Short Communication

Quercetin, a Natural Dietary Flavonoid Inhibits, Reverses, Retards Tumorigenesis in Prostate and Breast Cancer

Arunakaran J*
Meenakshi Academy of Higher Education and Research, West KK Nagar, Chennai, India


*Corresponding author: Arunakaran J, Meenakshi Academy of Higher Education and Research, West KK Nagar, Chennai, India


Published: 01 Sep, 2017
Cite this article as: Arunakaran J. Quercetin, a Natural Dietary Flavonoid Inhibits, Reverses, Retards Tumorigenesis in Prostate and Breast Cancer. Ann Pharmacol Pharm. 2017; 2(16): 1085.

Short Communication

Epidemiological and dietary intervention studies in animals and humans have suggested that bioflavonoids such as quercetin plays a beneficial role in inhibiting, reversing or retarding tumorigenesis in prostate and breast cancer. Quercetin 3,31,41,5,7 – pentahydroxyflavone a naturally occurring flavonoid, is a component of most edible fruits and vegetables with the highest concentrations being found in onions, apples and red wine [1]. Quercetin has a broad range of pharmacological properties that include antioxidant, anticancer and anti-inflammatory activities [2]. Quercetin has been shown to exert anticancer effects on prostate and breast cancer cell lines [3-6]. We have studied recently chemo preventive effect of quercetin in MNU and testosterone induced prostate cancer of Sprague – Dawley rats [7]. Epidermal growth factor (EGF) plays a key role in epithelial malignancies by enhancing cancer cell proliferation survival, invasion and metastasis. Quercetin prevented EGF induced cell proliferation and survival by regulating EGFR/P13K/AKt/mTOR and EGFR/Raf/ERK. Epidermal growth factor receptor (EGFR) is a key factor in epithelial malignancies and its activity, enhances tumor growth, invasion and metastasis [8]. EGFR is a member of the Erbβ family of tyrosine kinase receptors that transmit growth inducing signals to cells that have been stimulated by an EGFR ligand example TGFα and EGF [9]. The activation of the EGFR signaling pathway stimulates downstream signaling cascades involved in cell proliferation [Ras/mitogen-activated protein kinase (MAPK)] and anti-apoptosis (phosphatidylinositol 3 – kinase P13K/AKt) (Nicholson and Anderson, 2002). Protein kinase B/Akt is activated by the P13K pathway. Generation of P1P3 and P1 [3,4] P2 is necessary for the localization of PKB to the membrane surface. Protein dependent kinase (PDKI) phosphorylates AKt at threonine 308. The fully active multi phosphorylated AKt then dissociates from the plasma membrane and targets substrates located in the cytoplasm and nucleus. It causes the activation of genes involved in diverse cellular processes [10-11]. Epidermal growth factor regulates cancer metastasis by regulating epithelial to mesenchymal transitions (EMT) [12]. EMT trans-differentiation process involve the conversion of adherent epithelial cells into individual migratory cells leading to changes in cell phenotype into more loose mesenchymal like cells and promoting local invasion and metastatic dissemination of tumor cells [13].
Proliferating cell nuclear antigen (PCNA) is a ubiquitously expressed protein that plays crucial roles in many vital cellular processes. It is synthesized in all stages of the cell cycle with a half of approximately 20h and is elevation in early S phase to support cell cycle progression [14]. Over expression of PCNA is also a reliable biomarker for other tumor types including breast cancer [15]. PCNA is involved in DNA replication, repair and epigenetic maintenance and is often used as a diagnostic and prognostic marker. PCNA has been used as an independent marker for various cancers [16].
Quercetin prevents prostate cancer growth via EGFR signaling and prostate cancer progression by regulating cell adhesion molecules like E – cadherin, N cadherin and vimentin viz snail, slug and twist gene. Interestingly quercetin was effective in preventing carcinogenesis in both ventral and dorsolateral prostate. Quercetin supplementation significantly decreased the PCNA expression in both the lobes of chemically induced cancer rats [17].
In in vitro model quercetin prevents EGF induced EMT via EGFR/P13K/AKt/ERK1/2 pathway and by suppressing transcriptional repressor snail, slug and twist in prostate cancer cell line (PC 3). Thus, quercetin prevents cancer metastasis by targeting EMT [18]. We synthesized gold nanoparticle conjugated quercetin (AuNpQU-5) using a simple efficient method that was thoroughly characterized by several physico – chemical methods. AUNPs – QU5 showed an effective cytotoxicity and induction of apoptosis in breast cancer cell lines (both estrogen dependent and independent). AUNPs – QU5 [19] inhibited the EGFR phosphorylation and downstream molecules of P13K / AKt pathway in breast cancer cells. AUNPs – QU5 inhibits epithelial – mesenchymal transition, angiogenesis and invasiveness via EGFR / VEGFR – 2 mediated pathway in breast cancer [20]. Thus our studies proved that quercetin is effective in preventing prostate and breast cancer.


