Skip to main content
Log in

The effects of the esterified Quercetin with omega3 and omega6 fatty acids on viability, nanomechanical properties, and BAX/BCL-2 gene expression in MCF-7 cells

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Quercetin is one of the major flavonoids and it appears to have cytotoxic effects on various cancer cells through regulating the apoptosis pathway genes such as BAX and BCL2. Combination of Quercetin (Q) with other compounds can increase its effectiveness. In the present study, the effects of the Quercetin and its esterified derivatives on viability, nanomechanical properties of cells, and BAX/BCL-2 gene expression were investigated. Using the MTT and flow cytometry assays, the cytotoxic potential, apoptosis, and necrosis were investigated. The AFM assay was performed to find the nanomechanical properties of cells as the elastic modulus value and cellular adhesion forces. The BAX/BCL2 gene expression was investigated through the Real-Time PCR. The results showed that the esterification of Quercetin with linoleic acid (Q-LA) and α-linolenic acid (Q-ALA) increased the cytotoxic potential of Q. The elastic modulus value and cellular adhesion forces were increased using the esterified derivatives and the highest ratio of BAX/BCL2 gene expression was observed in Q-LA. Esterified Quercetin derivatives have a higher cytotoxic effect than the un-esterified form in a dose-dependent manner. Esterified derivatives caused the nanomechanical changes and pores formation on the cytoplasmic membrane. One of the internal apoptosis pathway regulation mechanisms of these compounds is increasing the BAX/BCL2 gene expression ratio.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Kabel AM, Baali FH (2015) Breast cancer: insights into risk factors, pathogenesis, diagnosis and management. J Cancer Res Treat 3(2):28–33

    CAS  Google Scholar 

  2. Siddiqui JA, Singh A, Chagtoo M, Singh N, Godbole MM, Chakravarti B (2015) Phytochemicals for breast cancer therapy: current status and future implications. Curr Cancer Drug Targets 15(2):116–135

    Article  CAS  Google Scholar 

  3. Yamazaki S, Sakakibara H, Takemura H, Yasuda M, Shimoi K (2014) Quercetin-3-O-glucronide inhibits noradrenaline binding to alpha2-adrenergic receptor, thus suppressing DNA damage induced by treatment with 4-hydroxyestradiol and noradrenaline in MCF-10A cells. J Steroid Biochem Mol Biol 143:122–129

    Article  CAS  Google Scholar 

  4. Sak K (2014) Site-specific anticancer effects of dietary flavonoid quercetin. Nutr Cancer 66(2):177–193

    Article  CAS  Google Scholar 

  5. Khorsandi L, Orazizadeh M, Niazvand F, Abbaspour MR, Mansouri E, Khodadadi A (2017) Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells. Bratisl Med J 118(2):123–128

    Article  CAS  Google Scholar 

  6. Khan F, Niaz K, Maqbool F, Ismail Hassan F, Abdollahi M, Venkata KCN, Nabavi SM, Bishayee A (2016) Molecular targets underlying the anticancer effects of quercetin: an update. Nutrients 8(9):529

    Article  Google Scholar 

  7. Salem JH, Chevalot I, Harscoat-Schiavo C, Paris C, Fick M, Humeau C (2011) Biological activities of flavonoids from Nitraria retusa (Forssk.) Asch. and their acylated derivatives. Food Chem 124(2):486–494

    Article  Google Scholar 

  8. Ewelina R, Pajak K, Jozwiak K (2013) Lipophilicity-methods of determination and its role in medicinal chemistry. Acta Pol Pharm 70(1):3–18

    Google Scholar 

  9. Saik AYH, Lim YY, Stanslas J, Choo WS (2017) Enzymatic synthesis of quercetin oleate esters using Candida antarctica lipase B. Biotechnol Lett 39(2):297–304

    Article  CAS  Google Scholar 

  10. Crauste C, Mélissa R, Thierry D, Joseph V (2016) Omega-3 polyunsaturated lipophenols, how and why? Biochimie. https://doi.org/10.1016/j.biochi.2015.07.018

  11. Jabłońska-Trypuć A (2017) Antioxidative and prooxidative properties of dietary unsaturated fatty acids. React Oxygen Species 4(12):372–381

    Google Scholar 

  12. Balakrishnan S, Mukherjee S, Das S, Bhat FA, Singh PR, Patra CR, Arunakaran J (2017) Gold nanoparticles-conjugated quercetin induces apoptosis via inhibition of EGFR/PI3K/Akt-mediated pathway in breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct 35(4):217–231

