Document Type : Original Research


1 Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran

3 Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

4 Department of Genetics, Islamic Azad University, Tehran North Branch, Tehran, Iran

5 Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran


Background & Objective: Breast cancer is the most common cancer among women. One of the most effective treatments for breast cancer is chemotherapy, in which specific drugs destroy the mass and its proliferation is inhibited. Chemotherapy is the most effective adjunctive therapy when multiple medications are used concurrently. Also, combining the drugs with nanocarrier has become an important strategy in targeted therapy. This study is designed to assess the apoptosis induction, cell cycle arrest, and anti-cancer potential of Tamoxifen-Curcumin-loaded niosomes against MCF-7 Cancer Cells.
Methods: A novel niosomal formulation of tamoxifen-curcumin with Span 80 and lipid to drug ratio of 20 was employed. The MCF-7 cells were cultured and then treated with IC50 value of tamoxifen-curcumin-loaded niosomes, the combination of tamoxifen and curcumin, tamoxifen, and curcumin alone. Flow cytometry, Real-Time PCR, and cell cycle analysis tests were conducted to evaluate the induction of apoptosis.
Results: Drug-loaded niosomes caused up-regulation of bax and p53 genes and down-regulation of bcl2 gene. Flow cytometry studies showed that niosomes containing tamoxifen-curcumin increased apoptosis rate in MCF-7 cells compared to the combination of tamoxifen and curcumin owing to the synergistic effect between the two drugs along with higher cell uptake by formulation niosomal. These results were also confirmed by cell cycle analysis.
Conclusion: Co-delivery of curcumin and tamoxifen using optimized niosomal formulation revealed that at acidic pH of MCF-7 cancer cells, released drugs from niosomal carriers would be  more effective than physiological pH. This feature of niosomal nanoparticles can reduce the side effects of drugs in normal cells. Niosomal nanoparticles might be used as a biological anti-cancer factor in treatment of  breast cancer.


