Investigating the cell proliferation and migration inhibition by cerium oxide nanoparticles loaded with doxorubicin in MDA-MB-231 cell line

Document Type : Research Paper

Authors

1 Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran

2 Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran

Abstract

Objective(s): Cerium oxide nanoparticles (Ceo2 NPs) are considered one of the most effective nanomaterials for drug delivery. The current study aimed to investigate the anticancer activities of doxorubicin-loaded Ceo2 NPs (DOX-Ceo2 NPs) against the MDA-MB-231 human breast cancer cell line.
Materials and Methods: Ceo2 NPs were synthesized using the GREEN synthesis method and loaded with DOX (DOX-Ceo2 NPs). The physicochemical properties of the Ceo2 NPs were evaluated using FTIR, XRD, DLS, zeta potential, and electron microscopy (SEM/TEM). Cultured MDA-MB-231 cells were treated with different concentrations of bare Ceo2 NPs, free DOX, and DOX-Ceo2 NPs. In addition, HDF cells were treated with different concentrations of Ceo2 NPs. MTT, wound healing, and flow cytometry assays were performed to determine the cell viability, migration, and apoptosis, respectively. qPCR was performed to investigate the expression of genes involved in apoptosis, including caspase (CASP) 3, 8, 9, and Bcl-2. 
Results: The XRD and FTIR results confirmed the synthesis of pure and crystalline structured- Ceo2 NPs. The average size, PDI, and zeta potential of the Ceo2 NPs were approximately 239.1 nm, 0.074, and -9.04 mV, respectively. In vitro assays showed that DOX-Ceo2 NPs exhibited higher cell proliferation inhibition, migration suppression, and apoptosis induction through the upregulation of CASP3, CASP8, and CASP9 genes and downregulation of Bcl-2. 
Conclusion: Our data demonstrate the potential of Ceo2 NPs for the efficient delivery of DOX and, subsequently, the improvement of its anticancer activities. Therefore, DOX-Ceo2 NPs have the potential to be proposed as promising anticancer agents for breast cancer.