    Article  CAS  Google Scholar 

  13. Sultan AS, Khalil MI, Sami BM, Alkhuriji AF, Sadek O (2017) Quercetin induces apoptosis in triple-negative breast cancer cells via inhibiting fatty acid synthase and β-catenin. Int J Clin Exp Pathol 10(1):156–172

    CAS  Google Scholar 

  14. Lakshmi BA, Bae JY, An JH, Kim S (2019) Facile design and spectroscopic characterization of novel bio-inspired Quercetin-conjugated tetrakis (dimethylsulfoxide) dichlororuthenium (II) complex for enhanced anticancer properties. Inorg Chim Acta 495:118989

    Article  CAS  Google Scholar 

  15. Jembrek MJ, Vlainić J, Čadež V, Šegota S (2018) Atomic force microscopy reveals new biophysical markers for monitoring subcellular changes in oxidative injury: neuroprotective effects of quercetin at the nanoscale. PLoS ONE 13(10):e0200119

    Article  Google Scholar 

  16. Kocábová J, Kolivoška V, Gál M, Sokolová R (2018) Tuning phospholipid bilayer permeability by flavonoid apigenin: electrochemical and atomic force microscopy study. J Electroanal Chem 821:67–72

    Article  Google Scholar 

  17. Pi J, Li B, Tu L, Zhu H, Jin H, Yang F, Huaihong C, Cai J (2016) Investigation of Quercetin-induced HepG2 cell apoptosis-associated cellular biophysical alterations by atomic force microscopy. Scanning 38(2):100–112

    Article  CAS  Google Scholar 

  18. Jamali Z, Rezaei Behbehani G, Zare K, Gheibi N (2019) Effect of chrysin omega-3 and 6 fatty acid esters on mushroom tyrosinase activity, stability, and structure. J Food Biochem 43(3):e12728

    PubMed  Google Scholar 

  19. Jamali Z, Rezaei Behbahan GR, Zare K, Gheibi N (2020) Quercetin fatty acid esters: from synthesis to the mushroom tyrosinase inhibition. J Chem Health Risks 10(3):185–193

    CAS  Google Scholar 

  20. Gheibi N, Mohamad G, Hanifeh S, Alireza F (2020) Effects of unsaturated fatty acids (arachidonic/oleic acids) on stability and structural properties of Calprotectin using molecular docking and molecular dynamics simulation approach. PLoS ONE 15(3):e0230780. https://doi.org/10.1371/journal.pone.0230780,2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Asghari H, Chegini KG, Amini A, Gheibi N (2016) Effect of poly and mono-unsaturated fatty acids on stability and structure of recombinant S100A8/A9. Int J Biol Macromol 84:35–42

    Article  CAS  Google Scholar 

  22. Abedi F, Sahmani M, Moghbelinejad S, Azad M, Rahmani B, Pishkhan S, Saeideh GK, Zahra MG, Gheibi N (2020) Changes of WIF-1 and WT-1 genes expression following the anti-cancer effects of omega-3 and omega-6 on gastric cancer cells. Gene Rep 21:100826

    Article  Google Scholar 

  23. Jiang P, Li B, Lvying T, Zhu H, Jin H, Yang F, Bai H, Cai H, Ca J (2016) Investigation of Quercetin-induced HepG2 cell apoptosis associated cellular biophysical alterations by atomic force microscopy. Scanning 38:100–112

    Article  Google Scholar 

  24. Sudhanshu S, Rupasinghe HPV (2015) Antiproliferative activity of long chain acylated esters of quercetin-3-O-glucoside in hepatocellular carcinoma HepG2 cells. Exp Biol Med 2015(240):1452–1464

    Google Scholar 

  25. Warnakulasuriya SN, Rupasinghe HP (2014) Long chain fatty acid acylated derivatives of quercetin-3-o-glucoside as antioxidants to prevent lipid oxidation. Biomolecules 4(4):980–993

    Article  Google Scholar 

  26. Srivastava S, Somasagara RR, Hegde M, Nishana M, Tadi SK, Srivastava M, Choudhary B, Raghavan SC (2016) Quercetin, a natural flavonoid interacts with DNA, arrests cell cycle and causes tumor regression by activating mitochondrial pathway of apoptosis. Sci Rep 6(1):1–13

    Article  Google Scholar 

  27. Maurya AK, Vinayak M (2019) Improved synergistic anticancer efficacy of quercetin in combination with PI-103, rottlerin, and G0 6983 against MCF-7 and RAW 264.7 cells. In Vitro Cell Dev Biol Anim 55(1):36–44

