Nanomedicine Research Journal

Nanomedicine Research Journal

Inhibition of miR-96 and miR-183 expression in treatment with fisetin-loaded chitosan nanoparticles in breast cancer cell lines

Document Type : Original Research Article

Authors
Zohreh Habibi Khoei 1
Razieh Heidari 2
Garshasb Rigi 1
Somayeh Reiisi 1
1 Department of Genetics, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran
2 Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
10.22034/nmrj.2023.03.008
Abstract
Objective(s): Several efforts have been made to improve the treatment of breast cancer. Nanotechnology has been proposed as a promising strategy for the formulation of pharmaceutical compounds and increasing their efficiency. Fisetin is a natural flavonoid with anti-cancer properties. This study was conducted with the aim of improving the anti-cancer effect of fisetin with the chitosan nanoparticles delivery system and investigating some molecular pathways after treating breast cancer cell lines (MCF7 and MDA-MB231). 
Methods: After the synthesis of chitosan nanoparticles, the shape, size and surface charge of nanoparticles were measured by SEM, DLS and zeta sizer. Drug loading in nanoparticles was confirmed by FTIR. The drug release rate was evaluated in acidic and neutral environments.  Also, the cell cytotoxicity of fisetin and nanofisetin was investigated using MTT assay. The expression level of miR-183 and miR-96 investigated in both cell lines using real-time PCR. 
Results: Our results showed that fisetin was successfully loaded into nanoparticles. The pH-dependent release of this nanosystem facilitated the release of fisetin in the acidic environment of the tumor. Chitosan nanoparticles containing fisetin with a size of 60 nm with significant efficiency exhibited higher toxicity to the viability of cells than free fisetin, and this decrease in survival was more pronounced for the triple negative MDA-MB-231. Fisetin also significantly decreased the expression of miR-96 and miR-183 in both cell lines. 
Conclusions: The nanoformulation of this herbal compound and its effect can present nanofisetin as a potential candidate for the treatment of metastatic breast cancer.
Keywords
Fisetin
chitosan nanoparticles
Breast cancer
miR-183
miR-96
Subjects
  1. A. G. Waks and E. P. Winer, Breast cancer treatment: a review, Jama, vol. 321, no. 3, pp. 288-300, 2019. https://doi.org/10.1001/jama.2018.19323
  2. G. Bianchini, C. De Angelis, L. Licata, and L. Gianni, Treatment landscape of triple-negative breast cancer-Expanded options, evolving needs, Nature reviews Clinical oncology, vol. 19, no. 2, pp. 91-113, 2022. https://doi.org/10.1038/s41571-021-00565-2  
  3. K. Unger-Saldaña, Challenges to the early diagnosis and treatment of breast cancer in developing countries, World journal of clinical oncology, vol. 5, no. 3, p. 465, 2014. https://doi.org/10.5306/wjco.v5.i3.465  
  4. S. Ohnishi and H. Takeda, Herbal medicines for the treatment of cancer chemotherapy-induced side effects, Frontiers in pharmacology, vol. 6, p. 14, 2015. https://doi.org/10.3389/fphar.2015.00014  
  5. R. K. Lall, D. N. Syed, V. M. Adhami, M. I. Khan, and H. Mukhtar, Dietary polyphenols in prevention and treatment of prostate cancer, International journal of molecular sciences, vol. 16, no. 2, pp. 3350-3376, 2015. https://doi.org/10.3390/ijms16023350  
  6. D. Kashyap et al., Fisetin and quercetin: promising flavonoids with chemopreventive potential, Biomolecules, vol. 9, no. 5, p. 174, 2019. https://doi.org/10.3390/biom9050174  
  7. J.-M. Jeong, C.-H. Choi, S.-K. Kang, I.-H. Lee, J.-Y. Lee, and H. Jung, Antioxidant and chemosensitizing effects of flavonoids with hydroxy and/or methoxy groups and structure-activity relationship, Journal of Pharmacy & Pharmaceutical Sciences, vol. 10, no. 4, pp. 537-546, 2007. https://doi.org/10.18433/J3KW2Z  
  8. S. J. Lee et al., Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy, Journal of Controlled Release, vol. 152, no. 1, pp. 21-29, 2011. https://doi.org/10.1016/j.jconrel.2011.03.027  
  9. S. Yu, X. Xu, J. Feng, M. Liu, and K. Hu, Chitosan and chitosan coating nanoparticles for the treatment of brain disease, International journal of pharmaceutics, vol. 560, pp. 282-293, 2019. https://doi.org/10.1016/j.ijpharm.2019.02.012  
  10. Y. Herdiana, N. Wathoni, S. Shamsuddin, I. M. Joni, and M. Muchtaridi, Chitosan-based nanoparticles of targeted drug delivery system in breast cancer treatment, Polymers, vol. 13, no. 11, p. 1717, 2021. https://doi.org/10.3390/polym13111717  
  11. S. K. Golombek et al., Tumor targeting via EPR: Strategies to enhance patient responses, Advanced drug delivery reviews, vol. 130, pp. 17-38, 2018. https://doi.org/10.1016/j.addr.2018.07.007  
  12. M. F. Attia, N. Anton, J. Wallyn, Z. Omran, and T. F. Vandamme, An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites, Journal of Pharmacy and Pharmacology, vol. 71, no. 8, pp. 1185-1198, 2019. https://doi.org/10.1111/jphp.13098  
