.73±1.84	5.41±1.37	17.82±1.95^a
Nab-p 10	3	1.55±2.11	1.68±2.30	32.03±1.55^a	31.94±1.84^a
Nab-p 15	3	5.11±0.79^a	20.02±1.22^a	64.37±2.34^a	90.13±1.05^a
Nab-p 20	3	36.31±1.92^a	54.68±1.73^a	83.72±1.67^a	93.56±1.82^a
APA+Nab-p 5	3	5.23±2.44	33.51±1.40^ab	82.26±1.27^ab	95.15±1.88^ab
APA+Nab-p 10	3	5.16±0.74^ab	26.72±1.09^ab	83.26±2.01^ab	96.02±1.44^ab
APA+Nab-p 15	3	21.23±0.81^ab	73.04±1.35^ab	89.66±1.79^ab	96.85±1.99^ab
APA+Nab-p 20	3	42.45±1.93^a	97.26±1.58^ab	91.03±2.25^a	97.91±0.76
F值		432.074	510.147	257.155	369.602
P值		< 0.001	< 0.001	< 0.001	< 0.001

表1 apatinib和nab-Paclitaxel诱导MDA-MB-231细胞杀伤率比较（﹪，±s）

分组	实验次数	6 h	12 h	24 h	48 h
阴性对照	3	2.31±1.83	2.16±0.99	3.74±1.67	3.97±2.31
APA	3	2.24±0.86^a	27.43±1.52^a	55.72±2.13^a	86.05±2.61^a
Nab-p 5	3	2.45±1.58	1.73±1.84	5.41±1.37	17.82±1.95^a
Nab-p 10	3	1.55±2.11	1.68±2.30	32.03±1.55^a	31.94±1.84^a
Nab-p 15	3	5.11±0.79^a	20.02±1.22^a	64.37±2.34^a	90.13±1.05^a
Nab-p 20	3	36.31±1.92^a	54.68±1.73^a	83.72±1.67^a	93.56±1.82^a
APA+Nab-p 5	3	5.23±2.44	33.51±1.40^ab	82.26±1.27^ab	95.15±1.88^ab
APA+Nab-p 10	3	5.16±0.74^ab	26.72±1.09^ab	83.26±2.01^ab	96.02±1.44^ab
APA+Nab-p 15	3	21.23±0.81^ab	73.04±1.35^ab	89.66±1.79^ab	96.85±1.99^ab
APA+Nab-p 20	3	42.45±1.93^a	97.26±1.58^ab	91.03±2.25^a	97.91±0.76
F值		432.074	510.147	257.155	369.602
P值		< 0.001	< 0.001	< 0.001	< 0.001

表2 流式细胞术检测统计结果（﹪，±s）

分组	实验次数	晚期凋亡率		早期凋亡率		总凋亡率
分组	实验次数	24 h	48 h	24 h	48 h	24 h	48 h
阴性对照	3	11.34±0.55	18.50±1.72	10.17±1.34	13.16±1.38	21.51±1.50	31.66±1.26
APA	3	30.42±0.99^a	50.35±1.93^a	6.73±1.69^a	19.24±1.82^a	45.24±1.36^a	69.59±1.85^a
Nab-p 5	3	25.07±2.02^a	18.74±2.01	1.73±1.84^a	22.51±1.35^a	31.8±1.48^a	41.25±2.11^a
APA+Nab-p 5	3	63.45±0.94^a	87.05±1.70^a	12.66±1.25	2.18±1.04^a	76.11±1.14^ab	89.23±1.66^ab
Nab-p 10	3	23.51±0.79^a	30.63±2.14^a	9.74±2.03	15.25±1.85	33.25±1.77^a	45.88±1.50^a
APA+Nab-p 10	3	86.25±1.84^ab	90.37±1.95^ab	3.25±0.91^ab	2.93±0.74^ab	89.4±1.07^ab	93.3±1.10^ab
F值		609.227	783.285	526.841	539.104	733.972	527.734
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

表2 流式细胞术检测统计结果（﹪，±s）

分组	实验次数	晚期凋亡率		早期凋亡率		总凋亡率
分组	实验次数	24 h	48 h	24 h	48 h	24 h	48 h
阴性对照	3	11.34±0.55	18.50±1.72	10.17±1.34	13.16±1.38	21.51±1.50	31.66±1.26
APA	3	30.42±0.99^a	50.35±1.93^a	6.73±1.69^a	19.24±1.82^a	45.24±1.36^a	69.59±1.85^a
Nab-p 5	3	25.07±2.02^a	18.74±2.01	1.73±1.84^a	22.51±1.35^a	31.8±1.48^a	41.25±2.11^a
APA+Nab-p 5	3	63.45±0.94^a	87.05±1.70^a	12.66±1.25	2.18±1.04^a	76.11±1.14^ab	89.23±1.66^ab
Nab-p 10	3	23.51±0.79^a	30.63±2.14^a	9.74±2.03	15.25±1.85	33.25±1.77^a	45.88±1.50^a
APA+Nab-p 10	3	86.25±1.84^ab	90.37±1.95^ab	3.25±0.91^ab	2.93±0.74^ab	89.4±1.07^ab	93.3±1.10^ab
F值		609.227	783.285	526.841	539.104	733.972	527.734
P值		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

