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Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice

  • Mohammad Reza. Shiran , Davar Amani , Abolghasem Ajami , Mahshad Jalalpourroodsari , Maghsoud Khalizadeh and Mohsen Rashidi EMAIL logo
Published/Copyright: March 8, 2021
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Hormone Molecular Biology and Clinical Investigation
From the journal Hormone Molecular Biology and Clinical Investigation Volume 42 Issue 3

Abstract

Objectives

Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide.

Methods

In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels.

Results

There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment.

Conclusions

In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

Keywords: angiogenesis; anti-angiogenesis; Auraptene; breast cancer; immunostimulatory activity; natural compounds
Corresponding author: Mohsen Rashidi, Assistant Professor of Pharmacology, Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; and The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran, E-mail:

Funding source: Mazandaran University of Medical Sciences, Sari, Iran

  1. Research funding: This work was supported by Mazandaran University of Medical Sciences, Sari, Iran (Ethical ID: IR.MAZUMS.REC.1398.3616 Grant ID: 3616).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: All animal experiments were performed in accordance with the Principles for the Care and Use of Laboratory Animals approved by the Ethics Committee of the Mazandaran Medical University (Code: IR.MAZUMS.REC.1398.3616). All animals had free access to food and purified water and are kept under standard light and temperature conditions. After intraperitoneal administration of ketamine (80 mg/kg) and xylazine (8 mg/kg), the animals were sacrificed by cervical dislocation.

References

1. Akbarzadeh, M, Movassaghpour, AA, Ghanbari, H, Kheirandish, M, Maroufi, NF, Rahbarghazi, R, et al.. The potential therapeutic effect of melatonin on human ovarian cancer by inhibition of invasion and migration of cancer stem cells. Sci Rep 2017;7:1–11. https://doi.org/10.1038/s41598-017-16940-y.Search in Google Scholar PubMed PubMed Central

2. 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. Artificial cells, nanomedicine, and biotechnology 2018;46:283–92. https://doi.org/10.1080/21691401.2017.1423493.Search in Google Scholar PubMed

3. 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 Investig 2017;31. https://doi.org/10.1515/hmbci-2017-0019.Search in Google Scholar PubMed

4. 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

5. 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 Schmiedebergs Arch Pharmacol 2020;393:1–11. https://doi.org/10.1007/s00210-019-01692-5.Search in Google Scholar PubMed

6. 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

7. 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;27:613–20. https://doi.org/10.1007/s12282-020-01055-6.Search in Google Scholar PubMed

8. Mishan, MA, Ahmadiankia, N, Bahrami, AR. CXCR4 and CCR7: two eligible targets in targeted cancer therapy. Cell Biol Int 2016;40:955–67. https://doi.org/10.1002/cbin.10631.Search in Google Scholar PubMed

9. 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

10. 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

11. Ahmadiankia, N, Moghaddam, HK, Mishan, MA, Bahrami, AR, Naderi-Meshkin, H, Bidkhori, HR, et al.. Berberine suppresses migration of MCF-7 breast cancer cells through down-regulation of chemokine receptors. Iranian J Basic Med Sci 2016;19:125.Search in Google Scholar

12. 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;47:4749–65.10.1007/s11033-020-05515-2Search in Google Scholar PubMed

13. Curini, M, Epifano, F, Maltese, F, Marcotullio, MC, Tubaro, A, Altinier, G, et al.. Synthesis and anti-inflammatory activity of natural and semisynthetic geranyloxycoumarins. Bioorg Med Chem Lett 2004;14:2241–3. https://doi.org/10.1016/j.bmcl.2004.02.009.Search in Google Scholar PubMed

14. 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

15. Soltani, F, Mosaffa, F, Iranshahi, M, Karimi, G, Malekaneh, M, Haghighi, F, et al.. Auraptene from Ferula szowitsiana protects human peripheral lymphocytes against oxidative stress. Phytother Res 2010;24:85–9. https://doi.org/10.1002/ptr.2874.Search in Google Scholar PubMed

16. Tanaka, T, de Azevedo, MB, Durán, N, Alderete, JB, Epifano, F, Genovese, S, et al.. Colorectal cancer chemoprevention by 2 β‐cyclodextrin inclusion compounds of auraptene and 4′‐geranyloxyferulic acid. Int J Cancer 2010;126:830–40. https://doi.org/10.1002/ijc.24833.Search in Google Scholar PubMed

17. Pulaski, BA, Ostrand‐Rosenberg, S. Mouse 4T1 breast tumor model. Curr Protoc Immunol 2000;39:20–2. https://doi.org/10.1002/0471142735.im2002s39.Search in Google Scholar PubMed

