Anti-breast Cancer Activities <italic style="font-style: italic">in Vitro</italic> of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/<italic style="font-style: italic">β</italic>-catenin

Bei-bei ZHANG; Yan ZAHNG; Feng-xian WANG; Ting YANG; Jing XU; Wei XIE; Jin WANG

doi:10.13422/j.cnki.syfjx.20212423

您当前的位置：

首页 >

文章列表页 >

Anti-breast Cancer Activities in Vitro of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/β-catenin

更新时间：2021-11-12

- Anti-breast Cancer Activities in Vitro of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/β-catenin
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 27, Issue 24, Pages: 109-117(2021)
- 作者机构：
  
  上海健康医学院药学院，上海 201318
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20212423
  CLC： R22;R242;R2-031;R285.5
- Published：20 December 2021，
  
  Published Online：26 October 2021，
  
  Received：27 August 2021，
- 稿件说明：
扫描看全文
张贝贝,张艳,王风仙等.基于Wnt/β-catenin调控EMT探讨氧化苦参碱联合贝伐珠单抗抗乳腺癌的体外活性机制[J].中国实验方剂学杂志,2021,27(24):109-117.

ZHANG Bei-bei,ZAHNG Yan,WANG Feng-xian,et al.Anti-breast Cancer Activities in Vitro of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/β-catenin[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(24):109-117.
张贝贝,张艳,王风仙等.基于Wnt/β-catenin调控EMT探讨氧化苦参碱联合贝伐珠单抗抗乳腺癌的体外活性机制[J].中国实验方剂学杂志,2021,27(24):109-117. DOI： 10.13422/j.cnki.syfjx.20212423.

ZHANG Bei-bei,ZAHNG Yan,WANG Feng-xian,et al.Anti-breast Cancer Activities in Vitro of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/β-catenin[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(24):109-117. DOI： 10.13422/j.cnki.syfjx.20212423.

摘要

目的

观察氧化苦参碱（OM）联合贝伐珠单抗（BV）对乳腺癌MCF-7细胞增殖、侵袭和迁移的作用，并基于分泌型糖蛋白（Wnt）/

-连环蛋白（

-catenin）信号通路对OM调控BV引起的上皮间质转化（EMT）的机制进行探讨。

方法

采用细胞增殖与活性检测（CCK-8）实验观察OM（0，0.5，1.0，2.0，4.0，8.0，16.0 mmol·L

-1

）及BV（0，0.25×10

-4

，0.50×10

-4

，1.00×10

-4

，2.00×10

-4

，4.00×10

-4

，8.00×10

-4

mmol·L

-1

）联合后对MCF-7细胞增殖的影响；通过侵袭小室法（transwell）和划痕损伤修复实验观察OM（4.0 mmol·L

-1

）与BV（2.00×10

-4

mmol·L

-1

）联合后对MCF-7细胞侵袭与迁移能力的影响；采用蛋白免疫印迹法（Western blot）观察OM（4.0 mmol·L

-1

）与BV（2.00×10

-4

mmol·L

-1

）联合后对MCF-7细胞增殖相关蛋白的影响，并对Wnt/

-catenin信号通路及EMT相关蛋白的表达水平进行检测。

结果

与空白组比较，OM（2.0，4.0，8.0，16.0 mmol·L

-1

）可呈浓度依赖性地抑制MCF-7细胞的增殖（

0.05，

0.01），而BV未表现出抑制MCF-7细胞增殖的作用，两药联合对MCF-7细胞增殖的抑制作用与OM比较差异无统计学意义。与空白组比较，OM可显著减少MCF-7细胞的迁移距离和侵袭细胞数目（

