Abstract
Objectives
Angiogenesis is the most important challenge in breast cancer treatment. Recently, scientists become interesting in rare natural products and intensive researches was performed to identify their pharmacological profile. Auraptene shows helpful effects such as cancer chemo-preventive, anti-inflammatory, anti-oxidant, immuno-modulatory. In this regard, we investigated the anti-angiogenesis effect of Auraptene in in-vitro and in-vivo model of breast cancer.
Methods
In this study, 4T, MDA-MB-231 and HUVEC cell lines were used. The proliferation study was done by MTT assay. For tube formation assay, 250 matrigel, 1 × 104 HUVEC treated with Auraptene, 20 ng/mL EGF, 20 ng/mL bFGF and 20 ng/mL VEGF were used. Gene expression of important gene related to angiogenesis in animal model of breast cancer was investigated by Real-time PCR. Protein expression of VCAM-1 and TNFR-1 gene related to angiogenesis in animal model of breast cancer was investigated by western-blot.
Results
Auraptene treatment led to reduction in cell viability of MDA-MB-231 in a concentration-dependent manner. Also, we observed change in the number of tubes or branches formed by cells incubated with 40 and 80 μM Auraptene. Auraptene effect the gene expression of important gene related to angiogenesis (VEGF, VEGFR2, COX2, IFNɣ). Moreover, the western blot data exhibited that Auraptene effect the protein expression of VCAM-1 and TNFR-1.
Conclusions
Overall, this study shows that Auraptene significantly suppressed angiogenesis via down-regulation of VEGF, VEGFR2, VCAM-1, TNFR-1, COX-2 and up-regulation of IFNγ.
Funding source: Mazandaran University of Medical Sciences http://dx.doi.org/10.13039/501100004160
Award Identifier / Grant number: 1532
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Research funding: This work finically supported by a grant of Mazandaran University of Medical Sciences (grant No: 1532).
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Author contributions: Mohammad Reza Shiran: Conceptualization, Methodology, Software. Elham Mahmoudian: Writing – review & editing, Methodology. Abolghasem Ajami: Conceptualization, Methodology, Software, Resources. Seyed Mostafa Hosseini: Data curation. Ayjamal Khojasteh: Writing – original draft, Mohsen Rashidi & Nazila Fathi Maroufi: Writing – review & editing.
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Competing interests: All authors declare that no conflicts of interest.
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Ethical approval: All the animal experiments were performed based on the principles of laboratory animals which approved by the Ethics Committee affiliated with Shahid Beheshti University of Medical Sciences (ID Number: IR.SBMU.MSP.REC.1396.824).
References
1. Maroufi, NF, Vahedian, V, Akbarzadeh, M, Mohammadian, M, Zahedi, M, Isazadeh, A, et al.. The Apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Breast Cancer 2020;27:1–8. https://doi.org/10.1007/s12282-020-01055-6.Search in Google Scholar PubMed
2. Maroufi, NF, Vahedian, V, Mazrakhondi, SAM, Kooti, W, Khiavy, HA, Bazzaz, R, et al.. Sensitization of MDA-MBA231 breast cancer cell to docetaxel by myricetin loaded into biocompatible lipid nanoparticles via sub-G1 cell cycle arrest mechanism. Naunyn-Schmiedeberg’s Arch Pharmacol 2020;393:1–11. https://doi.org/10.1007/s00210-019-01692-5.Search in Google Scholar PubMed
3. Maroufi, NF, Aghayi, E, Garshasbi, H, Matin, MG, Bedoustani, AB, Amoudizaj, FF, et al.. Association of rs1946518 C/A polymorphism in promoter region of interleukin 18 gene and breast cancer risk in Iranian women: a case-control study. Iran J Allergy, Asthma Immunol 2019;18:671–8. https://doi.org/10.18502/ijaai.v18i6.2180.Search in Google Scholar PubMed
4. Waks, AG, Winer, EP. Breast cancer treatment: a review. JAMA 2019;321:288–300. https://doi.org/10.1001/jama.2018.19323.Search in Google Scholar PubMed
5. Fathi Maroufi, N, Gholampour Matin, M, Ghanbari, N, Khorrami, A, Amini, Z, Haj Azimian, S, et al.. Influence of single nucleotide polymorphism in IL-27 and IL-33 genes on breast cancer. Br J Biomed Sci 2019;76:89–91. https://doi.org/10.1080/09674845.2018.1545554.Search in Google Scholar PubMed