Main Subjects

  1. Wiechmann L, Kuerer HM. The molecular journey from ductal carcinoma in situ to invasive breast cancer. Cancer. 2008;112(10):2130-42. [DOI:10.1002/cncr.23430] [PMID]
  2. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11(2):155-68.
  3. Rashidisabet H, Thomas PJ, Ajilore O, Zulueta J, Moore RC, Leow AJCOiSB. A systems biology approach to the digital behaviorome. 2020. [DOI:10.1016/j.coisb.2020.07.003]
  4. Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, McCullough ML, et al. The American cancer society cancer prevention study II nutrition cohort: rationale, study design, and baseline characteristics. Cancer. 2002;94(9):2490-501. [DOI:10.1002/cncr.101970] [PMID]
  5. Waggoner SE. Cervical cancer. Lancet. 2003;361(9376):2217-25. [DOI:10.1016/S0140-6736(03)13778-6]
  6. Sarhadi M, Aryan L, Zarei M. The Estrogen Receptor and Breast Cancer: A Complete Review.
  7. Molani S, Madadi M, Williams DJm. Investigating the Effectiveness of Breast Cancer Supplemental Screening Considering Radiologists' Bias. 2020. [DOI:10.1101/2020.12.16.20248373]
  8. Molani S, Madadi M, Wilkes WJO. A partially observable Markov chain framework to estimate overdiagnosis risk in breast cancer screening: Incorporating uncertainty in patients adherence behaviors. 2019;89:40-53. [DOI:10.1016/]
  9. Sudhakar A. History of Cancer, Ancient and Modern Treatment Methods. J Cancer Sci Ther. 2009;1(2):1-4. [DOI:10.4172/1948-5956.100000e2] [PMID]
  10. Chen A, Xu J, Johnson A. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1. Oncogene. 2006;25(2):278. [DOI:10.1038/sj.onc.1209019] [PMID]
  11. Kim LA, Amarnani D, Gnanaguru G, Tseng WA, Vavvas DG, D'Amore PA. Tamoxifen toxicity in cultured retinal pigment epithelial cells is mediated by concurrent regulated cell death mechanisms. Investig Ophthalmol Vis Sci. 2014;55(8):4747-58. [DOI:10.1167/iovs.13-13662] [PMID] [PMCID]
  12. Akbarzadeh I, Shayan M, Bourbour M, Moghtaderi M, Noorbazargan H, Eshrati Yeganeh F, et al. Preparation, Optimization and In-Vitro Evaluation of Curcumin-Loaded Niosome@ calcium Alginate Nanocarrier as a New Approach for Breast Cancer Treatment. Biology. 2021;10(3):173. [DOI:10.3390/biology10030173] [PMID] [PMCID]
  13. Darakhshan S, Bidmeshkipour A, Khazaei M, Rabzia A, Ghanbari A. Synergistic effects of tamoxifen and tranilast on VEGF and MMP-9 regulation in cultured human breast cancer cells. Asian Pac J Cancer Prev. 2013;14(11):6869-74. [DOI:10.7314/APJCP.2013.14.11.6869] [PMID]
  14. Sailaja AK, Amareshwar P, Chakravarty P. Chitosan nanoparticles as a drug delivery system. Res J Pharm Biol Chem Sci. 2010;1(3):474-84.
  15. Amale FR, Ferdowsian S, Hajrasouliha S, Kazempoor R, Mirzaie A, Dakkali MS, et al. Gold nanoparticles loaded into niosomes: A novel approach for enhanced antitumor activity against human ovarian cancer. 2021.
  16. Davahli MR, Karwowski W, Taiar R. A System Dynamics Simulation Applied to Healthcare: A Systematic Review. Int J Environ Res Public Health. 2020;17(16):5741. [DOI:10.3390/ijerph17165741] [PMID] [PMCID]
  17. Boran G, Tavakoli S, Dierking I, Kamali AR, Ege D. Synergistic effect of graphene oxide and zoledronic acid for osteoporosis and cancer treatment. Sci Rep. 2020;10(1):7827. [DOI:10.1038/s41598-020-64760-4] [PMID] [PMCID]
  18. Dragojevic S, Ryu JS, Raucher D. Polymer-Based Prodrugs: Improving Tumor Targeting and the Solubility of Small Molecule Drugs in Cancer Therapy. Molecules. 2015;20(12):21750-69. [DOI:10.3390/molecules201219804] [PMID] [PMCID]
  19. Akbarzadeh I, Fatemizadeh M, Heidari F, Niri NM. Niosomal formulation for co-administration of hydrophobic anticancer drugs into MCF-7 cancer cells. Arch Adv Biosci. 2020 May 16;11(2). [DOI:10.22037/aab.v11i2.28906]
  20. Uchegbu IF, Vyas SP. Non-ionic surfactant based vesicles (niosomes) in drug delivery. Int J Pharm. 1998;172(1-2):33-70. [DOI:10.1016/S0378-5173(98)00169-0]
  21. Hedayati Ch M, Abolhassani Targhi A, Shamsi F, Heidari F, Salehi Moghadam Z, Mirzaie A, et al. Niosome-encapsulated tobramycin reduced antibiotic resistance and enhanced antibacterial activity against multidrug-resistant clinical strains of Pseudomonas aeruginosa. J Biomed Mater Res A. 2021;109(6):966-80. [DOI:10.1002/jbm.a.37086] [PMID]
  22. Moghaddam FD, Akbarzadeh I, Marzbankia E, Farid M, Khaledi L, Reihani AH, et al. Delivery of Melittin Loaded Niosomes for Breast Cancer Treatment: an in-vitro and in-vivo Evaluation of Anti-cancer Effect. 2020. [DOI:10.21203/]
