Synergistic cytotoxicity effect of the combination of chitosan nanoencapsulated imatinib mesylate and quercetin in BCR-ABL positive K562 cells

Document Type : Original Article

Authors

1 Department of Veterinary Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Department of Veterinary Surgery, Science and Research Branch, Islamic Azad University, Tehran, Iran

3 Gene Therapy Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Intolerable side effects and resistance to chemotherapeutic drugs have encouraged scientists to develop new methods of drug combinations with fewer complications. This study aimed to investigate the synergistic effects of quercetin and imatinib encapsulated in chitosan nanoparticles on cytotoxicity, apoptosis, and cell growth of the K562 cell line.
Materials and Methods: Imatinib and quercetin were encapsulated in chitosan nanoparticles and their physical properties were determined using standard methods and SEM microscope images. BCR-ABL positive K562 cells were cultured in a cell culture medium, cytotoxicity of drugs was determined by MTT assay and the effects of nano drugs on apoptosis in cells were investigated by Annexin V-FITC staining. The expression level of genes associated with apoptosis in cells was measured by real-time PCR. 
Results: The IC50 for the combination of the nano drugs at 24 and 48 hr was 9.324 and 10.86 μg/ml, respectively. The data indicated that the encapsulated form of drugs induced apoptosis more effectively than the free form (P<0.05). Moreover, the synergistic effect of nano drugs in statistical analysis was proved (P=0.001). The combination of nano drugs resulted in the caspase 3, 8, and TP53 genes upregulation (P=0.001).
Conclusion: The results of the present study showed that the encapsulated form of imatinib and quercetin nano drugs with chitosan has more cytotoxicity than the free form of the drugs. In addition, the combination of imatinib and quercetin as a nano-drug complex has a synergistic effect on the induction of apoptosis in imatinib-resistant K562 cells.

