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Quercetin potentiates the chemosensitivity of MCF-7 breast cancer cells to 5-fluorouracil

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Abstract

Background

Breast cancer is one of the leading causes of cancer mortality worldwide. 5-fluorouracil (5-FU) is one of the chemotherapy drugs to treat breast cancer, but it is associated with several side effects. Combination therapy is a way to increase the effectiveness of chemo drugs and decrease their usage dose. Quercetin (Quer) is one of the natural polyphenols with anti-cancer properties. This study investigated the apoptotic effect of 5-FU in combination with Quer compared with 5-FU alone on MCF-7 breast cancer cells.

Method and results

Different single and combined concentrations of 5-FU and Quer were applied to MCF 7 cells for 48 h. Cell viability, apoptosis, gene expression of Bax, Bcl2, and p53, caspase activity, and colony number were assessed using MTT assay, flow cytometry, quantitative real-time PCR, enzyme-linked immunosorbent (ELISA), and Colony formation assay, respectively. The combination of 5-FU and Quer compared to 5-FU alone improved apoptosis by increasing the gene expression of Bax and p53 and caspase-9 activity and decreasing the Bcl2 gene expression. Colony formation in MCF-7 cells significantly decreased in the combined state compared to 5-FU alone.

Conclusion

Quer potentiates the sensitivity of breast cancer to 5-FU so that this combination may be proposed as a treatment for breast cancer. Therefore, this combination can be suggested for future in vivo studies.

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References

  1. Elmadany N, Khalil E, Vaccari L, Birarda G, Yousef I, Abu-Dahab R (2018) Antiproliferative activity of the combination of doxorubicin/quercetin on MCF7 breast cancer cell line: a combined study using colorimetric assay and synchrotron infrared microspectroscopy. Infrared Phys Technol 95:141–147

    CAS  Google Scholar 

  2. Kawabata R, Oie S, Takahashi M, Kanayama H, Oka T, Itoh K (2011) Up-regulation of insulin-like growth factor-binding protein 3 by 5-fluorouracil (5-FU) leads to the potent anti-proliferative effect of androgen deprivation therapy combined with 5-FU in human prostate cancer cell lines. Int J Oncol 38:1489–1500

    CAS  PubMed  Google Scholar 

  3. Zhang D, Liu X, Gao J et al (2017) The role of epithelial cell adhesion molecule N-glycosylation on apoptosis in breast cancer cells. Tumor Biol 39:1010428317695973

    Google Scholar 

  4. Ponce-Cusi R, Calaf GM (2016) Apoptotic activity of 5-fluorouracil in breast cancer cells transformed by low doses of ionizing α-particle radiation. Int J Oncol 48:774–782

    CAS  PubMed  Google Scholar 

  5. Castillo RR, Colilla M, Vallet-Regí M (2017) Advances in mesoporous silica-based nanocarriers for co-delivery and combination therapy against cancer. Expert Opin Drug Deliv 14:229–243

    CAS  PubMed  Google Scholar 

  6. Khurana RK, Jain A, Jain A, Sharma T, Singh B, Kesharwani P (2018) Administration of antioxidants in cancer: debate of the decade. Drug Discov Today 23:763–770

    CAS  PubMed  Google Scholar 

  7. Sun W, Sanderson PE, Zheng W (2016) Drug combination therapy increases successful drug repositioning. Drug Discov Today 21:1189–1195

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gusdinar T, Herowati R, Kartasasmita R, Adnyana I (2011) Anti-inflammatory and antioxidant activity of quercetin-3, 3′,4′-triacetate. J Pharmacol Toxicol 6:182–188

    CAS  Google Scholar 

  9. Ganesan S, Faris AN, Comstock AT et al (2012) Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res 94:258–271

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Chou C-C, Yang J-S, Lu H-F et al (2010) Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharmacal Res 33:1181–1191

    CAS  Google Scholar 

  11. Ferry DR, Smith A, Malkhandi J et al (1996) Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2:659–668

    CAS  PubMed  Google Scholar 

  12. Ajji PK, Walder K, Puri M (2020) Combination of Balsamin and flavonoids induce apoptotic effects in liver and breast cancer cells. Front Pharmacol 11:574496

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Niazvand F, Orazizadeh M, Khorsandi L, Abbaspour M, Mansouri E, Khodadadi A (2019) Effects of quercetin-loaded nanoparticles on MCF-7 human breast cancer cells. Medicina 55:114

    PubMed Central  Google Scholar 

  14. Duo J, Ying G-G, Wang G-W, Zhang L (2012) Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol Med Rep 5:1453–1456

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  16. Akbas SH, Timur M, Ozben T (2005) The effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB 231 human breast cancer cells1. J Surg Res 125:49–55

    CAS  PubMed  Google Scholar 

  17. Schlachterman A, Valle F, Wall KM et al (2008) Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 1:19–27

    PubMed  PubMed Central  Google Scholar 

  18. Du G, Lin H, Wang M et al (2010) Quercetin greatly improved therapeutic index of doxorubicin against 4T1 breast cancer by its opposing effects on HIF-1α in tumor and normal cells. Cancer Chemother Pharmacol 65:277

    CAS  PubMed  Google Scholar 

  19. Du G, Lin H, Yang Y et al (2010) Dietary quercetin combining intratumoral doxorubicin injection synergistically induces rejection of established breast cancer in mice. Int Immunopharmacol 10:819–826

    CAS  PubMed  Google Scholar 

  20. Václavíková R, Kondrová E, Ehrlichová M et al (2008) The effect of flavonoid derivatives on doxorubicin transport and metabolism. Bioorg Med Chem 16:2034–2042

    PubMed  Google Scholar 

  21. Vickers NJ (2017) Animal communication: when i’m calling you, will you answer too? Curr Biol 27:R713–R715

    CAS  PubMed  Google Scholar 

  22. Satari A, Amini SA, Raeisi E, Lemoigne Y, Heidarian E (2019) Synergetic impact of combined 5-fluorouracil and rutin on apoptosis in pc3 cancer cells through the modulation of p53 gene expression. Adv Pharm Bull 9:462

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Khedri A, Khaghani S, Kheirollah A et al (2019) Signaling Crosstalk of FHIT, p53, and p38 in etoposide-induced apoptosis in MCF-7 cells. J Cell Biochem 120:9125–9137

    CAS  PubMed  Google Scholar 

  24. Corrie PG (2011) Cytotoxic chemotherapy: clinical aspects. Medicine 39:717–722

    Google Scholar 

  25. Kaushik S, Shyam H, Sharma R, Balapure AK (2016) Genistein synergizes centchroman action in human breast cancer cells. Indian J Pharmacol 48:637

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ahmed A, Redmond HP, Wang JH (2013) Links between Toll-like receptor 4 and breast cancer. Oncoimmunology 2:e22945

    PubMed  PubMed Central  Google Scholar 

  27. Medzhitov R, Preston-Hurlburt P, Janeway CA (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397

    CAS  PubMed  Google Scholar 

  28. Ashton JC (2015) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 75:2400–2400

    CAS  PubMed  Google Scholar 

  29. Beatrice Magne Nde C, Zingue S, Winter E et al (2015) Flavonoids, breast cancer chemopreventive and/or chemotherapeutic agents. Curr Med Chem 22:3434–3446

    Google Scholar 

  30. Gao X, Wang B, Wei X et al (2012) Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer. Nanoscale 4:7021–7030

    CAS  PubMed  Google Scholar 

  31. Cao H-H, Tse AK-W, Kwan H-Y et al (2014) Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling. Biochem Pharmacol 87:424–434

    CAS  PubMed  Google Scholar 

  32. Spagnuolo C, Russo M, Bilotto S, Tedesco I, Laratta B, Russo GL (2012) Dietary polyphenols in cancer prevention: the example of the flavonoid quercetin in leukemia. Ann N Y Acad Sci 1259:95–103

    CAS  PubMed  Google Scholar 

  33. Ren K-W, Li Y-H, Wu G et al (2017) Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells. Int J Oncol 50:1299–1311

    CAS  PubMed  Google Scholar 

  34. Ren MX, Deng XH, Ai F, Yuan GY, Song HY (2015) Effect of quercetin on the proliferation of the human ovarian cancer cell line SKOV-3 in vitro. Exp Ther Med 10:579–583

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tc CHOU, TaLaLay P (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115:207–216

    Google Scholar 

  36. Riahi-Chebbi I, Souid S, Othman H et al (2019) The phenolic compound kaempferol overcomes 5-fluorouracil resistance in human resistant LS174 colon cancer cells. Sci Rep 9:1–20

    CAS  Google Scholar 

  37. Amorim R, Pinheiro C, Miranda-Gonçalves V et al (2015) Monocarboxylate transport inhibition potentiates the cytotoxic effect of 5-fluorouracil in colorectal cancer cells. Cancer Lett 365:68–78

    CAS  PubMed  Google Scholar 

  38. Naus PJ, Henson R, Bleeker G, Wehbe H, Meng F, Patel T (2007) Tannic acid synergizes the cytotoxicity of chemotherapeutic drugs in human cholangiocarcinoma by modulating drug efflux pathways. J Hepatol 46:222–229

    CAS  PubMed  Google Scholar 

  39. Fu Z, Ma K, Dong B et al (2019) The synergistic antitumor effect of Huaier combined with 5-florouracil in human cholangiocarcinoma cells. BMC Complement Altern Med 19:1–12

    Google Scholar 

  40. Gao Y, Xiao X, Zhang C et al (2017) Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI 3K/AKT and NF-κB/iNOS signaling pathways. J Pineal Res 62:e12380

    Google Scholar 

  41. Dai W, Gao Q, Qiu J, Yuan J, Wu G, Shen G (2016) Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. Tumor Biol 37:6307–6313

    CAS  Google Scholar 

  42. Ghosh S, Pal A, Ray M (2017) 5-FU synergistically inhibits MCF-7 in combination with methylglyoxal. Clin Oncol 2:1353

    Google Scholar 

  43. Su P, Ahmad B, Zou K, Zou L (2020) β-Elemene enhances the chemotherapeutic effect of 5-fluorouracil in triple-negative breast cancer via PI3K/AKT, RAF-MEK-ErK, and NF-κB signaling pathways. Onco Targets Ther 13:5207

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sang J, Tang R, Yang M, Sun Q (2020) Metformin inhibited proliferation and metastasis of colorectal cancer and presented a synergistic effect on 5-FU. BioMed Res Int. https://doi.org/10.1155/2020/9312149

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The research was financially supported by the Cellular and Molecular Research Center of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Grant No. CMRC - 9810). This paper was extracted from Msc thesis of fatemeh mawalizadeh.

Funding

The research was financially supported by the Cellular and Molecular Research Center of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. The results described in this paper were part of student thesis (Grant No. CMRC - 9907).

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Dr. MR: made substantial contributions to the conception and design of the work. Dr. GM: drafted the work and revised it. Dr. AK: analysis, interpretation of data. FM: the acquisition, analysis, interpretation of data.

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Correspondence to Mojtaba Rashidi.

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Mawalizadeh, F., Mohammadzadeh, G., Khedri, A. et al. Quercetin potentiates the chemosensitivity of MCF-7 breast cancer cells to 5-fluorouracil. Mol Biol Rep 48, 7733–7742 (2021). https://doi.org/10.1007/s11033-021-06782-3

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