Triphenylethylene-Coumarin Hybrid TCH-5c Suppresses Tumorigenic Progression in Breast Cancer Mainly Through the Inhibition of Angiogenesis

Author(s): Naipeng Cui, Dan-Dan Lin, Yang Shen, Jian-Guo Shi, Bing Wang, Ming-Zhi Zhao, Lishuang Zheng, Hua Chen*, Jian-Hong Shi*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 10 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Coumarins are a wide group of naturally occurring compounds which exhibit a wide range of biological properties such as anti-cancer activities. Here, we characterized the biological functions of three Triphenylethylene-Coumarin Hybrids (TCHs) both in cell culture and nude mouse model.

Methods: Cell proliferation assay was performed in the cell cultures of both EA.hy926 endothelial cell and breast cancer cell lines treated with different concentrations of compound TCH-10b, TCH-5a and TCH-5c. Flowcytometry assay and Western blotting were used to further investigate the effect and mechanism of TCH-5c on EA.hy926 cell proliferation and cell cycle. The effects of TCH-5c on endothelial cell migration and angiogenesis were determined using cytoskeleton staining, migration assay and tube formation assay. Inhibition of breast cancer cell line derived VEGF by TCH-5c was shown through ELISA and the use of conditioned media. SK-BR-3 xenograft mouse model was established to further study the anti-tumorigenic role of compound TCH-5c in vivo.

Results: We found that compound TCH-5c has inhibitory effects on both vascular endothelial cells and breast cancer cell lines. Compound TCH-5c inhibited proliferation, resulted in cell death, increased p21 protein expression to induce G0/G1 arrest and changed endothelial cell cytoskeleton organization and migration in EA.hy926 endothelial cells. Compound TCH-5c also inhibited breast cancer cell line derived VEGF secretion, decreased breast cancer cell-induced endothelial cell tube formation in vitro and suppressed SK-BR-3 breast cancer cell-initiated tumor formation in vivo.

Conclusion: Our study demonstrates that the coumarin derivative TCH-5c exerts its anti-cancer effects by 1. inhibiting endothelial cell proliferation, migration. 2. suppressing tube formation and angiogenesis induced by breast cancer cells in vitro and in vivo. Our results have potential implications in developing new approaches against breast cancer.

Keywords: Breast neoplasms, angiogenesis inhibitors, vascular endothelial growth factor, coumarin, TCH-5c, western blotting.