Keywords

References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022; 72:7-33.
2. Fernandes A, Shanmuganathan N, Branford S. Genomic mechanisms influencing outcome in chronic myeloid leukemia. Cancers (Basel) 2022; 14:620.-624
3. Sumi K, Tago K, Nakazawa Y, Takahashi K, Ohe T, Mashino T, et al. Novel mechanism by a bis-pyridinium fullerene derivative to induce apoptosis by enhancing the MEK-ERK pathway in a reactive oxygen species-independent manner in BCR-ABL-positive chronic myeloid leukemia-derived K562 cells. Int J Mol Sci 2022; 23:749-753.
4. Sampaio MM, Santos MLC, Marques HS, Goncalves VLS, Araujo GRL, Lopes LW, et al. Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review. World J Clin Oncol 2021; 12:69-94.
5. Amarante-Mendes GP, Rana A, Datoguia TS, Hamerschlak N, Brumatti G. BCR-ABL1 tyrosine kinase complex signaling transduction: challenges to overcome resistance in chronic myeloid leukemia. Pharmaceutics 2022; 14:215-219.
6. Kayabasi C, Caner A, Yilmaz Susluer S, Balci Okcanoglu T, Ozmen Yelken B, Asik A, et al. Comparative expression analysis of dasatinib and ponatinib-regulated lncRNAs in chronic myeloid leukemia and their network analysis. Med Oncol 2022; 39:1-13.
7. De Santis S, Monaldi C, Mancini M, Bruno S, Cavo M, Soverini S. Overcoming resistance to kinase inhibitors: the paradigm of chronic myeloid leukemia. Onco Targets Ther 2022; 15:103-116.
8. Chandrasekhar C, Kumar PS, Sarma P. Novel mutations in the kinase domain of BCR-ABL gene causing imatinib resistance in chronic myeloid leukemia patients. Sci Rep 2019; 9:2412-2417.
9. Jang B, Kwon H, Katila P, Lee SJ, Lee H. Dual delivery of biological therapeutics for multimodal and synergistic cancer therapies. Adv Drug Deliv Rev 2016; 98:113-133.
10. Wang S, Liu X, Wang S, Ouyang L, Li H, Ding J, et al. Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia. J Control Release 2021; 338:190-200.
11. Oaxaca DM, Yang-Reid SA, Ross JA, Rodriguez G, Staniswalis JG, Kirken RA. Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment. Tumour Biol 2016; 37:12643-12654.
12. Wei Y, To KK, Au-Yeung SC. Synergistic cytotoxicity from combination of imatinib and platinum-based anticancer drugs specifically in Bcr-Abl positive leukemia cells. J Pharmacol Sci 2015; 129:210-215.
13. Zhou W, Zhu W, Ma L, Xiao F, Qian W. Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein. Oncol Lett 2015; 10:2899-2904.
14. La Rosee P, O’Dwyer M, Druker B. Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. Leukemia 2002; 16:1213-1219.
15. Dharmapuri G, Doneti R, Philip GH, Kalle AM. Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways. Leuk Res 2015; 39:696-701.
16. Jin Y, Yao Y, Chen L, Zhu X, Jin B, Shen Y, et al. Depletion of γ-catenin by histone deacetylase inhibition confers elimination of CML stem cells in combination with imatinib. Theranostics 2016; 6:1947-1952.
17. Tang SM, Deng XT, Zhou J, Li QP, Ge XX, Miao L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed Pharmacother 2020; 121:109604-109609.
18. Reyes-Farias M, Carrasco-Pozo C. The anti-cancer effect of quercetin: molecular implications in cancer metabolism. Int J Mol Sci 2019; 20:3177-3180.
19. Vafadar A, Shabaninejad Z, Movahedpour A, Fallahi F, Taghavipour M, Ghasemi Y, et al. Quercetin and cancer: new insights into its therapeutic effects on ovarian cancer cells. Cell Biosci 2020; 10:1-17.
20. Hashemzaei M, Delarami Far A, Yari A, Heravi RE, Tabrizian K, Taghdisi SM, et al. Anticancer and apoptosis‑inducing effects of quercetin in vitro and in vivo. Oncol Rep 2017; 38:819-828.
21. Ren KW, Li YH, Wu G, Ren JZ, Lu HB, Li ZM, et al. Quercetin nanoparticles display antitumor activity via proliferation inhibition and apoptosis induction in liver cancer cells. Int J Oncol 2017; 50:1299-1311.
22. Srivastava NS, Srivastava RAK. Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/beta-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine 2019; 52:117-128.
23. Rahaiee S, Assadpour E, Faridi Esfanjani A, Silva AS, Jafari SM. Application of nano/microencapsulated phenolic compounds against cancer. Adv Colloid Interface Sci 2020; 279:102153-102156.
24. Barakat H. Amygdalin as a plant-based bioactive constituent: a mini-review on intervention with gut microbiota, anticancer mechanisms, bioavailability, and microencapsulation. Proceedings 2020; 61:15-19.
25. Avramovic N, Mandic B, Savic-Radojevic A, Simic T. Polymeric nanocarriers of drug delivery systems in cancer therapy. Pharmaceutics 2020; 12:298-304.
