Skip to main content

Advertisement

SpringerLink
Log in

Synergistic effect of chrysin and radiotherapy against triple-negative breast cancer (TNBC) cell lines

  • RESEARCH ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Purpose

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, accounting for 20% of cases. Due to the lack of a molecular target, limited options are available for TNBC treatment. Radiation therapy (RT) is a treatment modality for the management of TNBC following surgery; however, it has a detrimental effect on surrounding healthy tissues/cells at a higher rate.

Methods

We examined the effect of RT in combination with chrysin as a possible radiosensitizing agent in an MDA-MB-231 cell line as a model of a TNBC. The growth inhibitory effects of chrysin were examined using an MTT assay. Flow cytometry was performed to evaluate apoptosis and expression of hypoxia-induced factor-1α (HIF-1α). The protein expression of p-STAT3/STAT3 and Cyclin D1 was examined using western blotting. Real-time PCR determined apoptotic-related genes (Bax, BCL2, p53).

Results

Treatment of MDA-MB-231 cells with chrysin in combination with RT caused synergistic antitumor effects, with an optimum combination index (CI) of 0.495. Our results indicated that chrysin synergistically potentiated RT-induced apoptosis in MDA-MB-231 compared with monotherapies (chrysin and/or RT alone). Expression of HIF-1α was decreased in the cells exposed to combinational therapy. The apoptotic effect of combinational therapy was correlated with increased Bax (pro-apoptotic gene) and p53 levels along with reduced expression of Bcl-2 (anti-apoptotic gene). Increased apoptosis was associated with reduced expression of Cyclin D1, p-STAT3.

Conclusion

These findings highlight the potential effect of chrysin as a radiosensitizer, indicating the synergistic anti-cancer effect of chrysin and RT in TNBC. Further investigation is warranted in this regard.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data are available from the corresponding author on reasonable request.

References

  1. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31–46.

    Article  CAS  PubMed  Google Scholar 

  2. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438–51.

    Article  PubMed  Google Scholar 

  3. Krzyszczyk P, Acevedo A, Davidoff EJ, Timmins LM, Marrero-Berrios I, Patel M, et al. The growing role of precision and personalized medicine for cancer treatment. Technology. 2018;6(03n04):79–100.

    Article  PubMed  Google Scholar 

  4. Derakhshan F, Reis-Filho JS. Pathogenesis of triple-negative breast cancer. Annu Rev Pathol. 2022;17:181.

    Article  PubMed  PubMed Central  Google Scholar 

  5. O’Reilly EA, Gubbins L, Sharma S, Tully R, Guang MHZ, Weiner-Gorzel K, et al. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA clinical. 2015;3:257–75.

    Article  PubMed  PubMed Central  Google Scholar 

  6. He MY, Rancoule C, Rehailia-Blanchard A, Espenel S, Trone J-C, Bernichon E, et al. Radiotherapy in triple-negative breast cancer: current situation and upcoming strategies. Crit Rev Oncol Hematol. 2018;131:96–101.

    Article  PubMed  Google Scholar 

  7. Martin OA, Martin RF. Cancer radiotherapy: understanding the price of tumor eradication. Front Cell Dev Biol. 2020;8:261.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Forte GI, Minafra L, Bravatà V, Cammarata FP, Lamia D, Pisciotta P, et al. Radiogenomics: the utility in patient selection. Transl Cancer Res. 2017;6(Suppl 5):852S-S74.

    Article  Google Scholar 

  9. Yi J, Zhu J, Zhao C, Kang Q, Zhang X, Suo K, et al. Potential of natural products as radioprotectors and radiosensitizers: opportunities and challenges. Food Funct. 2021;12(12):5204–18.

    Article  CAS  PubMed  Google Scholar 

  10. Naz S, Imran M, Rauf A, Orhan IE, Shariati MA, Shahbaz M, et al. Chrysin: Pharmacological and therapeutic properties. Life Sci. 2019;235:116797.

    Article  CAS  PubMed  Google Scholar 

  11. Adangale SC, Wairkar S. Potential therapeutic activities and novel delivery systems of chrysin-a nature’s boon. Food Biosci. 2021;45:101316.

