Wee1 kinase inhibitor MK-1775 induces apoptosis of acute lymphoblastic leukemia cells and enhances the efficacy of doxorubicin involving downregulation of Notch pathway.

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy affecting pediatric and adult populations. Although the outcomes of ALL in children have improved markedly in previous years, limited treatment strategies are available at present for adult patients with ALL. Wee1 is a crucial cell cycle checkpoint kinase of G2/M that regulates cell cycle progression and maintains chromatin integrity. MK-1775, a selective inhibitor of Wee1 has recently been identified to be able to induce apoptosis of tumor cells by abrogating G2/M checkpoint. The present study investigated the anti-leukemic activity of MK-1775 alone and in combination with doxorubicin (Adriamycin®; ADM) in various human ALL cell lines. MK-1775 treatment induced apoptosis of ALL cells, accompanied by unscheduled mitotic entry and downregulation of Notch pathway. The anti-leukemic activity of MK-1775 was in a concentration- and time-dependent manner. The data also indicated that it decreased the half-maximal inhibitory concentration (IC50) of ADM compared with the control group. The combination of MK-1775 and ADM induced an increased apoptotic rate compared with each agent alone. In addition, the human bone marrow stromal cell HS-5 cell line was detected to exhibit an increased IC50 value of MK-1775 treatment in contrast to ALL cell lines. It indicates that the hematopoietic supportive capability may remain intact during the treatment of MK-1775. Taken together, the Wee1 inhibitor MK-1775 may be an attractive agent in the treatment of patients with ALL.