26. Shakeran Z, Keyhanfar M, Varshosaz J, Sutherland DS. Biodegradable nanocarriers based on chitosan-modified mesoporous silica nanoparticles for delivery of methotrexate for application in breast cancer treatment. Mater Sci Eng C Mater Biol Appl 2021; 118:111526-111530.
27. Hu Q, Luo Y. Chitosan-based nanocarriers for encapsulation and delivery of curcumin: A review. Int J Biol Macromol 2021; 179:125-135.
28. Agarwal M, Agarwal MK, Shrivastav N, Pandey S, Das R, Gaur P. Preparation of chitosan nanoparticles and their in-vitro characterization. Int J Life Sci Scienti Res 2018; 4:1713-1720.
29. Yang L, Li D, Tang P, Zuo Y. Curcumin increases the sensitivity of K562/DOX cells to doxorubicin by targeting S100 calcium-binding protein A8 and P-glycoprotein. Oncol Lett 2020; 19:83-92.
30. Mitupatum T, Aree K, Kittisenachai S, Roytrakul S, Puthong S, Kangsadalampai S, et al. mRNA expression of Bax, Bcl-2, p53, Cathepsin B, Caspase-3 and Caspase-9 in the HepG2 cell line following induction by a novel monoclonal Ab Hep88 mAb: cross-talk for paraptosis and apoptosis. Asian Pac J Cancer Prev 2016; 17:703-712.
31. Zhou H, Zhou M, Hu Y, Limpanon Y, Ma Y, Huang P, et al. TNF-alpha triggers RIP1/FADD/Caspase-8-mediated apoptosis of astrocytes and RIP3/MLKL-mediated necroptosis of neurons induced by Angiostrongylus cantonensis infection. Cell Mol Neurobiol 2022; 42:1841-1857.
32. Oien DB, Pathoulas CL, Ray U, Thirusangu P, Kalogera E, Shridhar V. Repurposing quinacrine for treatment-refractory cancer. Semin Cancer Biol 2021; 68:21-30.
33. Du W, Huang H, Sorrelle N, Brekken RA. Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight 2018; 3-11.
34. Marslin G, Revina AM, Khandelwal VKM, Balakumar K, Prakash J, Franklin G, et al. Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity. Int J Nanomedicine 2015; 10:3163-3168.
35. Khakrizi E, BikhofTorbati M, Shaabanzadeh M. The study of anticancer effect of magnetic chitosan-hydroxyurea nanodrug on HeLa cell line: a laboratory study. JRUMS 2018; 17:715-730.
36. Feng C, Wang Z, Jiang C, Kong M, Zhou X, Li Y, et al. Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: in vitro and in vivo evaluation. Int J Pharm 2013; 457:158-167.
37. Hou Z, Zhan C, Jiang Q, Hu Q, Li L, Chang D, et al. Both FA-and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution. Nanoscale Res Lett 2011; 6:1-11.
38. Cao X, Chen C, Yu H, Wang P. Horseradish peroxidase-encapsulated chitosan nanoparticles for enzyme-prodrug cancer therapy. Biotechnol Lett 2015; 37:81-88.
39. Ragelle H, Riva R, Vandermeulen G, Naeye B, Pourcelle V, Le Duff CS, et al. Chitosan nanoparticles for siRNA delivery: optimizing formulation to increase stability and efficiency. J Control Release 2014; 176:54-63.
40. Shokrzadeh M, Ebrahimnejad P, Omidi M, Shadboorestan A, Zaalzar Z. Cytotoxity evaluation of docetaxel nanoparticles by culturing HepG2 carcinoma cell lines. J Mazandaran Univ Med Sci 2012; 22:2-10.
41. Zhang R, Li Y, Zhou M, Wang C, Feng P, Miao W, et al. Photodynamic chitosan nano-assembly as a potent alternative candidate for combating antibiotic-resistant bacteria. ACS Appl Mater Interfaces 2019; 11:26711-26721.
42. Sang M, Han L, Luo R, Qu W, Zheng F, Zhang K, et al. CD44 targeted redox-triggered self-assembly with magnetic enhanced EPR effects for effective amplification of gambogic acid to treat triple-negative breast cancer. Biomater Sci 2020; 8:212-223.
43. Badran MM, Alomrani AH, Harisa GI, Ashour AE, Kumar A, Yassin AE. Novel docetaxel chitosan-coated PLGA/PCL nanoparticles with magnified cytotoxicity and bioavailability. Biomed Pharmacother 2018; 106:1461-1468.
44. Alomrani A, Badran M, Harisa GI, ALshehry M, Alhariri M, Alshamsan A, et al. The use of chitosan-coated flexible liposomes as a remarkable carrier to enhance the antitumor efficacy of 5-fluorouracil against colorectal cancer. Saudi Pharm J 2019; 27:603-611.
45. Lu H-Y, Chen J, SH D, Jia P-M, Tong J-H, Wu Y-L, et al. Effects of quercetin on chronic myeloid leukemia cell line resistant to imatinib and its mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2017; 25:346-352.
46. Li W, Zhao Y, Qiu L, Ma J. [Effect of quercetin on wnt/beta-catenin signal pathway of K562 and K562R cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2019; 27:1409-1415.
47. Hassanzadeh A, Hosseinzadeh E, Rezapour S, Vahedi G, Haghnavaz N, Marofi F. Quercetin promotes cell cycle arrest and apoptosis and attenuates the proliferation of human chronic myeloid leukemia cell line-K562 through interaction with HSPs (70 and 90), MAT2A and FOXM1. Anticancer Agents Med Chem 2019; 19:1523-1534.
 
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 3
March 2023
Pages 359-366

Files

Share

How to cite

Statistics