6. Maroufi, NF, Rashidi, MR, Vahedian, V, Akbarzadeh, M, Fattahi, A, Nouri, M. Therapeutic potentials of Apatinib in cancer treatment: possible mechanisms and clinical relevance. Life Sci 2020;241:117106. https://doi.org/10.1016/j.lfs.2019.117106.Search in Google Scholar PubMed
7. Zeng, K, He, B, Yang, BB, Xu, T, Chen, X, Xu, M, et al.. The pro-metastasis effect of circANKS1B in breast cancer. Mol Cancer 2018;17:1–19. https://doi.org/10.1186/s12943-018-0914-x.Search in Google Scholar PubMed PubMed Central
8. Soheilyfar, S, Velashjerdi, Z, Hajizadeh, YS, Maroufi, NF, Amini, Z, Khorrami, A, et al.. In vivo and in vitro impact of miR-31 and miR-143 on the suppression of metastasis and invasion in breast cancer. J BUON 2018;23:1290–6.Search in Google Scholar
9. Maroufi, NF, Vahedian, V, Hemati, S, Rashidi, M, Akbarzadeh, M, Zahedi, M, et al.. Targeting cancer stem cells by melatonin: effective therapy for cancer treatment. Pathol Res Pract 2020;216:152919. https://doi.org/10.1016/j.prp.2020.152919.Search in Google Scholar PubMed
10. Cimpean, AM, Tamma, R, Ruggieri, S, Nico, B, Toma, A, Ribatti, D. Mast cells in breast cancer angiogenesis. Crit Rev Oncol Hematol 2017;115:23–6. https://doi.org/10.1016/j.critrevonc.2017.04.009.Search in Google Scholar PubMed
11. Akbarzadeh, M, Maroufi, NF, Tazehkand, AP, Akbarzadeh, M, Bastani, S, Safdari, R, et al.. Current approaches in identification and isolation of cancer stem cells. J Cell Physiol 2019;234:14759–72. https://doi.org/10.1002/jcp.28271.Search in Google Scholar PubMed
12. Maroufi, NF, Ashouri, N, Mortezania, Z, Ashoori, Z, Vahedian, V, Amirzadeh-Iranaq, MT, et al.. The potential therapeutic effects of melatonin on breast cancer: an invasion and metastasis inhibitor. Pathol Res Pract 2020;216:153226. https://doi.org/10.1016/j.prp.2020.153226.Search in Google Scholar PubMed
13. Maroufi, NF, Amiri, M, Dizaji, BF, Vahedian, V, Akbarzadeh, M, Roshanravan, N, et al.. Inhibitory effect of melatonin on hypoxia-induced vasculogenic mimicry via suppressing epithelial-mesenchymal transition (EMT) in breast cancer stem cells. Eur J Pharmacol 2020;881:173282. https://doi.org/10.1016/j.ejphar.2020.173282.Search in Google Scholar PubMed
14. Fathi Maroufi, N, Taefehshokr, S, Rashidi, M-R, Taefehshokr, N, Khoshakhlagh, M, Isazadeh, A, et al.. Vascular mimicry: changing the therapeutic paradigms in cancer. Mol Biol Rep 2020;47:1–17. https://doi.org/10.1007/s11033-020-05515-2.Search in Google Scholar PubMed
15. Singh, B, Lucci, A. Role of cyclooxygenase-2 in breast cancer. J Surg Res 2002;108:173–9. https://doi.org/10.1006/jsre.2002.6532.Search in Google Scholar PubMed
16. Chen, Q, Massagué, J. Molecular pathways: VCAM-1 as a potential therapeutic target in metastasis. Clin Cancer Res 2012;18:5520–5. https://doi.org/10.1158/1078-0432.ccr-11-2904.Search in Google Scholar
17. Sharma, R, Sharma, R, Khaket, TP, Dutta, C, Chakraborty, B, Mukherjee, TK. Breast cancer metastasis: putative therapeutic role of vascular cell adhesion molecule-1. Cell Oncol 2017;40:199–208. https://doi.org/10.1007/s13402-017-0324-x.Search in Google Scholar PubMed
18. Schlesinger, M, Bendas, G. Vascular cell adhesion molecule‐1 (VCAM‐1)—an increasing insight into its role in tumorigenicity and metastasis. Int J Cancer Res 2015;136:2504–14. https://doi.org/10.1002/ijc.28927.Search in Google Scholar PubMed
19. Jamialahmadi, K, Salari, S, Alamolhodaei, NS, Avan, A, Gholami, L, Karimi, G. Auraptene inhibits migration and invasion of cervical and ovarian cancer cells by repression of matrix metalloproteinasas 2 and 9 activity. J Pharmacopuncture 2018;21:177. https://doi.org/10.3831/KPI.2018.21.021.Search in Google Scholar PubMed PubMed Central
20. Krishnan, P, Yan, KJ, Windler, D, Tubbs, J, Grand, R, Li, BD, et al.. Citrus auraptene suppresses cyclin D1 and significantly delays N-methyl nitrosourea induced mammary carcinogenesis in female Sprague-Dawley rats. BMC Cancer 2009;9:259. https://doi.org/10.1186/1471-2407-9-259.Search in Google Scholar PubMed PubMed Central
21. Hajipour, H, Hamishehkar, H, Nazari Soltan Ahmad, S, Barghi, S, Maroufi, NF, Taheri, RA. Improved anticancer effects of epigallocatechin gallate using RGD-containing nanostructured lipid carriers. Artif Cell Nanomed Biotechnol 2018;46:283–92. https://doi.org/10.1080/21691401.2017.1423493.Search in Google Scholar PubMed
