title: Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors.
abstract: Leukemia stem cells (LSCs) are considered to be the main reason for relapse and are also regarded as a major hurdle for the success of acute myeloid leukemia chemotherapy. Thus, new drugs targeting LSCs are urgently needed. Triptolide (TPL) is cytotoxic to LSCs. Low dose of TPL enhances the cytotoxicity of idarubicin (IDA) in LSCs. In this study, the ability of TPL to induce apoptosis in leukemic stem cell (LSC)-like cells derived from acute myeloid leukemia cell line KG1a was investigated. LSC-like cells sorted from KG1a were subjected to cell cycle analysis and different treatments, and then followed by in vitro methyl thiazole tetrazolium bromide cytotoxicity assay. The effects of different drug combinations on cell viability, intracellular reactive-oxygen species (ROS) activity, colony-forming ability and apoptotic status were also examined. Combination index-isobologram analysis indicates a synergistic effect between TPL and IDA, which inhibits the colony-forming ability of LSC-like cells and induces their apoptosis. We further investigated the expression of Nrf2, HIF-1α and their downstream target genes. LSC-like cells treated with both TPL and IDA have increased levels of ROS, decreased expression of Nrf2 and HIF-1α pathways. Our findings indicate that the synergistic cytotoxicity of TPL and IDA in LSCs-like cells may attribute to both induction of ROS and inhibition of the Nrf2 and HIF-1α pathways.
authors: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors: Y
authors: Y
authors: Liu
authors: F
authors: F
authors: Chen
authors: S
authors: S
authors: Wang
authors: X
authors: X
authors: Guo
authors: P
authors: P
authors: Shi
authors: W
authors: W
authors: Wang
authors: B
authors: B
authors: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C001899:triptolide; D015255:Idarubicin