Psoralidin exerts anti-tumor, anti-angiogenic, and immunostimulatory activities in 4T1 tumor‐bearing balb/c mice

Davar Amani; Elham Shakiba; Ehsan Motaghi; Hiva Alipanah; Mahshad Jalalpourroodsari; Mohsen Rashidi

doi:10.1515/hmbci-2021-0028

Article

Psoralidin exerts anti-tumor, anti-angiogenic, and immunostimulatory activities in 4T1 tumor‐bearing balb/c mice

Davar Amani , Elham Shakiba , Ehsan Motaghi , Hiva Alipanah , Mahshad Jalalpourroodsari and Mohsen Rashidi

Published/Copyright: September 9, 2021

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Hormone Molecular Biology and Clinical Investigation Volume 43 Issue 1

Abstract

Background

Psoralidin as a compound of the Psoralea corylifolia seeds exhibited several anti-cancer potentials in various cancers.

Materials and methods

In this study, 4T1 tumor‐bearing Balb/c mice were treated by intraperitoneal administration of Psoralidin, and Paraffin, as a control group to investigate anti-tumor, anti-angiogenic, and immunostimulatory activities in breast cancer. Body weight and tumor volume measurement were performed. Hematoxylin and Eosin (H&E) staining as well as immunohistochemistry for Ki-67, CD31 and VEGF markers were conducted. In addition, ELISA assay was performed for evaluating the serum level of IFN-γ and IL-4. Moreover, real time assay was performed to evaluate the expression of angiogenesis and immunostimulatory related genes.

Results

There were no significant changes in the body weight of all animal groups. The anti-cancer effects of Psoralidin were significantly observed after 24 days of the last treatment, confirmed by smaller tumor volume and also H&E staining. The expression level of Ki‐67, CD31 and VEGF were significantly decreased in tumor tissues of the Psoralidin-treated group in comparison with Paraffin-treated group. Moreover, there was a significant reduction in the serum level of IL-4 in tumor-bearing mice after Psoralidin treatment while the serum level of IFN-γ was significantly augmented in all groups. Moreover, the reduction in expression of VEGF-a and IL-1β was observed. Interestingly Psoralidin treatment led to expression increase of FOXp3.

Conclusions

Psoralidin shows the anti-cancer potential in an animal model of breast cancer; however, further studies are recommended to elucidate its mechanisms of action.

Keywords: anti-angiogenesis; breast cancer; immunostimulatory activity; natural compounds; psoralidin

Corresponding author: Mohsen Rashidi, Assistant Professor of Pharmacology, Department of Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran, Phone: 00989127987237, E-mail: dr.mohsenrashidi@yahoo.com

Funding source: Shahid Beheshti University of Medical Sciences

Research funding: This work was supported by Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Author contributions: Davar Amani: Conceptualization, Methodology, Software. Elham Shakiba: Writing – review & editing, Methodology. Ehsan Motaghi: Conceptualization, Methodology, Software, Resources. Hiva Alipanah: Data curation. Mahshad Jalalpourroodsari: Writing – original draft, Mohsen Rashidi: Writing – review and editing. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
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, 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

2. 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

3. 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

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

5. 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

6. 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

7. 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

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. Paller, CJ, Denmeade, SR, Carducci, MA. Challenges of conducting clinical trials of natural products to combat cancer. Clin Adv Hematol Oncol 2016;14:447–55.Search in Google Scholar

10. 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

11. Chopra, B, Dhingra, AK, Dhar, KL. Psoralea corylifolia L. (Buguchi)—folklore to modern evidence. Fitoterapia 2013;90:44–56. https://doi.org/10.1016/j.fitote.2013.06.016.Search in Google Scholar PubMed

12. Wulandari, R, Susilo, H, Kuswandi, D. Penggunaan multimedia interaktif bermuatan game edukasi untuk meningkatkan aktivitas dan hasil belajar siswa sekolah dasar. J Pendidik Teori Penelitian dan Pengembangan 2017;2:1024–9.Search in Google Scholar

13. Yang, Y-M, Hyun, J-W, Sung, M-S, Chung, H-S, Kim, B-K, Paik, W-H, et al.. The cytotoxicity of psoralidin from Psoralea corylifolia. Planta Med 1996;62:353–4. https://doi.org/10.1055/s-2006-957901.Search in Google Scholar PubMed

14. Mar, W, Je, K-H, Seo, E-K. Cytotoxic constituents ofPsoralea corylifolia. Arch Pharm Res (Seoul) 2001;24:211. https://doi.org/10.1007/bf02978259.Search in Google Scholar

15. Hao, W, Zhang, X, Zhao, W, Chen, X. Psoralidin induces autophagy through ROS generation which inhibits the proliferation of human lung cancer A549 cells. PeerJ 2014;2:e555. https://doi.org/10.7717/peerj.555.Search in Google Scholar PubMed PubMed Central