18. 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

19. Petrelli, F, Viale, G, Cabiddu, M, Barni, S. Prognostic value of different cut-off levels of Ki-67 in breast cancer: a systematic review and meta-analysis of 64,196 patients. Breast Cancer Res Treat 2015;153:477–91. https://doi.org/10.1007/s10549-015-3559-0.Search in Google Scholar PubMed

20. Fasching, PA, Heusinger, K, Haeberle, L, Niklos, M, Hein, A, Bayer, CM, et al.. Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 2011;11:486. https://doi.org/10.1186/1471-2407-11-486.Search in Google Scholar PubMed PubMed Central

21. Fasching, PA, Gass, P, Häberle, L, Volz, B, Hein, A, Hack, CC, et al.. Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer. Breast Canc Res Treat 2019;175:617–25. https://doi.org/10.1007/s10549-019-05198-9.Search in Google Scholar PubMed

22. Afshari, AR, Roshan, MK, Soukhtanloo, M, Ghorbani, A, Rahmani, F, Jalili-Nik, M, et al.. Cytotoxic effects of auraptene against a human malignant glioblastoma cell line. Avicenna J Phytomedi 2019;9:334.Search in Google Scholar

23. Charmforoshan, E, Karimi, E, Oskoueian, E, Es-Haghi, A, Iranshahi, M. Inhibition of human breast cancer cells (MCF-7 cell line) growth via cell proliferation, migration, and angiogenesis by Auraptene of Ferula szowitsiana root extract. J Food Meas Charact 2019;13:2644–53. https://doi.org/10.1007/s11694-019-00185-6.Search in Google Scholar

24. Krishnan, P, Kleiner-Hancock, H. Effects of Auraptene on IGF-1 stimulated cell cycle progression in the human breast cancer cell line, MCF-7. Int J Breast Cancer 2012;2012:1–8. https://doi.org/10.1155/2012/502092.Search in Google Scholar PubMed PubMed Central

25. 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

26. 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

27. 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 2020:153226. https://doi.org/10.1016/j.prp.2020.153226.Search in Google Scholar PubMed

28. 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

29. Rashedi, J, Akbarzadeh, M, Ajami Khiyav, H, Haiaty, S, Vahedian, V, Hasanzadeh, O, et al.. The role of folic acid in carcinogenesis, diagnosis, and treatment of cancer. Int J Biomed Public Health 2018;1:114–21.Search in Google Scholar

30. Jang, Y, Han, J, Kim, SJ, Kim, J, Lee, MJ, Jeong, S, et al.. Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation. Oncotarget 2015;6:38127. https://doi.org/10.18632/oncotarget.5511.Search in Google Scholar PubMed PubMed Central

31. Moon, JY, Kim, H, Cho, SK. Auraptene, a major compound of supercritical fluid extract of phalsak (Citrus Hassaku Hort ex Tanaka), induces apoptosis through the suppression of mTOR pathways in human gastric cancer SNU-1 cells. Evid-Based Complement Altern Med 2015;2015:1–10. https://doi.org/10.1155/2015/402385.Search in Google Scholar PubMed PubMed Central

32. Stassi, G, Todaro, M, Zerilli, M, Ricci-Vitiani, L, Di Liberto, D, Patti, M, et al.. Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res 2003;63:6784–90.Search in Google Scholar

33. Prokopchuk, O, Liu, Y, Henne-Bruns, D, Kornmann, M. Interleukin-4 enhances proliferation of human pancreatic cancer cells: evidence for autocrine and paracrine actions. Br J Cancer 2005;92:921–8. https://doi.org/10.1038/sj.bjc.6602416.Search in Google Scholar PubMed PubMed Central

34. Conticello, C, Pedini, F, Zeuner, A, Patti, M, Zerilli, M, Stassi, G, et al.. IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. J Immunol 2004;172:5467–77. https://doi.org/10.4049/jimmunol.172.9.5467.Search in Google Scholar PubMed

35. Little, AC, Pathanjeli, P, Wu, Z, Bao, L, Goo, LE, Yates, JA, et al.. IL-4/IL-13 stimulated macrophages enhance breast cancer invasion via rho-GTPase regulation of synergistic VEGF/CCL-18 signaling. Front Oncol 2019;9:456. https://doi.org/10.3389/fonc.2019.00456.Search in Google Scholar PubMed PubMed Central

