Lu Jin-Jian, Meng Ling-Hua, Cai Yu-Jun, Chen Qin, Tong Lin-Jiang, Lin Li-Ping, Ding Jian
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China.
Cancer Biol Ther. 2008 Jul;7(7):1017-23. doi: 10.4161/cbt.7.7.6035. Epub 2008 Apr 4.
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.
双氢青蒿素（DHA）是青蒿素衍生物的主要活性代谢产物，是青蒿素最有效的抗疟类似物之一。在本研究中，我们发现DHA抑制了一组源自不同组织类型的肿瘤细胞的增殖。DHA有效诱导人早幼粒细胞白血病HL-60细胞凋亡，这伴随着线粒体功能障碍和半胱天冬酶激活。进一步研究表明，DHA诱导的凋亡是铁依赖性的。尽管DHA轻微引发超氧阴离子，但这些活性氧（ROS）对DHA诱导的HL-60细胞凋亡贡献不大。此外，DHA时间依赖性地激活丝裂原活化蛋白激酶（MAPKs），特异性抑制p38 MAPK而非c-Jun氨基末端激酶（JNK）或细胞外信号调节激酶（ERK）可消除DHA诱导的凋亡，表明p38 MAPK的激活是DHA诱导HL-60细胞凋亡所必需的。总之，我们的数据揭示了DHA诱导HL-60细胞凋亡依赖于铁和p38 MAPK激活而非ROS。