0.01），BV可明显增加MCF-7细胞的迁移距离和侵袭细胞数目（

0.05，

0.01）。与BV比较，联合后OM可显著抑制BV引起的MCF-7细胞的侵袭和迁移（

0.01）。与空白组比较，OM及两药联用可明显抑制MCF-7细胞中与细胞增殖相关蛋白激酶B（Akt）和细胞外调节蛋白激酶1/2（ERK1/2）蛋白的磷酸化（

0.01）；OM及两药联用后显著降低Wnt/

-catenin信号通路中

-catenin，原癌基因（c-Myc），CD44，G

/S-特异性周期蛋白-D

（cyclin D

）蛋白表达（

0.05，

0.01）；OM及两药联用可显著降低EMT中钙离子依赖的细胞

-钙黏蛋白（

-cadherin），波形蛋白（Vimentin）蛋白表达，增加钙离子依赖的细胞E-钙黏蛋白（E-cadherin）的表达水平（

0.01），BV组上述相关蛋白的表达相反（

0.05，

0.01）。

结论

OM与BV联合后OM可通过有效抑制BV引起的Wnt/

-catenin通路激活逆转EMT机制发挥抗乳腺癌的作用。

Abstract

Objective

To observe the effect of oxymatrine （OM） combined with bevacizumab （ BV ） on the proliferation， invasion， and migration of breast cancer MCF-7 cells and explore the mechanism of OM in regulating BV-induced epithelial-mesenchymal transition （EMT） based on the Wnt/

-catenin signaling pathway.

Method

The effect of different concentrations of OM（0， 0.5， 1.0， 2.0， 4.0， 8.0， 16.0 mmol·L

-1

）and BV（0， 0.25×10

-4

， 0.50×10

-4

， 1.00×10

-4

， 2.00×10

-4

， 4.00×10

-4

， and 8.00×10

-4

mmol·L

-1

）on the proliferation of MCF-7 cells were detected by cell counting kit-8（CCK-8）assay. The effect of OM（4.0 mmol·L

-1

） combined with BV（2.00×10

-4

mmol·L

-1

）on the invasion and migration of MCF-7 cells were observed in transwell and scratch repair tests. Western blot was conducted to investigate the effect of OM（4.0 mmol·L

-1

）combined with BV （2.00×10

-4

mmol·L

-1

） on proliferation-related proteins in MCF-7 cells， followed by the detection of the expression levels of Wnt/

-catenin signaling pathway- and EMT-related proteins.

Result

Compared with the blank group， OM （2.0，4.0，8.0，16.0 mmol·L

-1

） inhibited the proliferation of MCF-7 cells in a concentration-dependent manner （

0.01）， while BV did not show the inhibitory effect against the proliferation of MCF-7 cells. The inhibitory effect of the combination of the two drugs on the proliferation of MCF-7 cells was not significantly different from that of OM. Compared with the blank group， OM significantly reduced the migration distance of MCF-7 cells and the number of invaded cells（

0.01）， while BV increased the migration distance of MCF-7 cells and the number of invaded cells （

0.05，

0.01）. Compared with BV， its combination with OM significantly inhibited the invasion and migration of MCF-7 cells induced by BV （

0.01）. Compared with the blank group， both OM and the combined medication obviously inhibited the phosphorylation of proliferation-related protein kinase B（Akt） and extracellular-signal-regulated protein kinase 1/2 （ERK1/2）in MCF-7 cells （

0.01） and down-regulated the protein expression levels of

-catenin， proto-oncogene （c-Myc）， CD44， and G

/S-specific cyclin D

in Wnt/

-catenin signaling pathway （

0.05，

0.01）. Besides， OM and the combination of two drugs both significantly reduced the protein expression levels of calcium-dependent cell adhesion protein

-cadherin and Vimentin in EMT， whereas increased the expression of calcium-dependent cell adhesion protein E-cadherin（

0.01）. However， the expression of the above-mentioned proteins in the BV group was reversed （

0.05，

0.01）.

Conclusion

After the combination with BV， OM plays an anti-breast cancer role by effectively inhibiting the activation of Wnt/

-catenin pathway induced by BV and reversing EMT.

关键词

氧化苦参碱贝伐珠单抗乳腺癌分泌型糖蛋白（Wnt）/β-连环蛋白（β-catenin）信号通路上皮间质转化（EMT）

Keywords

oxymatrinebevacizumabbreast cancerWnt/β-catenin signaling pathwayepithelial-mesenchymal transition （EMT）

references

刘宗超，李哲轩，张阳，等. 2020全球癌症统计报告解读［J］. 肿瘤综合治疗电子杂志，2021，7（2）：1-14.

JOHNSON R H，ANDERS C K，LITTON J K，et al. Breast cancer in adolescents and young adults［J］. Pediatr Blood Cancer，2018，65（12）：1-9.

JÁSZAI J，SCHMIDT M H H. Trends and challenges in tumor anti-angiogenic therapies［J］. Cells，2019，8（9）：1101-1135.