36. Kawaguchi, K, Sakurai, M, Yamamoto, Y, Suzuki, E, Tsuda, M, Kataoka, TR, et al.. Alteration of specific cytokine expression patterns in patients with breast cancer. Sci Rep 2019;9:1–12. https://doi.org/10.1038/s41598-019-39476-9.Search in Google Scholar PubMed PubMed Central

37. Aspord, C, Pedroza-Gonzalez, A, Gallegos, M, Tindle, S, Burton, EC, Su, D, et al.. Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development. J Exp Med 2007;204:1037–47. https://doi.org/10.1084/jem.20061120.Search in Google Scholar PubMed PubMed Central

38. Ivashkiv, LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 2018;18:545. https://doi.org/10.1038/s41577-018-0029-z.Search in Google Scholar PubMed PubMed Central

39. Wang, W, Green, M, Choi, JE, Gijón, M, Kennedy, PD, Johnson, JK, et al.. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 2019;569:270. https://doi.org/10.1038/s41586-019-1170-y.Search in Google Scholar PubMed PubMed Central

40. Ni, L, Lu, J. Interferon gamma in cancer immunotherapy. Cancer Med 2018;7:4509–16. https://doi.org/10.1002/cam4.1700.Search in Google Scholar PubMed PubMed Central

Received: 2020-12-13
Accepted: 2021-02-18
Published Online: 2021-03-08

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Original Articles
  3. Investigating the relationship between insulin resistance and adipose tissue in a randomized Tehrani population
  4. Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice
  5. Voluntary exercise improves sperm parameters in high fat diet receiving rats through alteration in testicular oxidative stress, mir-34a/SIRT1/p53 and apoptosis
  6. Assessment of AXL and mTOR genes expression in medullary thyroid carcinoma (MTC) cell line in relation with over expression of miR-144 and miR-34a
  7. Is there a relation between serum methylarginine levels and infertility?
  8. Evaluation of Y chromosome microdeletions and chromosomal anomalies in infertile men
  9. Threshold values of antibodies to estrogen, progesteron and benzo [a] pyrene as a risk factor for the development of endometriosis
  10. Altered methylarginine levels after surgery in subjects with multinodular goiter
  11. Effects of eight weeks exercise training on serum levels of adropin in male volleyball players
  12. Urinary bisphenol A in women with polycystic ovary syndrome – a possible suppressive effect on steroidogenesis?
  13. Complementary role of p57kip2 immunostaining in diagnosing hydatidiform mole subtypes
  14. Short Communications
  15. Circulating Inhibitory Factor 1 levels in adult patients with Prader–Willi syndrome
  16. Determinants of serum adiponectin levels: a cross-sectional study
  17. Case Report
  18. Prophylactic gonadectomy in 46 XY females; why, where and when?
  19. Review Article
  20. Is the beta estradiol receptor receiving enough attention for its metabolic importance in postmenopause?
https://doi.org/10.1515/hmbci-2020-0090
Keywords for this article
angiogenesis; anti-angiogenesis; Auraptene; breast cancer; immunostimulatory activity; natural compounds

Articles in the same Issue

  1. Frontmatter
  2. Original Articles
  3. Investigating the relationship between insulin resistance and adipose tissue in a randomized Tehrani population
  4. Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice
  5. Voluntary exercise improves sperm parameters in high fat diet receiving rats through alteration in testicular oxidative stress, mir-34a/SIRT1/p53 and apoptosis
  6. Assessment of AXL and mTOR genes expression in medullary thyroid carcinoma (MTC) cell line in relation with over expression of miR-144 and miR-34a
  7. Is there a relation between serum methylarginine levels and infertility?
  8. Evaluation of Y chromosome microdeletions and chromosomal anomalies in infertile men
  9. Threshold values of antibodies to estrogen, progesteron and benzo [a] pyrene as a risk factor for the development of endometriosis
  10. Altered methylarginine levels after surgery in subjects with multinodular goiter
  11. Effects of eight weeks exercise training on serum levels of adropin in male volleyball players
  12. Urinary bisphenol A in women with polycystic ovary syndrome – a possible suppressive effect on steroidogenesis?
  13. Complementary role of p57kip2 immunostaining in diagnosing hydatidiform mole subtypes
  14. Short Communications
  15. Circulating Inhibitory Factor 1 levels in adult patients with Prader–Willi syndrome
  16. Determinants of serum adiponectin levels: a cross-sectional study
  17. Case Report
  18. Prophylactic gonadectomy in 46 XY females; why, where and when?
  19. Review Article
  20. Is the beta estradiol receptor receiving enough attention for its metabolic importance in postmenopause?
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