    Article  Google Scholar 

  12. Talebi M, Talebi M, Farkhondeh T, Simal-Gandara J, Kopustinskiene DM, Bernatoniene J, et al. Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin. Cancer Cell Int. 2021;21(1):1–20.

    Article  Google Scholar 

  13. Khaledi S, Jafari S, Hamidi S, Molavi O, Davaran S. Preparation and characterization of PLGA-PEG-PLGA polymeric nanoparticles for co-delivery of 5-fluorouracil and chrysin. J Biomater Sci Polym Ed. 2020;31(9):1107–26.

    Article  CAS  PubMed  Google Scholar 

  14. Pawlonka J, Rak B, Ambroziak U. The regulation of cyclin D promoters–review. Cancer Treat Res Commun. 2021;27:100338.

    Article  PubMed  Google Scholar 

  15. Qin A, Yu Q, Gao Y, Tan J, Huang H, Qiao Z, et al. Inhibition of STAT3/cyclinD1 pathway promotes chemotherapeutic sensitivity of colorectal caner. Biochem Biophys Res Commun. 2015;457(4):681–7.

    Article  CAS  PubMed  Google Scholar 

  16. Rasouli S, Zarghami N. Synergistic growth inhibitory effects of chrysin and metformin combination on breast cancer cells through hTERT and cyclin D1 suppression. Asian Pac J Cancer Prev. 2018;19(4):977.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Maasomi ZJ, Soltanahmadi YP, Dadashpour M, Alipour S, Abolhasani S, Zarghami N. Synergistic anticancer effects of silibinin and chrysin in T47D breast cancer cells. Asian Pac J Cancer Prev. 2017;18(5):1283.

    PubMed Central  Google Scholar 

  18. Samarghandian S, Azimi-Nezhad M, Borji A, Hasanzadeh M, Jabbari F, Farkhondeh T, et al. Inhibitory and cytotoxic activities of chrysin on human breast adenocarcinoma cells by induction of apoptosis. Pharmacogn Mag. 2016;12(Suppl 4):S436.

    PubMed  PubMed Central  Google Scholar 

  19. Wawryk-Gawda E, Chylińska-Wrzos P, Lis-Sochocka M, Chłapek K, Bulak K, Jędrych M, et al. P53 protein in proliferation, repair and apoptosis of cells. Protoplasma. 2014;251(3):525–33.

    Article  CAS  PubMed  Google Scholar 

  20. Huang R, Zhou P-K. HIF-1 signaling: a key orchestrator of cancer radioresistance. Radiat Med Prot. 2020;1(01):7–14.

    Article  Google Scholar 

  21. Moghadam ER, Ang HL, Asnaf SE, Zabolian A, Saleki H, Yavari M, et al. Broad-spectrum preclinical antitumor activity of chrysin: current trends and future perspectives. Biomolecules. 2020;10(10):1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zoi V, Galani V, Vartholomatos E, Zacharopoulou N, Tsoumeleka E, Gkizas G, et al. Curcumin and radiotherapy exert synergistic anti-glioma effect in vitro. Biomedicines. 2021;9(11):1562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chou T-C. Drug combination studies and their synergy quantification using the chou-talalay methodsynergy quantification method. Cancer Res. 2010;70(2):440–6.

    Article  CAS  PubMed  Google Scholar 

  24. Feng B, Guo YW, Huang CG, Li L, Jiao BH. Beta-D-glucosyl-(1–4)-alpha-L-thevetosides of 17beta-digitoxigenin from seeds of Cerbera manghas L. induces apoptosis in human hepatocellular carcinoma HepG2 cells. Exp Toxicol Pathol Off J Ges fur Toxikol Pathol. 2012;64(5):403–10. https://doi.org/10.1016/j.etp.2010.10.005.

    Article  CAS  Google Scholar 

  25. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004;5(5):429–41.

    Article  CAS  PubMed  Google Scholar 

  26. Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell. 2005;8(2):99–110.

    Article  CAS  PubMed  Google Scholar 

  27. Manjunath M, Choudhary B. Triple-negative breast cancer: a run-through of features, classification and current therapies. Oncol Lett. 2021;22(1):1–21.