Keywords

References

1.    Lukong KE. Understanding breast cancer–The long and winding road. BBA Clin. 2017;7:64-77.
2.    Katchman BA. From plasma peptide to phenotype: The emerging role of quiescin sulfhydryl oxidase 1 in tumor cell biology. Arizona State University; 2012.
3.    Farghadani R, Naidu R. Curcumin as an enhancer of therapeutic efficiency of chemotherapy drugs in breast cancer. Int J Mol Sci. 2022 Feb; 23(4): 2144.
4.    Christowitz C, Davis T, Isaacs A, Van Niekerk G, Hattingh S, Engelbrecht A-M. Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer. 2019;19(1):1-10.
5.    Cai F, Luis MAF, Lin X, Wang M, Cai L, Cen C, et al. Anthracycline‑induced cardiotoxicity in the chemotherapy treatment of breast cancer: Preventive strategies and treatment. Molecular and clinical oncology. 2019;11(1):15-23.
6.    Renu K, Abilash V, PB TP, Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy–An update. European journal of pharmacology. 2018;818:241-253.
7.    Ajaykumar C. Overview on the side effects of doxorubicin. Advances in Precision Medicine Oncology. 2020.
8.    Renu K, Pureti LP, Vellingiri B, Valsala Gopalakrishnan A. Toxic effects and molecular mechanism of doxorubicin on different organs–an update. Toxin Rev. 2022;41(2):650-674.
9.    Gote V, Nookala AR, Bolla PK, Pal D. Drug resistance in metastatic breast cancer: tumor targeted nanomedicine to the rescue.Int J Mol Sci. 2021;22(9):4673.
10.    Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2(2): 141–160.
11.    Wicki A, Witzigmann D, Balasubramanian V, Huwyler J. Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. J Control Release. 2015 Feb 28:200:138-157. 
12.    Roco MC. Broader societal issues of nanotechnology. J Nanoparticle Res. 2003;5:181-189.
13.    Mukherjee S, Liang L, Veiseh O. Recent advancements of magnetic nanomaterials in cancer therapy. Pharmaceutics. 2020;12(2):147.
14.    Reed K, Cormack A, Kulkarni A, Mayton M, Sayle D, Klaessig F, et al. Exploring the properties and applications of nanoceria: is there still plenty of room at the bottom? Environmental Science: Nano. 2014;1(5):390-405.
15.    Hasanzadeh L, Oskuee RK, Sadri K, Nourmohammadi E, Mohajeri M, Mardani Z, et al. Green synthesis of labeled CeO2 nanoparticles with 99mTc and its biodistribution evaluation in mice. Life Sci. 2018;212:233-420.
16.    Ma R, Zhang S, Wen T, Gu P, Li L, Zhao G, et al. A critical review on visible-light-response CeO2-based photocatalysts with enhanced photooxidation of organic pollutants. Catalysis Today. 2019;335:20-30.
17.    Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants. 2016;5(2):15.
18.    Das S, Dowding JM, Klump KE, McGinnis JF, Self W, Seal S. Cerium oxide nanoparticles: Applications and prospects in nanomedicine. Nanomedicine. 2013;8(9):1483-1508.
19.    Walkey C, Das S, Seal S, Erlichman J, Heckman K, Ghibelli L, et al. Catalytic properties and biomedical applications of cerium oxide nanoparticles. Environ Sci Nano.2015;2(1):33-53.
20.    Hirst SM, Karakoti AS, Tyler RD, Sriranganathan N, Seal S, Reilly CM. Anti‐inflammatory properties of cerium oxide nanoparticles. Small. 2009;5(24):2848-2856.
21.    Farias IAP, Santos CCLd, Sampaio FC. Antimicrobial activity of cerium oxide nanoparticles on opportunistic microorganisms: a systematic review. Biomed Res Int. 2018;2018:1923606.
22.    Nadeem M, Khan R, Afridi K, Nadhman A, Ullah S, Faisal S, et al. Green synthesis of cerium oxide nanoparticles (CeO2 NPs) and their antimicrobial applications: A review. Int J Nanomedicine. 2020:5951-5961.
23.    Gao Y, Chen K, Ma J-l, Gao F. Cerium oxide nanoparticles in cancer. Onco Targets Ther. 2014; 7: 835–840.
24.    Calvache-Muñoz J, Prado FA, Rodríguez-Páez JE. Cerium oxide nanoparticles: Synthesis, characterization and tentative mechanism of particle formation. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2017;529:146-159.
25.    Thakur N, Sadhukhan P, Kundu M, Singh TA, Hatimuria M, Pabbathi A, et al. Folic acid-functionalized cerium oxide nanoparticles as smart nanocarrier for pH-responsive and targeted delivery of Morin in breast cancer therapy. Inorganic Chemistry Communications. 2022;145:109976.
26.    Liying H, Yumin S, Lanhong J, Shikao S. Recent advances of cerium oxide nanoparticles in synthesis, luminescence and biomedical studies: a review. Journal of Rare Earths. 2015;33(8):791-799.
27.    Rajeshkumar S, Naik P. Synthesis and biomedical applications of cerium oxide nanoparticles–a review. Biotechnology Reports. 2018;17:1-5.
28.    Magudieshwaran R, Ishii J, Raja KCN, Terashima C, Venkatachalam R, Fujishima A, et al. Green and chemical synthesized CeO2 nanoparticles for photocatalytic indoor air pollutant degradation. Materials Letters. 2019;239:40-44.
29.    Arunachalam T, Karpagasundaram M, Rajarathinam N. Ultrasound assisted green synthesis of cerium oxide nanoparticles using Prosopis juliflora leaf extract and their structural, optical and antibacterial properties. Materials Science-Poland. 2017;35(4):791-798.
30.    Sohail M, Sun Z, Li Y, Gu X, Xu H. Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy. Expert Rev Anticancer Ther. 2021 Dec;21(12):1385-1398.
