Skip to main content

Advertisement

SpringerLink
Log in

Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells

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

Abstract

Quercetin, the plant-derived phenolic compounds, plays a pivotal role in controlling hemostasis, by having potent antioxidant and free-radical scavenging properties. This flavonoid in combination with chemotherapeutic drugs improves the efficacy of these agents in induction of apoptosis in cancer cells. This study investigated the role of nano-quercetin (phytosome) in doxorubicin-induced apoptosis. Nanoparticles were characterized for particle size, zeta potential, scanning electron microscopy (SEM) and differential scanning calorimetric assessments. Anti-proliferative effect of formulations was evaluated by MTT assay. mRNA expression levels of target genes were measured by real time RT-PCR. The mean size of nanoparticles was 85 ± 2 nm with nearly narrow size distribution which was confirmed by SEM analysis. Our results showed that co-treatment of MCF-7 breast cancer cells with nano-quercetin and doxorubicin increased the percentage of apoptosis from 40.11 ± 7.72–58 ± 7.13 (p < 0.05). Furthermore, mRNA expression levels for downstream genes including NQO1 and MRP1 showed a marked decrease (p < 0.05). Taken together, our results suggest that phytosome technology can elevate the efficacy of chemotherapeutics by increasing the permeability of tumor cells to chemical agents. Our findings introduce a novel phytosome-dependent strategy to improve delivery of doxorubicin to the breast cancerous tissues.

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

Similar content being viewed by others

References

  1. DeSantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin 64(1):52–62

    Article  PubMed  Google Scholar 

  2. Gatti L, Zunino F (2005) Overview of tumor cell chemoresistance mechanisms. In: Blumenthal RD (ed) Chemosensitivity: Volume II. Springer, New York, pp 127–148

    Chapter  Google Scholar 

  3. Li W-J, Zhong S-L, Wu Y-J, Xu W-D, Xu J-J, Tang J-H, Zhao J-H (2013) Systematic expression analysis of genes related to multidrug-resistance in isogenic docetaxel-and adriamycin-resistant breast cancer cell lines. Mol Biol Rep 40(11):6143–6150

    Article  CAS  PubMed  Google Scholar 

  4. Chang A (2011) Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer 71(1):3–10

    Article  PubMed  Google Scholar 

  5. Fodale V, Pierobon M, Liotta L, Petricoin E (2011) Mechanism of cell adaptation: When and how do cancer cells develop chemoresistance? Cancer J 17(2):89–95

    Article  CAS  PubMed  Google Scholar 

  6. Cengiz E, Karaca B, Kucukzeybek Y, Gorumlu G, Gul MK, Erten C, Atmaca H, Uzunoglu S, Karabulut B, Sanli UA (2010) Overcoming drug resistance in hormone-and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination. Mol Biol Rep 37(3):1269–1277

    Article  CAS  PubMed  Google Scholar 

  7. Rejinold NS, Baby T, Nair SV, Jayakumar R (2013) Paclitaxel loaded fibrinogen coated CdTe/ZnTe core shell nanoparticles for targeted imaging and drug delivery to breast cancer cells. J Biomed Nanotechnol 9(10):1657–1671

    Article  CAS  PubMed  Google Scholar 

  8. Brannon-Peppas L, Blanchette JO (2012) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 64:206–212

    Article  Google Scholar 

  9. Vriend J, Reiter RJ (2015) The Keap1-Nrf2-antioxidant response element pathway: a review of its regulation by melatonin and the proteasome. Mol Cell Endocrinol 401:213–220

    Article  CAS  PubMed  Google Scholar 

  10. Wen X, Thorne G, Hu L, Joy, Aleksunes LM (2015) Activation of NRF2 signaling in HEK293 cells by a first‐in‐class direct KEAP1‐NRF2 inhibitor. J Biochem Mol Toxicol 29(6):261–266

    Article  CAS  PubMed  Google Scholar 

  11. Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, Kikuchi N, Satoh H, Sakamoto T, Hizawa N (2009) Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15(10):3423–3432

    Article  CAS  PubMed  Google Scholar 

  12. Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, Copple IM, Williams S, Owen A, Neoptolemos JP (2011) Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer 10:37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moon EJ, Giaccia A (2015) Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radic Biol Med 79:292–299

