Chlorogenic acid suppresses angiogenesis in 4T1 breast tumors via Cox-2, Vegf, and Mmp-9 downregulation

Zahra Changizi, Shima Ababzadeh, Masoumeh Dolati, Azam Moslehi, Reihaneh Seyedebrahimi, Mohsen Eslami Farsani

Abstract


Background and purpose: Angiogenesis, as a physiological process, plays a key role in the development of invasive tumors. However, polyphenol compounds such as chlorogenic acid (CGA) can help reduce the risk of metastasis. This study explored the anti-angiogenic properties of CGA in a metastatic tumor model.

Experimental approach: Forty female BALB/c mice were randomly divided into 5 groups, including saline, receiving normal saline; breast cancer (BC), receiving 4T1 cells and normal saline; CGA group, receiving CGA solution; PR group, receiving simultaneously 4T1 cells and CGA; treatment group (TM), receiving CGA after tumor induction. The treatment period was 14 days. The anti-angiogenic effects of CGA were examined using the H&E and TB staining in breast, liver, and lung tissues of the metastatic tumor model. Real‐time RT‐PCR was also conducted to determine the expression of Vegf, Cox-2, and Mmp-9 genes in tumor vessels and metastatic tissues.

Findings/Results: Histomorphological evaluations demonstrated a significant reduction in the number of all types of breast vessels and many vessels of lung tissue in the TM group compared with the BC group. Also, the diameter of sinusoid capillaries and veins of liver tissue significantly decreased with the administration of CGA compared with the BC group. Moreover, real-time RT‐PCR results showed that CGA administration downregulated the expression of Cox-2, Vegf, and Mmp-9 levels compared with the BC group, significantly.

Conclusion and implications: CGA plays an important role in inhibiting angiogenesis by decreasing the expression of Cox-2, Vegf, and Mmp-9 genes. It could improve the invasion of 4T1 breast cancer tumors in BALB/c mice.

 


Keywords


Angiogenesis; Chlorogenic acid; Cox-2; Mmp-9; 4T1 breast cancer;Vegf.

Full Text:

PDF

References


Rahimmanesh I, Khanahmad H. Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer. Res Pharma Sci. 2021;16(5):447-454. DOI: 10.4103/1735-5362.323911.

Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, et al. Risk factors and preventions of breast cancer. Int J Biol Sci. 2017;13(11):1387-1397. DOI: 10.7150/ijbs.21635.

Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193-199. DOI: 10.7150/ijms.3635.

Agrawal S. Late effects of cancer treatment in breast cancer survivors. South Asian J Cancer. 2014;3(2):112-115. DOI: 10.4103/2278-330X.130445.

Kayl AE, Meyers CA. Side-effects of chemotherapy and quality of life in ovarian and breast cancer patients. Curr Opin Obstet Gynecol. 2006;18(1):24-28. DOI: 10.1097/01.gco.0000192996.20040.24.

Anderson PM, Lalla RV. Glutamine for amelioration of radiation and chemotherapy associated mucositis during cancer therapy. Nutrients. 2020;12(6):1675,1-15. DOI: 10.3390/nu12061675.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186.DOI: 10.1056/NEJM197111182852108.

Li T, Kang G, Wang T, Huang H. Tumor angiogenesis and anti-angiogenic gene therapy for cancer. Oncol Lett. 2018;16(1):687-702. DOI: 10.3892/ol.2018.8733.

Rahat MA, Kzhyshkowska J, Iragavarapu-Charyulu V. Editorial: targeting angiogenesis to treat autoimmune diseases and cancer. Front Immunol. 2020;11:1005,1-3. DOI: 10.3389/fimmu.2020.01005.

Jones D. Parallels of resistance between angiogenesis and lymphangiogenesis inhibition in cancer therapy. Cells. 2020;9(3):762,1-12. DOI: 10.3390/cells9030762.

Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res. 2020;39(1):204,1-19. DOI: 10.1186/s13046-020-01709-5.

Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med. 2019;9(1):84,1-21. DOI: 10.3390/jcm9010084.

Saman H, Raza SS, Uddin S, Rasul K. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers (Basel). 2020;12(5):1172,1-18. DOI: 10.3390/ cancer s12051172.

Meng XY, Zhang Q, Li Q, Lin S, Li J. Immunohistochemical levels of cyclo-oxygenase-2, matrix metalloproteinase-9 and vascular endothelial growth factor in papillary thyroid carcinoma and their clinicopathological correlations. J Int Med Res. 2014;42(3):619-627. DOI: 10.1177/0300060513505485.

Desai SJ, Prickril B, Rasooly A. Mechanisms of phytonutrient modulation of cyclooxygenase-2 (COX-2) and inflammation related to cancer. Nutr Cancer. 2018;70(3):350-375. DOI: 10.1080/01635581.2018.1446091.