31.    Yang J, Wu Y, Wang X, Xu L, Zhao X, Yang Y. Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy. Tumour Biol. 2017 Mar;39(3):1010428317692228.
32.    Ashrafizaveh S, Ashrafizadeh M, Zarrabi A, Husmandi K, Zabolian A, Shahinozzaman M, et al. Long non-coding RNAs in the doxorubicin resistance of cancer cells. Cancer Lett. 2021:508:104-114.
33.    van der Zanden SY, Qiao X, Neefjes J. New insights into the activities and toxicities of the old anticancer drug doxorubicin. FEBS J. 2021;288(21):6095-6111.
34.    Devi RV, Doble M, Verma RS. Nanomaterials for early detection of cancer biomarker with special emphasis on gold nanoparticles in immunoassays/sensors. Biosensors and Bioelectronics. 2015;68:688-698.
35.    Prabhu RH, Patravale VB, Joshi MD. Polymeric nanoparticles for targeted treatment in oncology: Current insights. Int J Nanomedicine. 2015:10:1001-1018.
36.    Luther DC, Huang R, Jeon T, Zhang X, Lee Y-W, Nagaraj H, et al. Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles. Adv Drug Deliv Rev. 2020:156:188-213.
37.    Borges A, de Freitas V, Mateus N, Fernandes I, Oliveira J. Solid lipid nanoparticles as carriers of natural phenolic compounds. Antioxidants. 2020;9(10):998.
38.    Aseyd Nezhad S, Es‐haghi A, Tabrizi MH. Green synthesis of cerium oxide nanoparticle using Origanum majorana L. leaf extract, its characterization and biological activities. Applied Organometallic Chemistry. 2020;34(2):e5314.
39.    Nadeem M, Tungmunnithum D, Hano C, Abbasi BH, Hashmi SS, Ahmad W, et al. The current trends in the green syntheses of titanium oxide nanoparticles and their applications. Green chemistry letters and reviews. 2018;11(4):492-502.
40.    Srikar SK, Giri DD, Pal DB, Mishra PK, Upadhyay SN. Green synthesis of silver nanoparticles: a review. Green and Sustainable Chemistry. 2016;6(01):34.
41.    Kargar H, Ghasemi F, Darroudi M. Bioorganic polymer-based synthesis of cerium oxide nanoparticles and their cell viability assays. Ceramics International. 2015;41(1):1589-1594.
42.    Patil SN, Paradeshi JS, Chaudhari PB, Mishra SJ, Chaudhari BL. Bio-therapeutic potential and cytotoxicity assessment of pectin-mediated synthesized nanostructured cerium oxide. Appl Biochem Biotechnol. 2016;180(4):638-654.
43.    Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nature reviews Drug discovery. 2010;9(8):615-627.
44.    Cheng Y, Dai Q, Morshed RA, Fan X, Wegscheid ML, Wainwright DA, et al. Blood‐brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging. Small. 2014;10(24):5137-5150.
45.    Liu B, Sun Z, Huang P-JJ, Liu J. Hydrogen peroxide displacing DNA from nanoceria: mechanism and detection of glucose in serum. J Am Chem Soc. 2015;137(3):1290-1295.
46.    Zhang J, Chen G, Guay D, Chaker M, Ma D. Highly active PtAu alloy nanoparticle catalysts for the reduction of 4-nitrophenol. Nanoscale. 2014;6(4):2125-2130.
47.    Karakoti A, Kuchibhatla SV, Babu KS, Seal S. Direct synthesis of nanoceria in aqueous polyhydroxyl solutions. The Journal of Physical Chemistry C. 2007;111(46):17232-17240.
48.    Giri S, Karakoti A, Graham RP, Maguire JL, Reilly CM, Seal S, et al. Nanoceria: A rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer. PLoS One. 2013;8(1):e54578.
49.    Hijaz M, Das S, Mert I, Gupta A, Al-Wahab Z, Tebbe C, et al. Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer. BMC Cancer. 2016;16(1):1-14.
50.    Wason MS, Colon J, Das S, Seal S, Turkson J, Zhao J, et al. Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production. Nanomedicine: Nanomedicine. 2013;9(4):558-569.
51.    Alpaslan E, Yazici H, Golshan NH, Ziemer KS, Webster TJ. pH-dependent activity of dextran-coated cerium oxide nanoparticles on prohibiting osteosarcoma cell proliferation. ACS Biomaterials Science & Engineering. 2015;1(11):1096-1103.
52.    Saranya J, Saminathan P, Ankireddy SR, Shaik MR, Khan M, Khan M, et al. Cerium oxide/graphene oxide hybrid: Synthesis, characterization, and evaluation of anticancer activity in a breast cancer cell line (MCF-7). Biomedicines. 2023;11(2):531.
53.    Chen C, Lu L, Yan S, Yi H, Yao H, Wu D, et al. Autophagy and doxorubicin resistance in cancer. Anti-cancer drugs. 2018;29(1):1-9.
54.    Das J, Choi Y-J, Han JW, Reza AMMT, Kim J-H. Nanoceria-mediated delivery of doxorubicin enhances the anti-tumour efficiency in ovarian cancer cells via apoptosis. Sci Rep. 2017;7(1):9513.
55.    Pramanik N, De T, Sharma P, Alakesh A, Jagirdar SK, Rangarajan A, et al. Surface-coated cerium nanoparticles to improve chemotherapeutic delivery to tumor cells. ACS Omega. 2022;7(36):31651-31657.
56.    Atlı Şekeroğlu Z, Şekeroğlu V, Aydın B, Kontaş Yedier S. Cerium oxide nanoparticles exert antitumor effects and enhance paclitaxel toxicity and activity against breast cancer cells. J Biomed Mater Res B Appl Biomater. 2023 Mar;111(3):579-589.
57.    Foroutan Z, Afshari AR, Sabouri Z, Mostafapour A, Far BF, Jalili‐Nik M, et al. Plant-based synthesis of cerium oxide nanoparticles as a drug delivery system in improving the anticancer effects of free temozolomide in glioblastoma (U87) cells. Ceramics International. 2022;48(20):30441-30450.
 
Nanomedicine Journal
Volume 11, Issue 4
October 2024
Pages 426-437

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