  13. D. Raja Azalea, M. Mohambed, S. Joji, and C. Sankar, Design and evaluation of chitosan nanoparticles as novel drug carriers for the delivery of donepezil, Iranian Journal of Pharmaceutical Sciences, vol. 8, no. 3, pp. 155-164, 2012.  
  14. N. Gholamian Dehkordi, F. Elahian, P. Khosravian, and S. A. Mirzaei, Intelligent TAT‐coupled anti‐HER2 immunoliposomes knock downed MDR1 to produce chemosensitize phenotype of multidrug resistant carcinoma, Journal of Cellular Physiology, vol. 234, no. 11, pp. 20769-20778, 2019. https://doi.org/10.1002/jcp.28683  
  15. S. Sur, A. Rathore, V. Dave, K. R. Reddy, R. S. Chouhan, and V. Sadhu, Recent developments in functionalized polymer nanoparticles for efficient drug delivery system, Nano-Structures & Nano-Objects, vol. 20, p. 100397, 2019. https://doi.org/10.1016/j.nanoso.2019.100397  
  16. W.-Y. Liu, C.-C. Lin, Y.-S. Hsieh, and Y.-T. Wu, Nanoformulation development to improve the biopharmaceutical properties of fisetin using design of experiment approach, Molecules, vol. 26, no. 10, p. 3031, 2021. https://doi.org/10.3390/molecules26103031  
  17. Z. Shakeran, M. Keyhanfar, J. Varshosaz, and D. S. Sutherland, Biodegradable nanocarriers based on chitosan-modified mesoporous silica nanoparticles for delivery of methotrexate for application in breast cancer treatment, Materials Science and Engineering: C, vol. 118, p. 111526, 2021. https://doi.org/10.1016/j.msec.2020.111526  
  18. E. Rostami, Progresses in targeted drug delivery systems using chitosan nanoparticles in cancer therapy: A mini-review, Journal of Drug Delivery Science and Technology, vol. 58, p. 101813, 2020. https://doi.org/10.1016/j.jddst.2020.101813  
  19. R. Lee et al., Hyaluronic acid-decorated glycol chitosan nanoparticles for pH-sensitive controlled release of doxorubicin and celecoxib in nonsmall cell lung cancer, Bioconjugate Chemistry, vol. 31, no. 3, pp. 923-932, 2020. https://doi.org/10.1021/acs.bioconjchem.0c00048  
  20. A. Pawar, S. Singh, S. Rajalakshmi, K. Shaikh, and C. Bothiraja, Development of fisetin-loaded folate functionalized pluronic micelles for breast cancer targeting, Artificial cells, nanomedicine, and biotechnology, vol. 46, no. sup1, pp. 347-361, 2018. https://doi.org/10.1080/21691401.2018.1423991  
  21. C. Feng, X. Yuan, K. Chu, H. Zhang, W. Ji, and M. Rui, Preparation and optimization of poly (lactic acid) nanoparticles loaded with fisetin to improve anti-cancer therapy, International journal of biological macromolecules, vol. 125, pp. 700-710, 2019. https://doi.org/10.1016/j.ijbiomac.2018.12.003  
  22. D. N. Syed, V. M. Adhami, N. Khan, M. I. Khan, and H. Mukhtar, Exploring the molecular targets of dietary flavonoid fisetin in cancer, in Seminars in cancer biology, 2016, vol. 40, pp. 130-140: Elsevier. https://doi.org/10.1016/j.semcancer.2016.04.003  
  23. P.-M. Yang, H.-H. Tseng, C.-W. Peng, W.-S. Chen, and S.-J. Chiu, Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy, International journal of oncology, vol. 40, no. 2, pp. 469-478, 2012.  
  24. B. Sung, M. K. Pandey, and B. B. Aggarwal, Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-κB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IκBα kinase activation, Molecular pharmacology, vol. 71, no. 6, pp. 1703-1714, 2007. https://doi.org/10.1124/mol.107.034512  
  25. M. Bhaskaran and M. Mohan, MicroRNAs: history, biogenesis, and their evolving role in animal development and disease, Veterinary pathology, vol. 51, no. 4, pp. 759-774, 2014. https://doi.org/10.1177/0300985813502820  
  26. W. Tan, B. Liu, S. Qu, G. Liang, W. Luo, and C. Gong, MicroRNAs and cancer: Key paradigms in molecular therapy, Oncology letters, vol. 15, no. 3, pp. 2735-2742, 2018.  
  27. S. Liu et al., miR-221/222 activate the Wnt/β-catenin signaling to promote triple-negative breast cancer, Journal of molecular cell biology, vol. 10, no. 4, pp. 302-315, 2018. https://doi.org/10.1093/jmcb/mjy041  
  28. M. F. Santolla et al., miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling, Journal of Experimental & Clinical Cancer Research, vol. 37, no. 1, p. 94, 2018. https://doi.org/10.1186/s13046-018-0767-6  
  29. W. y. Qin, S. c. Feng, Y. q. Sun, and G. q. Jiang, MiR‐96‐5p promotes breast cancer migration by activating MEK/ERK signaling, The Journal of Gene Medicine, vol. 22, no. 8, p. e3188, 2020. https://doi.org/10.1002/jgm.3188  
  30. M. Bagban, K. Sharma, S. Saifi, I. Ilangovan, S. Sultana, and E. N. Numanoğlu, miR-96 and its versatile role in cancer, Advances in Cancer Biology-Metastasis, p. 100082, 2022. https://doi.org/10.1016/j.adcanc.2022.100082  
  31. S. Mohammaddoust and M. Sadeghizadeh, Mir-183 functions as an oncogene via decreasing PTEN in breast cancer cells, 2022. https://doi.org/10.21203/rs.3.rs-2267284/v1
Nanomedicine Research Journal
Volume 8, Issue 3
Summer 2023
Pages 290-300