图1 不同干预组MDA-MB-231 24 h处理的典型流式细胞术结果

表3 线粒体膜去极化检测结果比较（﹪，±s）

分组	实验次数	极化细胞		去极化细胞
分组	实验次数	24 h	48 h	24 h	48 h
阴性对照	3	79.02±2.13	59.63±1.69	12.35±1.05	22.48±1.35
APA	3	13.46±1.50^a	2.38±0.59^a	78.33±1.11^a	85.36±1.84^a
Nab-p 5	3	75.81±1.62	48.35±2.05	17.24±1.70	38.14±1.92
APA+Nab-p 5	3	20.63±1.17^ab	3.14±1.73^ab	68.47±1.94^ab	86.03±1.71^ab
Nab-p 10	3	52.05±2.03^a	6.37±1.99^a	46.74±1.75^a	68.44±1.50^a
APA+Nab-p 10	3	6.94±1.88^ab	2.52±1.34^ab	90.03±1.79^ab	94.27±1.44^ab
F值		520.471	974.113	801.356	736.066
P值		< 0.001	< 0.001	< 0.001	< 0.001

表3 线粒体膜去极化检测结果比较（﹪，±s）

分组	实验次数	极化细胞		去极化细胞
分组	实验次数	24 h	48 h	24 h	48 h
阴性对照	3	79.02±2.13	59.63±1.69	12.35±1.05	22.48±1.35
APA	3	13.46±1.50^a	2.38±0.59^a	78.33±1.11^a	85.36±1.84^a
Nab-p 5	3	75.81±1.62	48.35±2.05	17.24±1.70	38.14±1.92
APA+Nab-p 5	3	20.63±1.17^ab	3.14±1.73^ab	68.47±1.94^ab	86.03±1.71^ab
Nab-p 10	3	52.05±2.03^a	6.37±1.99^a	46.74±1.75^a	68.44±1.50^a
APA+Nab-p 10	3	6.94±1.88^ab	2.52±1.34^ab	90.03±1.79^ab	94.27±1.44^ab
F值		520.471	974.113	801.356	736.066
P值		< 0.001	< 0.001	< 0.001	< 0.001

图2 不同干预组MDA-MB-231细胞24 h处理典型流式细胞术结果

图3 倒置荧光显微镜观察MDA-MB-231细胞中caspase-8和caspase-9的激活情况（×100）

表4 apatinib和nab-Paclitaxel诱导MCF-10A细胞杀伤率比较（﹪，±s）

分组	实验次数	24 h	48 h	72 h
阴性对照	3	2.35±0.15	2.39±0.31	3.14±0.19
APA	3	1.74±0.07	3.85±0.10	4.02±0.13
Nab-p 5	3	1.92±0.06	3.54±0.21	6.76±0.39
APA+Nab-p 5	3	2.57±0.17	6.94±0.62	6.71±0.35
Nab-p 10	3	90.22±1.40^a	94.02±1.66^a	93.71±1.05^a
APA+Nab-p 10	3	84.37±1.50^a	91.36±1.73^a	95.11±1.68^a
F值		1021.088	583.704	702.935
P值		< 0.001	< 0.001	< 0.001

表4 apatinib和nab-Paclitaxel诱导MCF-10A细胞杀伤率比较（﹪，±s）

分组	实验次数	24 h	48 h	72 h
阴性对照	3	2.35±0.15	2.39±0.31	3.14±0.19
APA	3	1.74±0.07	3.85±0.10	4.02±0.13
Nab-p 5	3	1.92±0.06	3.54±0.21	6.76±0.39
APA+Nab-p 5	3	2.57±0.17	6.94±0.62	6.71±0.35
Nab-p 10	3	90.22±1.40^a	94.02±1.66^a	93.71±1.05^a
APA+Nab-p 10	3	84.37±1.50^a	91.36±1.73^a	95.11±1.68^a
F值		1021.088	583.704	702.935
P值		< 0.001	< 0.001	< 0.001

图4 倒置荧光显微镜观察MCF-10A细胞DNA损伤情况（×200）

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Synergistic anticancer effects of apatinib and nab-paclitaxel in MDA-MB-231 breast cancer cell line

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Synergistic anticancer effects of apatinib and nab-paclitaxel in MDA-MB-231 breast cancer cell line