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

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.