Wee1 kinase gene silencing by siRNA carried by TAT-CCMD Nanoparticle complex, could eliminate Doxorubicin resistance in Acute lymphoblastic leukemia

Abstract

Coping with drug resistance is a major challenge in the treatment of acute lymphoblastic leukemia (ALL). Activation of DNA damage response pathways (DDR) has been shown to play an important role in the development of this resistance. Wee1 serine/threonine kinase has been shown to be a major stimulant of DDR pathway activation in leukemic cells due to treatment with DNA-based chemotherapeutic drugs such as doxorubicin. Therefore, its rationale to inhibition of Wee1 kinase for decresing drug resistance in acute lymphoblastic leukemia. Materials and Methods: In this study, for the first time, nanoparticles were used as doxorubicin and siRNA transport systems to inhibit Wee1 and overcome drug resistance. Results: Doxorubicin and WEE1 siRNA carried by nanoparticles significantly decreased WEE1 expression and increased DNA damage in the genome, which resulted in elimination of doxorubicin-induced resistance in patient-derived cells and leukemia cell lines. The combination of NPs-WEE1 siRNA-Doxorubicin showed synergistic effects with each other and significantly increased cell death due to activation of apoptotic pathways.