SHIBUYA M. Vascular endothelial growth factor and its receptor system： physiological functions in angiogenesis and pathological roles in various diseases［J］. J Biochem，2013，153（1）：13-19.

BANYS-PALUCHOWSKI M，WITZEL I，RIETHDORF S，et al. The clinical relevance of serum vascular endothelial growth factor （VEGF） in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer［J］. Breast Cancer Res Treat，2018，172（1）：93-104.

LI T，KANG G，WANG T，et al. Tumor angiogenesis and anti-angiogenic gene therapy for cancer［J］. Oncol Lett，2018，16（1）：687-702.

AHMED M，ALOUCH N，AHMED A，et al. Worsening of renal function and uncontrolled hypertension from intravitreal bevacizumab injections［J］. Proc （Bayl Univ Med Cent），2021，34（4）：527-529.

LI M， KROETZ D L. Bevacizumab-induced hypertension： Clinical presentation and molecular understanding［J］. Pharmacol Ther，2018，182：152-160.

JORGE D M，TAVARES NETO J E D S，POLI-NETO O B，et al. Intravitreal bevacizumab （IVB） versus IVB in combination with pars plana vitrectomy for vitreous hemorrhage secondary to proliferative diabetic retinopathy： a randomized clinical trial［J］. Int J Retina Vitreous，2021，26：1-9.

LI L J，CHEN D F，WU G F，et al. Incidence and risk of thromboembolism associated with bevacizumab in patients with non-small cell lung carcinoma［J］. J Thorac Dis，2018，10（8）：5010-5022.

LEE I，ADIMADHYAM S，NUTESCU E A，et al. Bevacizumab use and the risk of arterial and venous thromboembolism in patients with high-grade gliomas： a nested case-control study［J］. Pharmacotherapy，2019，39（9）：921-928.

XU H，RAHIMPOUR S，NESVICK C L，et al. Activation of hypoxia signaling induces phenotypic transformation of glioma cells： implications for bevacizumab antiangiogenic therapy［J］. Oncotarget，2015，6（14）：11882-11893.

王承，张明发，沈雅琴. 氧化苦参碱的血管药理作用研究进展［J］. 药物评价研究，2021，44（7）：1555-1561.

史艳平，陈涛，李丹，等. 氧化苦参碱药理作用研究进展［J］. 陕西医学杂志，2018，47（2）：271-273.

张英，祁鑫，朱小云，等. 氧化苦参碱干预MCF-7细胞系肿瘤干细胞样细胞生物学行为的实验研究［J］. 中国中西医结合杂志，2016，36（12）：1504-1509.

张明发，沈雅琴. 氧化苦参碱抑制妇科肿瘤细胞增殖的药理作用研究进展［J］. 抗感染药学，2019，16（10）：1657-1662.

蔡加琴，魏晓霞，黄旭慧，等. 氧化苦参碱通过调控上皮间质转化抑制三阴性乳腺癌细胞侵袭转移［J］. 中国临床药理学与治疗学，2018，23（1）：13-17.

WANG X，LIU C，WANG J，et al. Oxymatrine inhibits the migration of human colorectal carcinoma RKO cells via inhibition of PAI-1 and the TGF-β1/Smad signaling pathway［J］. Oncol Rep，2017，37（2）：747-753.

刘百庆，张斌，许威，等. 氧化苦参碱对胰腺癌细胞上皮间质转化及Gli2表达影响［J］. 遵义医学院学报，2018，41（6）：705-709.

TAO Z，SHI A，LU C，et al. Breast cancer： epidemiology and etiology［J］. Cell Biochem Biophys，2015，72（2）：333-338.

KIMBUNG S， LOMAN N， HEDENFALK I. Clinical and molecular complexity of breast cancer metastases［J］. Semin Cancer Biol，2015，35：85-95.

GARCIA J，HURWITZ H I，SANDLER A B，et al. Bevacizumab （Avastin®） in cancer treatment： A review of 15 years of clinical experience and future outlook［J］. Cancer Treat Rev，2020，86：102017-102035.

CARBONE C，MOCCIA T，ZHU C，et al. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an EMT cell phenotype［J］. Clin Cancer Res，2011，17（17）：5822-5832.