References

  1. Balakrishnan S, Bhat FA, Raja Singh P, Mukherjee S, Elumalai P, Das S, et al. Gold nanoparticle – conjugated quercetin inhibits epithelial – masenchymal transition, angiogenesis and invastiveness via EGFR/VEGFR-2 mediated pathway in breast cancer. Cell Prolif. 2016;49(6):678-697.
  2. Balakrishnan S, Mukherjee S, Das S, Bhat FA, Raja Singh P, Patra CR2, et al. Gold nanoparticles conjugated quercetin induces apoptosis via inhibition of EGFR/P134/AKt medicated pathway in breast cancer cell lines (MCF – 7 and MDA – MB – 231) Cell Biochem Funct. 2017;35(4):217-231.
  3. Bhat FA, Sharmila G, Balakrishnan S, Arunkumar R, Elumalai P, Suganya S, Raja Singh P. Quercetin reverses EGF – induced epithelial to mesenchymal transition and invasiveness in prostate cancer cell line via EGFR/P13K/Akt pathway. J Nut Biochem. 2014;25(11):1132-1139.
  4. Firdous AB, Sharmila G, Balakrishnan S, RajaSingh P, Suganya S, Srinivasan N, et al. Quercetin a natural dietary flavonoid, acts as a chemopreventive agent against prostate cancer in an invivo model inhibiting the EGFR signaling pathway. Food Funct. 2014;5(10):2632-45.
  5. Bhat  FA, Sharmila G, Balakrishnan S, Rajasingh P, Srinivasan N, Arunakaran. J Epidermal growth factor induced prostate cancer (PC3) cell survival and proliferation is inhibited by quercetin, a plant flavonoid through apoptotic machinery. Biomed Prev Nut. 2014;4:450-468.
  6. Carpenter G, Cohen S. Epidermal growth factor. J Biol Chem. 1990;265(14):7709-12.
  7. Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell. 1996;84(3):345-57.
  8. Janmaat ML, Giaccone G. The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. Drugs Today (Barc). 2003;39 Suppl C:61-80.
  9. Lamson DW, Brignall MS. Antioxidants and cancer, part 3: quercetin. Altern Med Rev. 2000;5(3):196-208.
  10. Liu HL, Jiang WB, Xie MX. Flavonoids: recent advances as anticancer drugs. Recent Pat Anticancer Drug Discov. 2010;5(2):152-64.
  11. Maga G, Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci. 2003;116(Pt 15):3051-60.
  12. Mendez MG, Kojima S and Goldman RD. vimentin induces changes in cell shape, motility and adhesion during the epithelial to mesenchymal transition. FASEB J. 2010;24:1838-1851.
  13. Naryzhny SN1. Proliferating cell nuclear antigen: a proteomics view. Cell Mol Life Sci. 2008;65(23):3789-808.
  14. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002;14(5):381-95.
  15. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2-16.
  16. Senthilkumar K, Elumalai P, Arunkumar R, Banudevi S, Gunadharini DN, Sharmila G. Quercetin regulates insulin like growth factor signaling and induces intrinsic and extrinsic pathway mediated apoptosis in androgen independent prostate cancer cells (PC-3). Mol cell Biochem. 2010;344:173-184.
  17. Senthilkuma K, Arunkumar R, Elumalai P, Sharmila G, Gunadharini DN, Banudevi S, et al. Quercetin inhibit invasion, migration and signaling molecules involved in cell survival and proliferation of prostate cancer cell line (PC3). Cell Biochem Funct. 2011;29: 87-95.
  18. Sharmila G, Bhat FA, Arunkumar R, Elumalai P, Rajasingh P, Senthilkumar K et al. Chemo preventive effect of quercetin, a nature dietary flavonoid on prostate cancer in in vivo model. Clin Nut. 2013;13:S0261.
  19. Sharmila G, Athirai T, Kiruthiga B, Senthilkumar K, Elumalai P, Arunkumar R and Arunakaran J. Chemo preventive effect of quercetin in MNV and testosterone induced prostate cancer of Sprague – Dawley rats. Clin Nut. 2014;66:38-46.
  20. Stuart -Harris R, Caldas C, Pindu SE and Pharoah P. Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32, 825 patients. Breast J. 2008;17: 323-334.
  21. Sun ZJ, Chen G, Hu X, Zhang W, Liu Y, Zhu LX, et al. Activation of P13K/Akt/IKK-alpha/NF-K appa ß signaling pathway is required for the apoptosis - evasion in human salivary adenoid cystic carcinoma: its inhibition by quercetin. Apoptosis. 2010;15:850-863.
  22. Vijayababu MR, Arunkumar A, Kanagaraj P, Arunakaran J. Effects of quercetin on IGFS and their binding protein – 3(IGFBP-3) secretion and induction of apoptosis in human prostate cancer cells. J  Carcinogenesis. 2006;5:1-10.
  23. Vijayababu MR, Arunkumar A, Kangaraj P, Venkatarama O, Krishnamoorthy G, Arunakaran J. Quercetin downregulates matrix metalloproteases 2 and 9 proteins expression in prostate cancer cells (PC3). Mol Cell Biochem. 2006;287:109-116.