Novel SAHA­bendamustine hybrid NL­101 in combination with daunorubicin synergistically suppresses acute myeloid leukemia.

ABSTRACT

Acute myeloid leukemia (AML) is a highly aggressive disease with high mortality and recurrence rates, for which novel therapeutic approaches are required. Hybrid anticancer agents with dual effects have been reported to possess therapeutic potential to treat AML. However, the efficacy and underlying toxicity of these hybrids in combination with other agents remain unclear. NL­101 is a novel hybrid formed by fusing the DNA damage­inducing agent bendamustine with the histone deacetylase inhibitor vorinostat. In the present study, NL­101 treatment was combined with the conventional chemotherapeutic drug daunorubicin (DNR) in AML cells, and it was revealed that these two compounds exerted synergistic anti­AML effects. In addition, NL­101 enhanced DNR­induced cell apoptosis, as assessed by flow cytometry and as indicated by the upregulation of cleaved­poly (ADP­ribose) polymerase, cleaved­caspase­3, cleaved­caspase­7, BAD and BIM. Mechanistically, the DNA double­strand breaks marker γ­H2AX, and other proteins associated with DNA damage, were investigated, and it was demonstrated that NL­101 in combination with DNR synergistically promoted the DNA damage response. In vivo, this combination significantly delayed the progression of AML and prolonged the survival time in mice. Collectively, the present results suggested that NL­101 in combination with daunorubicin could be an alternative novel therapeutic strategy for treating leukemia.