Sohn, E.J.; Jung, D.B.; Lee, H.; Han, I.; Lee, J.; Lee, H.; Kim, S.H. CNOT2 promotes proliferation and angiogenesis via VEGF signaling in MDA-MB-231 breast cancer cells. Cancer Lett., 2018, 412, 88-98.
Bharti, J.N.; Rani, P.; Kamal, V.; Agarwal, P.N. Angiogenesis in breast cancer and its correlation with estrogen, progesterone receptors and other prognostic factors. J. Clin. Diagn. Res., 2015, 9(1), EC05-EC07.
Kopec, M.; Abramczyk, H. Angiogenesis - a crucial step in breast cancer growth, progression and dissemination by Raman imaging. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2018, 198, 338-345.
Mafu, T.S.; September, A.V.; Shamley, D. The potential role of angiogenesis in the development of shoulder pain, shoulder dysfunction, and lymphedema after breast cancer treatment. Cancer Manag. Res., 2018, 10, 81-90.
Tredan, O.; Lacroix-Triki, M.; Guiu, S.; Mouret-Reynier, M.A.; Barriere, J.; Bidard, F.C.; Braccini, A.L.; Mir, O.; Villanueva, C.; Barthelemy, P. Angiogenesis and tumor microenvironment: Bevacizumab in the breast cancer model. Target. Oncol., 2015, 10(2), 189-198.
Wehland, M.; Bauer, J.; Infanger, M.; Grimm, D. Target-based anti-angiogenic therapy in breast cancer. Curr. Pharm. Des., 2012, 18(27), 4244-4257.
Labanca, V.; Bertolini, F. A combinatorial investigation of the response to anti-angiogenic therapy in breast cancer: New strategies for patient selection and opportunities for reconsidering anti-VEGF, anti-PI3K and checkpoint inhibition. EBioMedicine, 2016, 10, 13-14.
Sairam, V.K.; Gurupadayya, B.M.; Chandan, R.S.; Nagesha, D.K.; Vishwanathan, B. A review on chemical profile of coumarins and their therapeutic role in the treatment of cancer. Curr. Drug Deliv., 2016, 13(2), 186-201.
Basanagouda, M.; Jambagi, V.B.; Barigidad, N.N.; Laxmeshwar, S.S.; Devaru, V. Narayanachar. Synthesis, structure-activity relationship of iodinated-4-aryloxymethyl-coumarins as potential anti-cancer and anti-mycobacterial agents. Eur. J. Med. Chem., 2014, 74, 225-233.
Kasaian, J.; Mosaffa, F.; Behravan, J.; Masullo, M.; Piacente, S.; Ghandadi, M.; Iranshahi, M. Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins. Fitoterapia, 2015, 103, 149-154.
Chen, W.; Li, J.; Sun, Z.; Wu, C.; Ma, J.; Wang, J.; Liu, S.; Han, X. Comparative pharmacokinetics of six coumarins in normal and breast cancer bone-metastatic mice after oral administration of Wenshen Zhuanggu Formula. J. Ethnopharmacol., 2018, 224, 36-44.
Iranshahi, M.; Barthomeuf, C.; Bayet-Robert, M.; Chollet, P.; Davoodi, D.; Piacente, S.; Rezaee, R.; Sahebkar, A. Drimane-type sesquiterpene coumarins from ferula gummosa fruits enhance doxorubicin uptake in doxorubicin-resistant human breast cancer cell line. J. Tradit. Complement. Med., 2014, 4(2), 118-125.
Chen, H.; Li, S.; Yao, Y.; Zhou, L.; Zhao, J.; Gu, Y.; Wang, K.; Li, X. Design, synthesis, and anti-tumor activities of novel triphenylethylene-coumarin hybrids, and their interactions with Ct-DNA. Bioorg. Med. Chem. Lett., 2013, 23(17), 4785-4789.
Shi, J.H.; Cui, N.P.; Wang, S.; Zhao, M.Z.; Wang, B.; Wang, Y.N.; Chen, B.P. Overexpression of YB1 C-terminal domain inhibits proliferation, angiogenesis and tumorigenicity in a SK-BR-3 breast cancer xenograft mouse model. FEBS Open Bio, 2016, 6(1), 33-42.
Rashid, O.M.; Nagahashi, M.; Ramachandran, S.; Dumur, C.; Schaum, J.; Yamada, A.; Terracina, K.P.; Milstien, S.; Spiegel, S.; Takabe, K. An improved syngeneic orthotopic murine model of human breast cancer progression. Breast Cancer Res. Treat., 2014, 147(3), 501-512.
Li, T.; Kang, G.; Wang, T.; Huang, H. Tumor angiogenesis and anti-angiogenic gene therapy for cancer. Oncol. Lett., 2018, 16(1), 687-702.
Albini, A.; Bruno, A.; Noonan, D.M.; Mortara, L. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: Implications for immunotherapy. Front. Immunol., 2018, 9, 527.
Okamoto, T.; Usuda, H.; Tanaka, T.; Wada, K.; Shimaoka, M. The functional implications of endothelial gap junctions and cellular mechanics in vascular angiogenesis. Cancers, 2019, 11(2), 237.
Mawalla, B.; Yuan, X.; Luo, X.; Chalya, P.L. Treatment outcome of anti-angiogenesis through VEGF-pathway in the management of gastric cancer: A systematic review of phase II and III clinical trials. BMC Res. Notes, 2018, 11(1), 21.
Li, X.; Gao, Y.; Li, J.; Zhang, K.; Han, J.; Li, W.; Hao, Q.; Zhang, W.; Wang, S.; Zeng, C.; Zhang, W.; Zhang, Y.; Li, M.; Zhang, C. FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer. Cell Death Dis., 2018, 9(7), 744.
Yen, L.; You, X.L.; Al Moustafa, A.E.; Batist, G.; Hynes, N.E.; Mader, S.; Meloche, S.; Alaoui-Jamali, M.A. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene, 2000, 19(31), 3460-3469.
Mashreghi, M.; Azarpara, H.; Bazaz, M.R.; Jafari, A.; Masoudifar, A.; Mirzaei, H.; Jaafari, M.R. Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis. J. Cell. Physiol., 2018, 233(4), 2949-2965.
Srikrishna, D.; Godugu, C.; Dubey, P.K. A review on pharmacological properties of coumarins. Mini Rev. Med. Chem., 2018, 18(2), 113-141.
Zhu, J.J.; Jiang, J.G. Pharmacological and nutritional effects of natural coumarins and their structure-activity relationships. Mol. Nutr. Food Res., 2018.e1701073

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1253 - 1261]
Pages: 9
DOI: 10.2174/1871520619666190404155230

Article Metrics

PDF: 71
HTML: 15