Abstract
Homoharringtonine combined with aclarubicin and cytarabine (HAA) is a highly effective treatment for acute myeloid leukemia (AML), especially for t(8;21) AML. However, the underlying mechanisms by which HAA kills t(8;21) AML cells remain unclear. In this study, SKNO‐1 and Kasumi‐1 cells with t(8;21) were used. Compared with individual or pairwise administration of homoharringtonine, aclarubicin, or cytarabine, HAA showed the strongest inhibition of growth and induction of apoptosis in SKNO‐1 and Kasumi‐1 cells. HAA caused cleavage of the AML1‐ETO (AE) oncoprotein to form truncated AE (ΔAE). Pretreatment with the caspase‐3 inhibitor caspase‐3 inhibitor Q‐DEVD‐OPh (QDO) not only suppressed HAA‐induced apoptosis but also abrogated the cleavage of AE and generation of ΔAE. These results suggest that HAA synergistically induces apoptosis in t(8;21) leukemia cells and triggers caspase‐3‐mediated cleavage of the AML1‐ETO oncoprotein, thus providing direct evidence for the strong activity of HAA toward t(8;21) AML.
Highlights
Acute myeloid leukemia (AML) with t(8;21) is considered a favorable cytogenetic subgroup, with a 3-year survival of over 80% according to recent results from our group and others [1,2,3]
Using Calcusyn 2.0, we found that homoharringtonine combined aclarubicin and cytarabine (HAA) (1:2.86:2.5) showed the strongest synergistic effect with combination index (CI) values of (X and Y) for SKNO-1 and Kasumi-1 cells, respectively (Fig. 1B–E and 2B–E)
Homoharringtonine combined with cytarabine and aclarubicin synergistically induced cleavage of the AML1-ETO (AE) oncoprotein in Kasumi-1 and SKNO-1 cells
Summary
Acute myeloid leukemia (AML) with t(8;21) is considered a favorable cytogenetic subgroup, with a 3-year survival of over 80% according to recent results from our group and others [1,2,3]. Homoharringtonine combined aclarubicin and cytarabine (HAA) has been demonstrated to achieve a high complete remission (CR) rate and provide a survival advantage in patients with acute myeloid leukemia (AML) [4, 5]. Our data showed that one cycle of HAA treatment can yield a 93% (28/30) CR rate in de novo t(8;21) AML patients [9]. These results suggest that the HAA regimen is highly effective against t(8;21) AML
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