    Article  CAS  Google Scholar 

  28. Wang H, Wang Z, Huang Y, Zhou Y, Sheng X, Jiang Q, Wang Y, Luo P, Luo M, Shi C (2020) Senolytics (DQ) mitigates radiation ulcers by removing senescent cells. Front Oncol 9:1576

    Article  Google Scholar 

  29. Rosner K, Röpke C, Pless V, Skovgaard GL (2006) Late type apoptosis and apoptosis free lethal effect of quercetin in human melanoma. Biosci Biotechnol Biochem 70(9):2169–2177

    Article  CAS  Google Scholar 

  30. Iturri J, Weber A, Moreno-Cencerrado A, Benítez R, Leporatti S, Toca-Herrera JL (2019) Resveratrol-induced temporal variation in the mechanical properties of MCF-7 breast cancer cells investigated by atomic force microscopy. Int J Mol Sci 20(13):3275

    Article  CAS  Google Scholar 

  31. Eldridge WJ, Ceballos S, Shah T, Park HS, Steelman ZA, Zauscher S, Wax A (2019) Shear modulus measurement by quantitative phase imaging and correlation with atomic force microscopy. Biophys J 117(4):696–705

    Article  CAS  Google Scholar 

  32. Mariafrancesca C, De Matteis V, Toma CC, Leporatti S (2018) Morphomechanical alterations induced by transforming growth factor- 1 in epithelial breast cancer cells. Cancers 10(234):2018

    Google Scholar 

  33. Yang X, Zhang W, Zhao Z, Li N, Mou Z, Sun D, Yongping C, Lin Y (2017) Quercetin loading CdSe/ZnS nanoparticles as efficient antibacterial and anticancer materials. J Inorg Biochem 167:36–48

    Article  CAS  Google Scholar 

  34. Li M, Liu L, Xi N, Wang Y (2018) Atomic force microscopy studies on cellular elastic and viscoelastic properties. Sci China Life Sci. https://doi.org/10.1007/s11427-016-9041-9

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ma L, Song B, Jin H, Pi J, Liu L, Jiang J, Cai J (2012) Cinobufacini induced MDA-MB-231 cell apoptosis-associated cell cycle arrest and cytoskeleton function. Bioorg Med Chem Lett 22(3):1459–1463

    Article  CAS  Google Scholar 

  36. Izdebska M, Hałas-Wiśniewska M, Zielińska W, Klimaszewska-Wiśniewska A, Grzanka D, Gagat M (2019) Lidocaine induces protective autophagy in rat C6 glioma cell line. Int J Oncol. https://doi.org/10.1016/j.acthis.2016.11.003

    Article  PubMed  Google Scholar 

  37. Liao H, Bao X, Zhu J, Qu J, Sun Y, Ma X, Wang E, Guo X, Kang Q, Zhen Y (2015) O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway. Chem Biol Interact 242:91–98

    Article  CAS  Google Scholar 

  38. Cho SY, Kim MK, Park KS, Choo H, Chong Y (2013) Quercetin-POC conjugates: differential stability and bioactivity profiles between breast cancer (MCF-7) and colorectal carcinoma (HCT116) cell lines. Bioorg Med Chem 21(7):1671–1679

    Article  CAS  Google Scholar 

  39. Nguyen TTT, Tran E, Nguyen TH, Do PT, Huyn TH, Huynh H (2004) The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis 25(5):647–659

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Dept of Research, Qazvin University of Medical Sciences.

Author information

Authors and Affiliations

Authors

Contributions

NG was responsible for the design of the study. LS conducted laboratory tests, data collection, and drafting the article. NG, LS, and LZ were involved in the interpretation of results. NG, AF and HAY conducted the correction and final check out. All authors reviewed this draft, contributed, and approved the final manuscript.

Corresponding author

Correspondence to Nematollah Gheibi.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

Ethical approval for this study was granted by the Research Ethics Committee at Qazvin University of Medical Sciences (Number IR.QUMS.REC.1397.312).

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 587 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soufi, L., Farasat, A., Ahmadpour-Yazdi, H. et al. The effects of the esterified Quercetin with omega3 and omega6 fatty acids on viability, nanomechanical properties, and BAX/BCL-2 gene expression in MCF-7 cells. Mol Biol Rep 48, 5161–5169 (2021). https://doi.org/10.1007/s11033-021-06516-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06516-5

Keywords

Navigation