    Article  CAS  PubMed  Google Scholar 

  14. Hou X, Bai X, Gou X, Zeng H, Xia C, Zhuang W, Chen X, Zhao Z, Huang M, Jin J (2015) 3′, 4′, 5′, 5, 7-Pentamethoxyflavone sensitizes cisplatin-resistant A549 cells to cisplatin by inhibition of Nrf2 pathway. Mol Cells 38(5):396–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Valenzuela M, Glorieux C, Stockis J, Sid B, Sandoval J, Felipe K, Kviecinski M, Verrax J, Calderon PB (2014) Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells. Br J Cancer 111(5):874–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chian S, Thapa R, Chi Z, Wang XJ, Tang X (2014) Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem Biophys Res Commun 447(4):602–608

    Article  PubMed  Google Scholar 

  17. Olayanju A, Copple IM, Bryan HK, Edge GT, Sison RL, Wong MW, Lai Z-Q, Lin Z-X, Dunn K, Sanderson CM (2015) Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity—implications for therapeutic targeting of Nrf2. Free Radic Biol Med 78:202–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sabzichi M, Hamishehkar H, Ramezani F, Sharifi S, Tabasinezhad M, Pirouzpanah M, Ghanbari P, Samadi N (2013) Luteolin-loaded phytosomes sensitize human breast carcinoma MDA-MB 231 cells to doxorubicin by suppressing Nrf2 mediated signalling. Asian Pac J Cancer Prev: APJCP 15(13):5311–5316

    Article  Google Scholar 

  19. Kahraman A, Çakar H, Köken T (2012) The protective effect of quercetin on long-term alcohol consumption-induced oxidative stress. Mol Biol Rep 39(3):2789–2794

    Article  CAS  PubMed  Google Scholar 

  20. Sun M, Nie S, Pan X, Zhang R, Fan Z, Wang S (2014) Quercetin-nanostructured lipid carriers: characteristics and anti-breast cancer activities in vitro. Colloids Surf B 113:15–24

    Article  CAS  Google Scholar 

  21. Amin T, Bhat SV (2012) A review on phytosome technology as a novel approach to improve the bioavailability of nutraceuticals. Int J Adv Res Technol 1(3):43–57

    Google Scholar 

  22. Patil M, Patil S, Chittam K, Wagh R (2012) Phytosomes: novel approach in herbal medicines. Asian J Pharm Sci Res 2:1–9

    Google Scholar 

  23. Jain N, Gupta BP, Thakur N, Jain R, Banweer J, Jain DK, Jain S (2010) Phytosome: a novel drug delivery system for herbal medicine. Int J Pharm Sci Drug Res 2(4):224–228

    CAS  Google Scholar 

  24. Chang C, Zhu Y, Tang X, Tao W (2011) The anti-proliferative effects of norcantharidin on human HepG2 cells in cell culture. Mol Biol Rep 38(1):163–169

    Article  CAS  PubMed  Google Scholar 

  25. Innamorato NG, Rojo AI, García-Yagüe ÁJ, Yamamoto M, De Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181(1):680–689

    Article  CAS  PubMed  Google Scholar 

  26. Lee J-S, Surh Y-J (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224(2):171–184

    Article  CAS  PubMed  Google Scholar 

  27. Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, Wu H, Bova SG, Biswal S (2010) Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther 9(2):336–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kweon M-H, Adhami VM, Lee J-S, Mukhtar H (2006) Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281(44):33761–33772

    Article  CAS  PubMed  Google Scholar 

  29. Huang C-S, Lii C-K, Lin A-H, Yeh Y-W, Yao H-T, Li C-C, Wang T-S, Chen H-W (2013) Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Arch Toxicol 87(1):167–178

    Article  CAS  PubMed  Google Scholar 

  30. Xu K, Liu B, Ma Y, Du J, Li G, Gao H, Zhang Y, Ning Z (2009) Physicochemical properties and antioxidant activities of luteolin-phospholipid complex. Molecules 14(9):3486–3493

