Exploring the ATR-CHK1 pathway in the response of doxorubicin-induced DNA damages in acute lymphoblastic leukemia cells

Abstract Doxorubicin (Dox) is one of the most commonly used anthracyclines for treatment solid and hematological tumors such as B?/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication causes direct intercalating into double helix. Eukaryotic cells respond to by activating ATM-CHK2 and/or ATR-CHK1 pathway, whose function regulate cycle progression, promote damage repair, control apoptosis. We evaluated efficacy a new drug schedule combining specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in human precursor ALL lines primary leukemic cells. found that G2/M checkpoint. Exposure Dox-pretreated VE-821 PX enhanced cytotoxic effect. This phenomenon was associated with abrogation checkpoint changes expression pCDK1 cyclin B1, entry mitosis, followed induction Indeed, inhibition led significant increment normal aberrant mitotic cells, including those showing tripolar spindles, metaphases lagging chromosomes, massive chromosomes fragmentation. In conclusion, we pathway involved response Dox-induced demonstrated our vitro combines ATR/CHK1 can increase cytotoxicity against while using lower doses. Graphical abstract • activates (ALL) doxorubicin-induced pathway. The synergizes doxorubicin induces chromosome segregation spindle defects doxorubicin-pretreated