  23. Moghtaderi M, Mirzaie A, Zabet N, Moammeri A, Mansoori-Kermani A, Akbarzadeh I, et al. Enhanced Antibacterial Activity of Echinacea angustifolia Extract against Multidrug-Resistant Klebsiella pneumoniae through Niosome Encapsulation. 2021;11(6):1573. [DOI:10.3390/nano11061573] [PMID] [PMCID]
  24. Targhi AA, Moammeri A, Jamshidifar E, Abbaspour K, Sadeghi S, Lamakani L, et al. Synergistic effect of curcumin-Cu and curcumin-Ag nanoparticle loaded niosome: Enhanced antibacterial and anti-biofilm activities. Bioorg Chem. 2021;115:105116. [DOI:10.1016/j.bioorg.2021.105116] [PMID]
  25. Naseroleslami M, Niri NM, Akbarzade I, Sharifi M, Aboutaleb N. Simvastatin-loaded nano-niosomes confer cardioprotection against myocardial ischemia/reperfusion injury. Drug Deliv Transl Res. 2021:1-10. [DOI:10.1007/s13346-021-01019-z]
  26. Mansouri M, Khayam N, Jamshidifar E, Pourseif T, Kianian S, Mirzaie A, et al. Streptomycin Sulfate-Loaded Niosomes Enables Increased Antimicrobial and Anti-Biofilm Activities. 2021:851. [DOI:10.3389/fbioe.2021.745099] [PMID] [PMCID]
  27. Jamshidifar E, Eshrati Yeganeh F, Shayan M, Tavakkoli Yaraki M, Bourbour M, Moammeri A, et al. Super magnetic niosomal nanocarrier as a new approach for treatment of breast cancer: a case study on SK-BR-3 and MDA-MB-231 cell lines. 2021;22(15):7948. [DOI:10.3390/ijms22157948] [PMID] [PMCID]
  28. Chen S, Hanning S, Falconer J, Locke M, Wen J. Recent advances in non-ionic surfactant vesicles (niosomes): Fabrication, characterization, pharmaceutical and cosmetic applications. Eur J Pharm Biopharm. 2019;144:18-39. [DOI:10.1016/j.ejpb.2019.08.015] [PMID]
  29. Mirzaie A, Peirovi N, Akbarzadeh I, Moghtaderi M, Heidari F, Yeganeh FE, et al. Preparation and optimization of ciprofloxacin encapsulated niosomes: A new approach for enhanced antibacterial activity, biofilm inhibition and reduced antibiotic resistance in ciprofloxacin-resistant methicillin-resistance Staphylococcus aureus. Bioorg Chem. 2020;103:104231. [DOI:10.1016/j.bioorg.2020.104231] [PMID]
  30. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-25. [DOI:10.1111/j.1472-8206.2004.00299.x] [PMID]
  31. Petyaev IM. Improvement of hepatic bioavailability as a new step for the future of statin. Arch Med Sci. 2015;11(2):406. [DOI:10.5114/aoms.2015.50972] [PMID] [PMCID]
  32. Alemi A, Zavar Reza J, Haghiralsadat F, Zarei Jaliani H, Haghi Karamallah M, Hosseini SA, et al. Paclitaxel and curcumin coadministration in novel cationic PEGylated niosomal formulations exhibit enhanced synergistic antitumor efficacy. J Nanobiotechnol. 2018;16(1):28. [DOI:10.1186/s12951-018-0351-4] [PMID] [PMCID]
  33. Ibiyeye KM, Nordin N, Ajat M, Zuki ABZ. Ultrastructural Changes and Antitumor Effects of Doxorubicin/Thymoquinone-Loaded CaCO3 Nanoparticles on Breast Cancer Cell Line. Front Oncol. 2019;9:599. [DOI:10.3389/fonc.2019.00599] [PMID] [PMCID]
  34. Westphal D, Dewson G, Czabotar PE, Kluck RM. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2011;1813(4):521-31. [DOI:10.1016/j.bbamcr.2010.12.019] [PMID]
  35. McBride O, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci. 1986;83(1):130-4. [DOI:10.1073/pnas.83.1.130] [PMID] [PMCID]
  36. Montenarh M. Biochemical, immunological, and functional aspects of the growth-suppressor/oncoprotein p53. Crit Rev Oncog. 1992;3(3):233-56. [DOI:10.3892/ijo.1.1.37]
  37. Gotow T, Shibata M, Kanamori S, Tokuno O, Ohsawa Y, Sato N, et al. Selective localization of Bcl-2 to the inner mitochondrial and smooth endoplasmic reticulum membranes in mammalian cells. Cell Death Differ. 2000;7(7):666-74. [DOI:10.1038/sj.cdd.4400694] [PMID]
  38. Jürgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci. 1998;95(9):4997-5002. [DOI:10.1073/pnas.95.9.4997] [PMID] [PMCID]
  39. Wood WG, Igbavboa U, Muller WE, Eckert GP. Statins, Bcl-2, and apoptosis: cell death or cell protection? Mol Neurobiol. 2013;48(2):308-14. [DOI:10.1007/s12035-013-8496-5] [PMID] [PMCID]
  40. Yoon O, Roh J. Downregulation of KLF4 and the Bcl-2/Bax ratio in advanced epithelial ovarian cancer. Oncol Lett. 2012;4(5):1033-6. [DOI:10.3892/ol.2012.834] [PMID] [PMCID]
  41. Hemann M, Lowe S. The p53-Bcl-2 connection. Nature Publishing Group; 2006. [DOI:10.1038/sj.cdd.4401962] [PMID] [PMCID]
  42. Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat Rev Cancer. 2002;2(8):594-604. [DOI:10.1038/nrc864] [PMID]
  43. Vaseva AV, Moll UM. The mitochondrial p53 pathway. Biochim Biophys Acta. 2009;1787(5):414-20. [DOI:10.1016/j.bbabio.2008.10.005] [PMID] [PMCID]