    Article  CAS  PubMed  Google Scholar 

  31. Lopez-Lazaro M (2009) Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 9(1):31–59

    Article  CAS  PubMed  Google Scholar 

  32. Akan Z, Garip AI (2013) Antioxidants may protect cancer cells from apoptosis signals and enhance cell viability. Asian Pac J Cancer Prev 14(8):4611–4614

    Article  PubMed  Google Scholar 

  33. Kawasaki Y, Ishigami S, Arigami T, Uenosono Y, Yanagita S, Uchikado Y, Kita Y, Nishizono Y, Okumura H, Nakajo A (2015) Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer. BMC Cancer 15(1):5

    Article  PubMed  PubMed Central  Google Scholar 

  34. Liang G-Y, Lu S-X, Xu G, Liu X-D, Li J, Zhang D-S (2013) Expression of metallothionein and Nrf2 pathway genes in lung cancer and cancer-surrounding tissues. World J Surg Oncol 11(1):199

    Article  PubMed  PubMed Central  Google Scholar 

  35. Akbas SH, Timur M, Ozben T (2005) The effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB 231 human breast cancer cells 1. J Surg Res 125(1):49–55

    Article  CAS  PubMed  Google Scholar 

  36. Paulhill KJ (2008) Quercetin and dietary lipids alter the cellular redox environment of the colonocyte in the promotion stage of colon carcinogenesis. Texas A&M University, College Station

    Google Scholar 

  37. Chen C, Zhou J, Ji C (2010) Quercetin: a potential drug to reverse multidrug resistance. Life Sci 87(11):333–338

    Article  CAS  PubMed  Google Scholar 

  38. Kim MK, K-s Park, Choo H, Chong Y (2015) Quercetin–POM (pivaloxymethyl) conjugates: modulatory activity for P-glycoprotein-based multidrug resistance. Phytomedicine 22(7):778–785

    Article  CAS  PubMed  Google Scholar 

  39. Bhattacharya S, Ghosh AK (2009) Phytosomes: the emerging technology for enhancement of bioavailability of botanicals and nutraceuticals. Int  J Health Res 2(3):225–232

    CAS  Google Scholar 

  40. Suryawanshi S (2011) Phytosome: an emerging trend in herbal drug treatment. J Med Gene Geno 3:109–114

    Google Scholar 

  41. van Dijk C, Driessen AJ, Recourt K (2000) The uncoupling efficiency and affinity of flavonoids for vesicles. Biochem Pharmacol 60(11):1593–1600

    Article  PubMed  Google Scholar 

  42. Granado-Serrano AB, Martín M, Bravo L, Goya L, Ramos S (2012) Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: involvement of p38. Chem Biol Interact 195:154–164

    Article  CAS  PubMed  Google Scholar 

  43. Staedler D, Idrizi E, Kenzaoui BH, Juillerat-Jeanneret L (2011) Drug combinations with quercetin: doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother Pharmacol 68(5):1161–1172

    Article  CAS  PubMed  Google Scholar 

  44. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, Zhang DD (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci 108(4):1433–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hayes JD, McMahon M (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34(4):176–188

    Article  CAS  PubMed  Google Scholar 

  46. Laurand A, Laroche-Clary A, Larrue A, Huet S, Soma É, Bonnet J, Robert J (2004) Quantification of the expression of multidrug resistance-related genes in human tumour cell lines grown with free doxorubicin or doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres. Anticancer Res 24(6):3781–3788

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are sincerely grateful to Prof.Dastmalchi for providing the necessary structure for successful accomplishment of this research. This work was financially supported by the grant from Biotechnology Research Center, Tabriz University of Medical Sciences.

Author information

Authors and Affiliations

  1. Biotechnology Research Center and Department of Biochemistry & Clinical Laboratory, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Akbar Minaei & Nasser Samadi

  2. Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Mehdi Sabzichi

  3. Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Fatemeh Ramezani

  4. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Hamed Hamishehkar & Nasser Samadi

Authors
  1. Akbar Minaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehdi Sabzichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatemeh Ramezani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hamed Hamishehkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nasser Samadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nasser Samadi.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Minaei, A., Sabzichi, M., Ramezani, F. et al. Co-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells. Mol Biol Rep 43, 99–105 (2016). https://doi.org/10.1007/s11033-016-3942-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-016-3942-x

Keywords

Search

Navigation