22. Ghorbani, M, Mahmoodzadeh, F, Jannat, B, Maroufi, NF, Hashemi, B, Roshangar, L. Glutathione and pH‐responsive fluorescent nanogels for cell imaging and targeted methotrexate delivery. Polym Adv Technol 2019;30:1847–55. https://doi.org/10.1002/pat.4617.Search in Google Scholar
23. Taefehshokr, S, Taefehshokr, N, Derakhshani, A, Baghbanzadeh, A, Astamal, RV, Safaei, S, et al.. The regulatory role of pivotal microRNAs in the AKT signaling pathway in breast cancer. Curr Mol Med 2021. https://doi.org/10.2174/1566524021666210708095051.Search in Google Scholar PubMed
24. Rashedi, J, Akbarzadeh, M, Ajami Khiyav, H, Haiaty, S, Vahedian, V, Omid, H, et al.. The role of folic acid in carcinogenesis, diagnosis, and treatment of cancer. Int J Biomed Publ Health 2018;1:114–21.Search in Google Scholar
25. Ahmadi, M, Rasi, H, Mostafazadeh, M, Hajazimian, S, Maroufi, NF, Nahaei, MR, et al.. Analysis of cervical lesions for presence of HSV-2 and HPV-16 and HPV-18 in Iranian patients by PCR. Horm Mol Biol Clin Invest 2017;31. https://doi.org/10.1515/hmbci-2017-0019.Search in Google Scholar PubMed
26. Pourmohammad, P, Maroufi, NF, Rashidi, M, Vahedian, V, Pouremamali, F, Faridvand, Y, et al.. Potential therapeutic effects of melatonin mediate via miRNAs in cancer. Biochem Genet 2021:1–23. https://doi.org/10.1007/s10528-021-10104-4.Search in Google Scholar PubMed
27. Haiaty, S, Rashidi, MR, Akbarzadeh, M, Maroufi, NF, Yousefi, B, Nouri, M. Targeting vasculogenic mimicry by phytochemicals: a potential opportunity for cancer therapy. IUBMB Life 2020;72:825–41. https://doi.org/10.1002/iub.2233.Search in Google Scholar PubMed
28. Maroufi, NF, Rashidi, M, Vahedian, V, Jahanbazi, R, Mostafaei, S, Akbarzadeh, M, et al.. Effect of Apatinib plus melatonin on vasculogenic mimicry formation by cancer stem cells from breast cancer cell line. Breast Cancer 2021:1–14. https://doi.org/10.1007/s12282-021-01310-4.Search in Google Scholar PubMed
29. Tanaka, T, Kawabata, K, Kakumoto, M, Matsunaga, K, Mori, H, Murakami, A, et al.. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by citrus auraptene in rats. Carcinogenesis 1998;19:425–31. https://doi.org/10.1093/carcin/19.3.425.Search in Google Scholar PubMed
30. Hayashi, K, Suzuki, R, Miyamoto, S, Shin-Ichiroh, Y, Kohno, H, Sugie, S, et al.. Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice. Nutr Cancer 2007;58:75–84. https://doi.org/10.1080/01635580701308216.Search in Google Scholar PubMed
31. Kawabata, K, Tanaka, T, Yamamoto, T, Ushida, J, Hara, A, Murakami, A, et al.. Suppression of N‐nitrosomethylbenzylamine‐induced rat esophageal tumorigenesis by dietary feeding of 1′‐acetoxychavicol acetate. Jpn J Cancer Res 2000;91:148–55. https://doi.org/10.1111/j.1349-7006.2000.tb00926.x.Search in Google Scholar PubMed PubMed Central
32. Sakata, K, Hara, A, Hirose, Y, Yamada, Y, Kuno, T, Katayama, M, et al.. Dietary supplementation of the citrus antioxidant auraptene inhibits N, N-diethylnitrosamine-induced rat hepatocarcinogenesis. Oncology 2004;66:244–52. https://doi.org/10.1159/000078001.Search in Google Scholar PubMed
33. Tang, M, Ogawa, K, Asamoto, M, Hokaiwado, N, Seeni, A, Suzuki, S, et al.. Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer Sci 2007;98:471–7. https://doi.org/10.1111/j.1349-7006.2007.00417.x.Search in Google Scholar PubMed
34. Murakami, A, Kuki, W, Takahashi, Y, Yonei, H, Nakamura, Y, Ohto, Y, et al.. Auraptene, a citrus coumarin, inhibits 12‐0‐tetradecanoylphorbol‐13‐acetate‐induced tumor promotion in icr mouse skin, possibly through suppression of superoxide generation in leukocytes. Jpn J Cancer Res 1997;88:443–52. https://doi.org/10.1111/j.1349-7006.1997.tb00402.x.Search in Google Scholar PubMed PubMed Central
35. Kuki, W, Hosotani, K, Ohigashi, H, Murakami, A. Metabolism and absorption of auraptene (7-geranyloxylcoumarin) in male SD rats: comparison with 7-ethoxycoumarin. Nutr Cancer 2008;60:368–72. https://doi.org/10.1080/01635580701745327.Search in Google Scholar PubMed
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