HUANG W，ZHANG C，CUI M，et al. Inhibition of bevacizumab-induced epithelial-mesenchymal transition by BATF2 overexpression involves the suppression of Wnt/β-catenin signaling in glioblastoma cells［J］. Anticancer Res，2017，37（8）：4285-4294.

LYNN K D，ROLAND C L，BREKKEN R A. VEGF and pleiotrophin modulate the immune profile of breast cancer［J］. Cancers （Basel），2010，2（2）：970-988.

NI Z，YI J. Oxymatrine induces nasopharyngeal cancer cell death through inhibition of PI3K/Akt and NF-κB pathways［J］. Mol Med Rep，2017，16（6）：9701-9706.

郑文灿，法艳梅，吕亚青，等. 苦参碱抗肿瘤机制的分子生物学研究进展［J］.医学信息，2018，31（19）：51-53.

WANG Y，YANG S，ZHANG S，et al. Oxymatrine inhibits proliferation and migration of vulvar squamous cell carcinoma cells via attenuation of the RAS/RAF/MEK/ERK pathway［J］. Cancer Manag Res，2020，doi：10.2147/CMAR.S245696http://dx.doi.org/10.2147/CMAR.S245696.

JUNG Y Y， BAEK S H， NARULA A S， et al. Potential function of oxymatrine as a novel suppressor of epithelial-to-mesenchymal transition in lung tumor cells［J］. Life Sci， 2021，26（284）：119893.

SUAREZ-CARMONA M，LESAGE J，CATALDO D，et al. EMT and inflammation： inseparable actors of cancer progression［J］. Mol Oncol，2017，11（7）：805-823.

MITTAL V. Epithelial mesenchymal transition in tumor metastasis［J］. Annu Rev Pathol，2018，doi： 10.1146/annurev-pathol-020117-043854http://dx.doi.org/10.1146/annurev-pathol-020117-043854.

WANG W，DONG L，ZHAO B，et al. Ecadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT［J］. Oncol Rep，2018，40（3）：1641-1649.

TIAN H，LIAN R，LI Y，et al. Akt-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation［J］. Nat Commun， 2020，11（1）：5127-5142.

BØRRETZEN A， GRAVDAL K， HAUKAAS S A， et al. The epithelial-mesenchymal transition regulators Twist， Slug， and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients［J］. J Pathol Clin Res，2021，7（3）：253-270.

SAXENA K，JOLLY M K，BALAMURUGAN K. Hypoxia ， partial EMT and collective migration： Emerging culprits in metastasis［J］. Transl Oncol，2020，13（11）：100845-100859.

BASU S，CHERIYAMUNDATH S，BEN-ZE'EV A. Cell-cell adhesion： linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis［J］. F1000Res， 2018，18（7）：1488-1497.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Role of Aerobic Glycolysis in Breast Cancer and Traditional Chinese Medicine Intervention： A Review

Impact of Hypoxia Microenvironment on Breast Cancer and Intervention Effect of Traditional Chinese Medicine

Characteristics of STAT Family Association with Breast Cancer and Intervention Effect of Traditional Chinese Medicine

Analysis of Mechanism of Antidepressant Effect of Sophora flavescens Seed Extract

Danshen Injection Inhibits Platelets-induced Metastasis of Breast Cancer Cells In Vitro

Related Author

DENG Xianguang

RUAN Hui

LI Lian

FAN Hongqiao

LIU Lifang

WANG Xinnan

HU Wenxiu

SUN Shuo

Related Institution

The First Affiliated Hospital of Hunan University of Chinese Medicine

The First Clinical College of Traditional Chinese Medicine， Hunan University of Chinese Medicine

College of Traditional Chinese Medicine （TCM）， Formula-Pattern Research Center， Research Center of Differentiation and Development of TCM Basic Theory， Jiangxi University of Chinese Medicine

Henan University of Chinese Medicine

Institute of Chinese Materia Medica，China Academy of Chinese Medical Sciences

Postal code：100700
Tel：010-84076882 Email：syfjx_2010@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备11006657号-10 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰

Anti-breast Cancer Activities in Vitro of Oxymatrine Combined with Bevacizumab： An Exploration Focusing on EMT Regulation Through Wnt/β-catenin

DOI：10.13422/j.cnki.syfjx.20212423

摘要

Abstract

关键词

Keywords

references