Abstract
Acute myeloid leukemia (AML) is one of the most common forms of leukemia. Despite advances in the management of such malignancies and the progress of novel therapies, unmet medical needs still exist in AML because of several factors, including poor response to chemotherapy and high relapse rates. Ardisianone, a plant-derived natural component with an alkyl benzoquinone structure, induced apoptosis in leukemic HL-60 cells. The determination of dozens of apoptosis-related proteins showed that ardisianone upregulated death receptors and downregulated the inhibitor of apoptosis protein (IAPs). Western blotting showed that ardisianone induced a dramatic increase in tumor necrosis factor receptor 2 (TNFR2) protein expression. Ardisianone also induced downstream signaling by activating caspase-8 and -3 and degradation in Bid, a caspase-8 substrate. Furthermore, ardisianone induced degradation in DNA fragmentation factor 45 kDa (DFF45), a subunit of inhibitors of caspase-activated DNase (ICAD). Q-VD-OPh (a broad-spectrum caspase inhibitor) significantly diminished ardisianone-induced apoptosis, confirming the involvement of caspase-dependent apoptosis. Moreover, ardisianone induced pyroptosis. Using transmission electron microscopic examination and Western blot analysis, key markers including gasdermin D, high mobility group box1 (HMGB1), and caspase-1 and -5 were detected. Notably, ardisianone induced the differentiation of the remaining survival cells, which were characterized by an increase in the expression of CD11b and CD68, two markers of macrophages and monocytes. Wright–Giemsa staining also showed the differentiation of cells into monocyte and macrophage morphology. In conclusion, the data suggested that ardisianone induced the apoptosis and pyroptosis of leukemic cells through downregulation of IAPs and activation of caspase pathways that caused gasdermin D cleavage and DNA double-stranded breaks and ultimately led to programmed cell death. Ardisianone also induced the differentiation of leukemic cells into monocyte-like and macrophage-like cells. The data suggested the potential of ardisianone for further antileukemic development.
Highlights
We evaluate the antileukemic effect and underlying mechanisms of ardisianone on HL-60, a cell model of acute promyelocytic leukemia (APL), a type of Acute myeloid leukemia (AML)
Annexin V/propidium iodine (PI) staining was subsequently used to examine cell death; it showed that ardisianone induced a timeand concentration-dependent increase in cell necrosis and apoptosis (Figure 1A)
An ardisianone-mediated cytotoxic effect was substantiated by using flow cytometric analysis of PI staining, showing that ardisianone induced a concentration-dependent increase in the sub-G1 population (Figure 1B)
Summary
Leukemia is one group of hematological malignancies originating in the blood and bone marrow. Many types of leukemia exist and occur when considerable abnormal white blood cells are generated to interfere with the normal function of bone marrow and blood cells. Symptoms of leukemia are diverse and may include bleeding and bruising, fever, persistent fatigue and weakness, weight loss, and severe infections. Some leukemic conditions are potentially life-threatening and need urgent and intensive treatment. The treatment of leukemia depends on the disease type and can be complicated
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