isobavachalcone and Leukemia--Myeloid--Acute

Isobavachalcone (IBC) has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. Herein, IBC exhibited significant inhibition on the cell viability, proliferation, and the colony formation ability of AML cells. Moreover, IBC induced mitochondrial apoptosis evidenced by reduced mitochondrial membrane potential, increased Bax level, decreased Bcl-2, Bcl-xL, and Mcl-1 levels, elevated cytochrome c level in the cytosol and increased cleavage of caspase-9, caspase-3, and PARP. Furthermore, IBC obviously promoted the differentiation of AML cells, accompanied by the increase of the phosphorylation of MEK and ERK and the C/EBPα expression as well as the C/EBPβ LAP/LIP isoform ratio, which was significantly reversed by U0126, a specific inhibitor of MEK. Notably, IBC enhanced the intracellular ROS level. More importantly, IBC-induced apoptosis and differentiation of HL-60 cells were significantly mitigated by NAC. In addition, IBC also exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Together, our study suggests that the ROS-medicated signaling pathway is highly involved in IBC-induced apoptosis and differentiation of AML cells.

Topics: Animals; Apoptosis; Cell Differentiation; Chalcones; Female; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Membrane Potential, Mitochondrial; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Reactive Oxygen Species

Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Chalcones; Dihydroorotate Dehydrogenase; Disease Models, Animal; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Gene Expression; Gene Knockdown Techniques; Humans; Leukemia, Myeloid, Acute; Mice; Models, Molecular; Molecular Structure; Neoplastic Stem Cells; Oxidoreductases Acting on CH-CH Group Donors; Prognosis; RNA Interference; Structure-Activity Relationship; Xenograft Model Antitumor Assays