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Increased Susceptibility to Doxorubicin-Induced Cell Death in Acute Lymphocytic Leukemia Cells by Inhibiting Serine/Threonine Wee1 Kinase Expression Using the Chitosan-Carboxymethyl Dextran-Polyethylene Glycol-Tat Nanoparticles Publisher



Hosseinpour Feizi AA1 ; Vakilisamiani S2 ; Karpisheh V2 ; Masjedi A3, 4 ; Izadi S5 ; Adibfar S6 ; Nikkhoo A2 ; Hojjatfarsangi M7 ; Atyabi F8 ; Joodi Khanghah O9, 10 ; Movassaghpour AA1 ; Solali S2 ; Yousefi M10 ; Jadidiniaragh F2, 11, 12
Authors
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Authors Affiliations
  1. 1. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  2. 2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Institute of Experimental Hematology, School of Medicine, Technical University of Munich, Munich, 81675, Germany
  4. 4. Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, 81675, Germany
  5. 5. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
  6. 6. Department of Immunology, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
  7. 7. Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
  8. 8. Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  10. 10. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  11. 11. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
  12. 12. Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran

Source: Journal of Drug Delivery Science and Technology Published:2022


Abstract

Prevention of drug resistance is a significant challenge in treating Acute Lymphoblastic Leukemia. It has been demonstrated that activating DNA Damage Repair (DDR) pathways play an essential role in resistance mechanisms. WEE1 serine/threonine kinase overexpression is crucial for activating DDR pathways in normal and cancerous cells due to the treatment by DNA-damage-based chemotherapeutic agents such as doxorubicin (Dox). In this study, for the first time, TAT-conjugated polyethylene glycol chitosan Carboxymethyl Dextran (TAT-PEG-CCMD) nanoparticles (NPs) were used to deliver anti-WEE1 siRNA and Dox to ALL cells to inhibit WEE1 kinase overexpression to overcome drug-resistance. The results showed that TAT-PEG-CCMD NPs could efficiently deliver WEE1 kinase siRNA and Dox to ALL cell lines (Jurkat and NALM6) and ALL primary cells (peripheral blood and bone marrow mononuclear cells) isolated from patients with ALL. Transfection of leukemic cells led to silencing WEE1 in target cells. Interestingly, silencing of WEE1 in ALL cell lines and ALL primary cells significantly enhanced the apoptotic effects of Dox. These findings imply that combination therapy of ALL using TAT-PEG-CCMD NPs loaded with anti-WEE1 siRNA and Dox can be considered a novel anti-cancer therapeutic approach that should be further investigated in future studies. © 2022 Elsevier B.V.
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