title: Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species.
abstract: Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is one of the most effective anti-malarial analogs of artemisinin. In the current study, we found that DHA inhibited the proliferation of a panel of tumor cells originated from different tissue types. DHA effectively induced apoptosis in human promyelocytic leukemia HL-60 cells, which was accompanied with mitochondrial dysfunction and caspases activation. Further studies indicated that DHA-induced apoptosis was iron-dependent. Though DHA slightly elicited superoxide anion, these reactive oxygen species (ROS) contribute little to DHA-induced apoptosis in HL-60 cells. Moreover, DHA time-dependently activated mitogen-activeted protein kinases (MAPKs) and specific inhibition of p38 MAPK, but not c-Jun-NH2-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK), abolished DHA-induced apoptosis, indicating that activation of p38 MAPK is required for DHA-induced apoptosis in HL-60 cells. Altogether, our data uncover that DHA induces apoptosis is dependent of iron and p38 MAPK activation but not ROS in HL-60 cells.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.
authors.forename: Jin-Jian
authors.initials: JJ
authors.lastname: Lu
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Meng
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Cai
authors.forename: Qin
authors.initials: Q
authors.lastname: Chen
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D037621:Artemisinins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007501:Iron / Q000378:metabolism*; D020014:K562 Cells; D008564:Membrane Potentials; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C039060:artenimol; D007501:Iron; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue