Skip to main content
SpringerLink
Log in

Antiproliferative effects of quercetin through cell cycle arrest and apoptosis in human breast cancer MDA-MB-453 cells

  • Research Article
  • Drug Efficacy and Safety
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

To explore the anticancer effects of the flavonoid quercetin on human breast cancer MDA-MB-453 cells via cell cycle regulation and the induction of apoptosis, the antiproliferative effect of quercetin was first examined by MTT assay. When MDA-MB-453 cells were treated with quercetin for various periods of time (3–24 hrs) and at various doses (1–100 μM), cell growth decreased significantly in a time-and dose-dependent manner. To elucidate the mechanism underlying the antiproliferative effect of quercetin, cell cycle progression and the induction of apoptosis in MDA-MB-453 cells exposed to 100 μM quercetin for 24 hrs were investigated. Quercetin caused a remarkable increase in the number of sub-G1 phase cells, and an Annexin-V assay revealed that exposure to quercetin affected apoptosis. Moreover, treatment with quercetin increased Bax expression but decreased Bcl-2 expression. Cleaved caspase-3 and PARP expression was also increased by quercetin. Thus, quercetin has probable anticancer activity. Our results suggest the existence of multiple pathways for the induction of cell cycle arrest and apoptosis by quercetin.

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

Similar content being viewed by others

References

  • Abu-Qare, A. W. and Abou-Donia, M. B., Biomarkers of apoptosis: Release of cytochrome c, activation of caspase-3, induction of 8-hydroxy-2′-deoxyguanosine, increased 3-nitrotyrosine, and alteration of p53 gene. J. Toxicol. Environ. Health B Crit. Rev., 4, 313–332 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Agarwal, M. L., Agarwal, A., Taylor, W. R., and Stark, G. R., p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Nati. Acad. Sci. USA., 92, 8493–8497 (1995).

    Article  CAS  Google Scholar 

  • Alcocer, F., Whitley, D., Salazar-Gonzalez, J. F., Jordan, W. D., Sellers, M. T., Eckhoff, D. E., Suzuki, K., Macrae, C., and Bland, K. I., Quercetin inhibits human vascular smooth muscle cell proliferation and migration. Surgery, 131, 198–204 (2002).

    Article  PubMed  Google Scholar 

  • Chang, Y. F., Chi, C. W., and Wang, J. J., Reactive oxygen species production is involved in quercetin-induced apoptosis in human hepatoma cells. Nutr. Cancer, 55, 201–209 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Choi, E. J., Chee, K. M., and Lee, B. H., Anti-and prooxidant effects of chronic quercetin administration in rats. Eur. J. Pharmacol., 482, 281–285 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Collins, A. R., Antioxidant intervention as a route to cancer prevention. Eur. J., 41, 1923–1930 (2005).

    CAS  Google Scholar 

  • Cotelle, N., Role of flavonoids in oxidative stress. Curr. Top. Med. Chem., 1, 569–590 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Frankel, E. N., Kanner, J., German, J. B., Parks, E., and Kinsella, J. E., Inhibition of oxidation of human lowdensity lipoprotein by phenolic substances in red wine. Lancet, 341, 454–457 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Hertog, M. G., Bueno-de-Mesquita, H. B., Fehily, A. M., Sweetnam, P. M., Elwood P. C., and Kromhout, D., Fruit and vegetable consumption and cancer mortality in the Caerphilly Study. Cancer Epidemiol. Biomark. Prev., 5, 673–677 (1996).

    CAS  Google Scholar 

  • Hertog, M. G., Epidemiological evidence on potential health properties of flavonoids. Proc. Nutr. Soc., 55, 385–397 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Hertog, M. G., Hollman, P. C., Katan, M. B., and Kromhout, D., Intake of potentially anticarcinogenic flavonoids and their determinants in adults in the Netherlands. Nutr. Cancer, 20, 21–29 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Huang, S. L., Hsu, C. L., and Yen, G. C., Growth inhibitory effect of quercetin on SW 872 human liposarcoma cells. Life Sci., 79, 203–209 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Kandaswami, C. and Middleton, E. Jr., Free radical scavenging and antioxidant activity of plant flavonoids. Adv. Exp. Med. Biol., 366, 351–376 (1994).

    PubMed  CAS  Google Scholar 

  • Kandaswami, C., Lee, L. T., Lee, P. P., Hwang, J. J., Ke, F. C., Huang, Y. T., and Lee, M. T., The antitumor activities of flavonoids. In Vivo, 19, 895–909 (2005).

    PubMed  Google Scholar 

  • Kim, W. K., Bang, M. H., Kim, E. S., Kang, N. E., Jung, K. C., Cho, H. J., and Park, J. H., Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J. Nutr. Biochem., 16, 155–162 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Kook, D., Wolf, A. H., Yu, A. L., Neubauer, A. S., Priglinger, S. G., Kampik, A., and Welge-Lüssen, U. C., The protective effect of quercetin against oxidative stress in the human RPE in Vitro. Invest. Ophthalmol. Vis. Sci., 49, 1712–1720 (2008).

    Article  PubMed  Google Scholar 

  • Kris-Etherton, P. M. and Keen, C. L., Evidence that the antioxidant flavonoids in tea and cocoa are beneficial for cardiovascular health. Curr. Opin. Lipidol., 13, 41–49 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Lamson, D. W. and Brignall, M. S., Antioxidants and cancer, part 3: quercetin. Altern. Med. Rev., 5, 196–208 (2000).

    PubMed  CAS  Google Scholar 

  • Lepik, D., Jaks, V., Kadaja, L., Varv, S., and Maimets, T., Electroporation and carrier DNA cause p53 activation, cell cycle arrest, and apoptosis. Anal. Biochem., 318(1), 52–59 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Lim, J. H., Park, J. W., Min, D. S., Chang, J. S., Lee, Y. H., Park, Y. B., Choi, K. S., and Kwon, T. K., NAG-1 up-regulation mediated by EGR-1 and p53 is critical for quercetin-induced apoptosis in HCT116 colon carcinoma cells. Apoptosis, 12, 411–421 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Liu, H., Zhang, C., and Zeng, W., Estrogenic and antioxidant effects of a phytoestrogen daidzein on ovarian germ cells in embryonic chickens. Domest. Anim. Endocrinol., 31, 258–268 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Lazaro, M., Flavonoids as anticancer agents: structureactivity relationship study. Curr. Med. Chem. Anticancer Agents., 2, 691–714 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Metodiewa, D., Jaiswal, A. K., Cenas, N., Dickancaité, E., and Segura-Aguilar, J., Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product. Free Radic. Biol. Med., 26, 107–116 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Notoya, M., Tsukamoto, Y., Nishimura, H., Woo, J. T., Nagai, K., Lee, I. S., and Hagiwara, H., Quercetin, a flavonoid, inhibits the proliferation, differentiation, and mineralization of osteoblasts in vitro. Eur. J. Pharmacol., 48, 89–96 (2004).

    Article  CAS  Google Scholar 

  • Oakea, S. A., Lin, S. S., and Bassik, M. C., The control of endoplasmic reticulum-initiated apoptosis by the BCL-2 family of proteins. Curr. Mol. Med., 6, 99–109 (2006).

    Article  Google Scholar 

  • Park, M., Chae, H. D., Yun, J., Jung, M., Kim, Y. S., Kim, S. H., Han, M. H., and Shin, D. Y., Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G2-M arrest. Cancer Res., 60, 542–545 (2000).

    PubMed  CAS  Google Scholar 

  • Parker, M. A., Anderson, J. K., Corliss, D. A., Abraria, V. E., Sidman, R. L., Park, K. I., Teng, Y. D., Cotanche, D. A., and Snyder, E. Y., Expression profile of an operationallydefined neural stem cell clone. Exp. Neurol., 194, 320–332 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Pathak, S. K., Sharma, R. A., and Mellon, J. K., Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation (Review). Int. J. Oncol., 22, 5–13 (2003).

    PubMed  CAS  Google Scholar 

  • Porter, A. G. and Janicke, R. U., Emerging roles of caspase-3 in apoptosis. Cell Death Differ., 6, 99–104 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Ramos, A. A., Lima, C. F., Pereira, M. L., Fernandes-Ferreira, M., and Pereira-Wilson, C., Antigenotoxic effects of quercetin, rutin and ursolic acid on HepG2 cells: evaluation by the comet assay. Toxicol. Lett., 177, 66–73 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Rao, A. V. and Agarwal, S., Role of antioxidant lycopene in cancer and heart disease. J. Am. Coll. Nutr., 19, 563–569 (2000).

    PubMed  CAS  Google Scholar 

  • Ren, W., Qiao, Z., Wang, H., Zhu, L., and Zhang, L., Flavonoids: Promising anticancer agents. Med. Res. Rev., 23, 519–534 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Russo, G. L., Ins and outs of dietary phytochemicals in cancer chemoprevention. Biochem. Pharmacol., 74, 533–544 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Sahu, S. C. and Gray, G. C., Pro-oxidant activity of flavonoids: Effects on glutathione and glutathione S-transferase in isolated rat liver nuclei. Cancer Lett., 104, 193–196 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Shen, S. C., Chen, Y. C., Hsu, F. L., and Lee, W. R., Differential apoptosis-inducing effect of quercetin and its glycosides in human promyeloleukemic HL-60 cells by alternative activation of the caspase 3 cascade. J. Cell Biochem., 89, 1044–1055 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Singh, R. P. and Agarwal, R., Natural flavonoids targeting deregulated cell cycle progression in cancer cells. Curr. Drug Targets., 7, 345–354 (2006).

    Article  PubMed  CAS  Google Scholar 

  • van Delft, M. F. and Huang, D. C., How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res., 16, 203–213 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Zhang, J., Stanley, R. A., Adaim, A., Melton, L. D., and Skinner, M. A., Free radical scavenging and cytoprotective activities of phenolic antioxidants. Mol. Nutr. Food Res., 50, 996–1005 (2006).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, 137-040, Korea

    Woong Shick Ahn

  2. Cancer Research Institute, The Catholic University of Korea, Seoul, 137-040, Korea

    Eun Jeong Choi, Su Mi Bae & Woong Shick Ahn

Authors
  1. Eun Jeong Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Su Mi Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Woong Shick Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Woong Shick Ahn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, E.J., Bae, S.M. & Ahn, W.S. Antiproliferative effects of quercetin through cell cycle arrest and apoptosis in human breast cancer MDA-MB-453 cells. Arch. Pharm. Res. 31, 1281–1285 (2008). https://doi.org/10.1007/s12272-001-2107-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-001-2107-0

Key words

Search

Navigation