Santoro A, Bufo P, Russo G, Cagiano S, Papagerakis S, Bucci P, et al. Expression and clinical implication of cyclooxygenase-2 and E-cadherin in oral squamous cell carcinomas. Cancer Biol Ther. 2020;21(8):667-674. DOI: 10.1080/15384047.2015.1071741.

Tudor DV, Bâldea I, Lupu M, Kacso T, Kutasi E, Hopârtean A, et al. COX-2 as a potential biomarker and therapeutic target in melanoma. Cancer Biol Med. 2020;17(1):20-31. DOI: 10.20892/ j.issn.2095-3941.2019.0339.

Fujii T, Hirakata T, Kurozumi S, Tokuda S, Nakazawa Y, Obayashi S, et al. VEGF-A is associated with the degree of TILs and PD-L1 expression in primary breast cancer. In Vivo. 2020;34(5):2641-2646. DOI: 10.21873/invivo.12082.

Barillari G. The impact of matrix metalloproteinase-9 on the sequential steps of the metastatic process. Int J Mol Sci. 2020;21(12):4526,1-28. DOI: 10.3390/ijms21124526.

Fan J, Liu B, Long Y, Wang Z, Tong C, Wang W, et al. Sequentially-targeted biomimetic nano drug system for triple-negative breast cancer ablation and lung metastasis inhibition. Acta Biomater. 2020;113:554-569. DOI: 10.1016/j.actbio.2020.06.025.

Hwang ST, Um JY, Chinnathambi A, Alharbi SA, Narula AS, Namjoshi OA, et al. Evodiamine mitigates cellular growth and promotes apoptosis by targeting the c-Met pathway in prostate cancer cells. Molecules. 2020;25(6):1320,1-14. DOI: 10.3390/molecules25061320.

Montané X, Kowalczyk O, Reig-Vano B, Bajek A, Roszkowski K, Tomczyk R, et al. Current perspectives of the applications of polyphenols and flavonoids in cancer therapy. Molecules. 2020;25(15):3342,1-26. DOI: 10.3390/molecules25153342.

Hazafa A, Rehman KU, Jahan N, Jabeen Z. The role of polyphenol (flavonoids) compounds in the treatment of cancer cells. Nutr Cancer. 2020;72(3):386-397. DOI: 10.1080/01635581.2019.1637006.

Sun W, Shahrajabian MH. Therapeutic potential of phenolic compounds in medicinal plants-natural health products for human health. Molecules. 2023;28(4):1845,1-43.DOI: 10.3390/molecules28041845.

Huang S, Wang LL, Xue NN, Li C, Guo HH, Ren TK, et al. Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation. Theranostics. 2019;9(23):6745-6763.DOI: 10.7150/thno.34674.

Girsang E, Ginting CN, Lister INE, Widowati W, Yati A, Kusuma HSW, et al. Antiaging properties of chlorogenic acid through protein and gene biomarkers in human skin fibroblast cells as photoaging model. Res Pharm Sci. 2024;19(6):746-753. DOI: 10.4103/RPS.RPS-177-22.

Changizi Z, Moslehi A, Haeri Rohani A, Eidi A. Chlorogenic acid induces 4T1 breast cancer tumor's apoptosis via p53, Bax, Bcl‐2, and caspase‐3 signaling pathways in BALB/c mice. J Biochem Mol Toxicol. 2021;35(2):e22642. DOI: 10.1002/jbt.22642.

Tao K, Fang M, Alroy J, Sahagian GG. Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer. 2008;8:228,1-20. DOI: 10.1186/1471-2407-8-228.

Seyedebrahimi R, Azimzadeh M, Ababzadeh S, Heidarieh N, Bahrami M, Eslami Farsani M. Histopathological and enzymological evaluation of opium tincture and protective effects of chicory extract on liver structure in adult male rats. Pharm Chem J. 2023;57(3):395-400. DOI: 10.1007/s11094-023-02896-z.

Eslami Farsani M, Razavi S, Rasoolijazi H, Esfandiary E, Seyedebrahimi R, Ababzadeh S. Neuroprotective effects of rosemary extract on white matter of prefrontal cortex in old rats. Iran J Basic Med Sci. 2024;27(4):518-523. DOI: 10.22038/ijbms.2023.74168.16117.

Komeili-Movahhed T, Moslehi A. Protective effect of rosmarinic acid on inflammatory changes of hepatic cells in non-alcoholic steatohepatitis in mice: cyclooxygenase 2/prostaglandin E2 pathway (Persian). Qom Univ Med Sci J. 2023;16(11):868-879. DOI: 10.32598/qums.16.11.65.7.

Kim C, Yu HG, Sohn J. The anti-angiogenic effect of chlorogenic acid on choroidal neovascularization. Korean J Ophthalmol. 2010;24(3):163-168. DOI: 10.3341/kjo.2010.24.3.163.

Wu WB, Hung DK, Chang FW, Ong ET, Chen BH. Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum Linnaeus on human umbilical vein endothelial cells. Food Funct. 2012;3(10):1068-1081. DOI: 10.1039/C2FO30051F.