    Article  Google Scholar 

  28. Zhang Q-Y, Wang F-X, Jia K-K, Kong L-D. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front Pharmacol. 2018;9:1253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Molavi O, Torkzaban F, Jafari S, Asnaashari S, Asgharian P. Chemical compositions and anti-proliferative activity of the aerial parts and rhizomes of squirting cucumber, Cucurbitaceae. Jundishapur J Nat Pharm Prod. 2020;15(1):e82990.

  30. Huang M, Lu J-J, Ding J. Natural products in cancer therapy: past, present and future. Nat Prod Bioprospect. 2021;11(1):5–13.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Salari N, Faraji F, Jafarpour S, Faraji F, Rasoulpoor S, Dokaneheifard S, et al. Anti-cancer activity of chrysin in cancer therapy: a systematic review. Indian J Surg Oncol. 2022;13:1–10.

    Article  Google Scholar 

  32. Hennequin C, Guillerm S, Quero L. Combination of chemotherapy and radiotherapy: a thirty years evolution. Cancer/Radiothérapie. 2019;23(6–7):662–5.

    Article  CAS  PubMed  Google Scholar 

  33. Bernal-Estévez D, Sánchez R, Tejada RE, Parra-López C. Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient. BMC Cancer. 2016;16(1):1–13.

    Article  Google Scholar 

  34. Khoo BY, Chua SL, Balaram P. Apoptotic effects of chrysin in human cancer cell lines. Int J Mol Sci. 2010;11(5):2188–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hong TB, Rahumatullah A, Yogarajah T, Ahmad M, Yin KB. Potential effects of chrysin on MDA-MB-231 cells. Int J Mol Sci. 2010;11(3):1057–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Roy S, Sil A, Chakraborty T. Potentiating apoptosis and modulation of p53, Bcl2, and Bax by a novel chrysin ruthenium complex for effective chemotherapeutic efficacy against breast cancer. J Cell Physiol. 2019;234(4):4888–909.

    Article  CAS  PubMed  Google Scholar 

  37. Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ. 2018;25(1):104–13.

    Article  CAS  PubMed  Google Scholar 

  38. Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.

    Article  CAS  PubMed  Google Scholar 

  39. Johnston PA, Grandis JR. STAT3 signaling: anticancer strategies and challenges. Mol Interv. 2011;11(1):18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu Z-j, Semenza GL, Zhang H-f. Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B. 2015;16(1):32–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xu Q, Briggs J, Park S, Niu G, Kortylewski M, Zhang S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24(36):5552–60.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was financially supported by Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran (Pazhoohan ID: 70043).

Author information

Author notes

  1. Sevda Jafari and Sheida Dabiri have contributed equally to this work and should be considered co-first authors.

  2. Soheila Montazersaheb and Raheleh Farahzadi have contributed equally to this work.

Authors and Affiliations

  1. Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Sevda Jafari

  2. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Sevda Jafari, Sheida Dabiri & Elnaz Mehdizadeh Aghdam

  3. Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran

    Ezzatollah Fathi

  4. Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran

    Nazli Saeedi

  5. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614731, Iran

    Soheila Montazersaheb

  6. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614731, Iran

    Raheleh Farahzadi

Authors
  1. Sevda Jafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheida Dabiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elnaz Mehdizadeh Aghdam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ezzatollah Fathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nazli Saeedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Soheila Montazersaheb
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raheleh Farahzadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Soheila Montazersaheb or Raheleh Farahzadi.

Ethics declarations

Conflict of interest

We declare that there are no conflicts of interest associated with this study.

Ethical approval

Ethical consent was approved by an ethics committee at Tabriz University of Medical Sciences, Tabriz, Iran (Ethic Code No: IR.TBZMED.VCR.REC.1401.105).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jafari, S., Dabiri, S., Mehdizadeh Aghdam, E. et al. Synergistic effect of chrysin and radiotherapy against triple-negative breast cancer (TNBC) cell lines. Clin Transl Oncol 25, 2559–2568 (2023). https://doi.org/10.1007/s12094-023-03141-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03141-5

Keywords

Search

Navigation