16. Szliszka, E, Czuba, ZP, Sêdek, Ł, Paradysz, A, Król, W. Enhanced TRAIL-mediated apoptosis in prostate cancer cells by the bioactive compounds neobavaisoflavone and psoralidin isolated from Psoralea corylifolia. Pharmacol Rep 2011;63:139–48. https://doi.org/10.1016/s1734-1140(11)70408-x.Search in Google Scholar PubMed

17. Bronikowska, J, Szliszka, E, Jaworska, D, Czuba, ZP, Krol, W. The coumarin psoralidin enhances anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Molecules 2012;17:6449–64. https://doi.org/10.3390/molecules17066449.Search in Google Scholar PubMed PubMed Central

18. Jin, Z, Yan, W, Jin, H, Ge, C, Xu, Y. Psoralidin inhibits proliferation and enhances apoptosis of human esophageal carcinoma cells via NF-κB and PI3K/Akt signaling pathways. Oncol Lett 2016;12:971–6. https://doi.org/10.3892/ol.2016.4716.Search in Google Scholar PubMed PubMed Central

19. Yu, B, Wang, A-H, Zhou, K, Chai, L-J, Liu, L. Molecular pathway of psoralidin-induced apoptosis in HepG2 cell line. Chin J Integr Med 2019;25:757–62. https://doi.org/10.1007/s11655-016-2251-5.Search in Google Scholar PubMed

20. Jin, Z, Yan, W, Jin, H, Ge, C, Xu, Y. Differential effect of psoralidin in enhancing apoptosis of colon cancer cells via nuclear factor-κB and B-cell lymphoma-2/B-cell lymphoma-2-associated X protein signaling pathways. Oncol Lett 2016;11:267–72. https://doi.org/10.3892/ol.2015.3861.Search in Google Scholar PubMed PubMed Central

21. 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

22. 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

23. Manders, P, Beex, L, Tjan-Heijnen, V, Geurts-Moespot, J, Van Tienoven, T, Foekens, J, et al.. The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy. Br J Canc 2002;87:772–8. https://doi.org/10.1038/sj.bjc.6600555.Search in Google Scholar PubMed PubMed Central

24. Zhang, Y-Q, Chen, W-L, Zhang, F, Wei, X-L, Zeng, D, Liang, Y-K, et al.. Over-expression of both VEGF-C and twist predicts poor prognosis in human breast cancer. Clin Transl Oncol 2019;21:1250–9. https://doi.org/10.1007/s12094-019-02051-9.Search in Google Scholar PubMed

25. Li, X, Gao, Y, Li, J, Zhang, K, Han, J, Li, W, et al.. FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer. Cell Death Dis 2018;9:1–12. https://doi.org/10.1038/s41419-018-0790-8.Search in Google Scholar PubMed PubMed Central

26. Charpin, C, Garcia, S, Bouvier, C, Martini, F, Andrac, L, Bonnier, P, et al.. CD31/PECAM automated and quantitative immunocytochemical assays in breast carcinomas: correlation with patient follow-up. Am J Clin Pathol 1997;107:534–41. https://doi.org/10.1093/ajcp/107.5.534.Search in Google Scholar PubMed

27. 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. Canc Res 2003;63:6784–90.Search in Google Scholar

28. Todaro, M, Zerilli, M, Ricci-Vitiani, L, Bini, M, Alea, MP, Florena, AM, et al.. Autocrine production of interleukin-4 and interleukin-10 is required for survival and growth of thyroid cancer cells. Canc Res 2006;66:1491–9. https://doi.org/10.1158/0008-5472.can-05-2514.Search in Google Scholar

29. 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

30. 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

31. 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 Canc 2005;92:921–8. https://doi.org/10.1038/sj.bjc.6602416.Search in Google Scholar PubMed PubMed Central

32. 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

33. 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

34. Voronov, E, Carmi, Y, Apte, RN. The role IL-1 in tumor-mediated angiogenesis. Front Physiol 2014;5:114. https://doi.org/10.3389/fphys.2014.00114.Search in Google Scholar PubMed PubMed Central

35. Ivashkiv, LB. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 2018;18:545–58. https://doi.org/10.1038/s41577-018-0029-z.Search in Google Scholar PubMed PubMed Central

36. 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;569:270–4. https://doi.org/10.1038/s41586-019-1170-y.Search in Google Scholar PubMed PubMed Central

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

Received: 2021-03-23

Accepted: 2021-08-18

Published Online: 2021-09-09

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/hmbci-2021-0028

Keywords for this article

anti-angiogenesis; breast cancer; immunostimulatory activity; natural compounds; psoralidin