Kim J, Lee YM, Jung W, Park SB, Kim CS, Kim JS. Aster koraiensis extract and chlorogenic acid inhibit retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Evid Based Complement Alternat Med. 2018;2018:6402650,1-8. DOI: 10.1155/2018/6402650.

Bagdas D, Gul NY, Topal A, Tas S, Ozyigit MO, Cinkilic N, et al. Pharmacologic overview of systemic chlorogenic acid therapy on experimental wound healing. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(11):1101-1116.DOI: 10.1007/s00210-014-1034-9.

Shenoy AK, Lu J. Cancer cells remodel themselves and vasculature to overcome the endothelial barrier. Cancer Lett. 2016;380(2):534-544. DOI: 10.1016/j.canlet.2014.10.031.

van Zijl F, Krupitza G, Mikulits W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res. 2011;728(1-2):23-34. DOI: 10.1016/j.mrrev.2011.05.002.

Motawi TK, Abdelazim SA, Darwish HA, Elbaz EM, Shouman SA. Modulation of tamoxifen cytotoxicity by caffeic acid phenethyl ester in MCF-7 breast cancer cells. Oxid Med Cell Longev. 2016;2016:3017108,1-13. DOI: 10.1155/2016/3017108.

Wang X, Liu J, Xie Z, Rao J, Xu G, Huang K, et al. Chlorogenic acid inhibits proliferation and induces apoptosis in A498 human kidney cancer cells via inactivating PI3K/Akt/mTOR signalling pathway. J Pharm Pharmacol. 2019;71(7):1100-1109. DOI: 10.1111/jphp.13095.

Zeng A, Liang X, Zhu S, Liu C, Wang S, Zhang Q, et al. Chlorogenic acid induces apoptosis, inhibits metastasis and improves antitumor immunity in breast cancer via the NF‑κB signaling pathway. Oncol Rep. 2021;45(2):717-727. DOI: 10.3892/or.2020.7891.

Senchukova MA, Nikitenko NV, Tomchuk ON, Zaitsev NV, Stadnikov AA. Different types of tumor vessels in breast cancer: morphology and clinical value. Springerplus. 2015;4:512,1-11. DOI: 10.1186/s40064-015-1293-z.

Zhang Y, Dang S, Wan Y, Yang F, Li T. Influence of VEGF, COX-2, and MMP-9 expression on the molybdenum-targeted X-ray in breast cancer. Eur J Gynaecol Oncol. 2017;38(1):45-48. PMID: 29767863.

Ran Z, Hou L, Guo H, Wang K, Li X. Expression of VEGF, COX-2 and MMP-9 in breast cancer and their relationship with ultrasound findings. Int J Clin Exp Pathol. 2018;11(9):4264-4269. PMID: 31949822.

Hermansyah D, Paramita DA, Muhar AM, Amalina ND. Curcuma longa extract inhibits migration by reducing MMP-9 and Rac-1 expression in highly metastatic breast cancer cells. Res Pharm Sci. 2024;19(2):157-166. DOI: 10.4103/RPS.RPS_46_23.

Bisht A, Dickens M, Rutherfurd-Markwick K, Thota R, Mutukumira AN, Singh H. Chlorogenic acid potentiates the anti-inflammatory activity of curcumin in LPS-stimulated THP-1 cells. Nutrients. 2020;12(9):2706,1-12. DOI: 10.3390/nu12092706.

Liu CC, Zhang Y, Dai BL, Ma YJ, Zhang Q, Wang Y, et al. Chlorogenic acid prevents inflammatory responses in IL‑1β‑stimulated human SW‑1353 chondrocytes, a model for osteoarthritis. Mol Med Rep. 2017;16(2):1369-1375. DOI: 10.3892/mmr.2017.6698.

Mei X, Zhou L, Zhang T, Lu B, Sheng Y, Ji L. Chlorogenic acid attenuates diabetic retinopathy by reducing VEGF expression and inhibiting VEGF-mediated retinal neoangiogenesis. Vascul Pharmacol. 2018;101:29-37. DOI: 10.1016/j.vph.2017.11.002.

Lukitasari M, Saifur Rohman M, Nugroho DA, Widodo N, Nugrahini NIP. Cardiovascular protection effect of chlorogenic acid: focus on the molecular mechanism. F1000Res. 2020;9:1462,1-16. DOI: 10.12688/f1000research.26236.1.

Pan D, Gong X, Wang X, Li M. Role of active components of medicinal food in the regulation of angiogenesis. Front Pharmacol. 2021;11:594050,1-21.DOI: 10.3389/fphar.2020.594050.

Zhou J, Zhang F, Chen J, Zhang S, Wang H. Chlorogenic acid inhibits human glioma U373 cell progression via regulating the SRC/MAPKs signal pathway: based on network pharmacology analysis. Drug Des Devel Ther. 2021;15:1369-1383. DOI: 10.2147/DDDT.S296862.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.