title: Triptolide induces apoptosis in human leukemia cells through caspase-3-mediated ROCK1 activation and MLC phosphorylation.
abstract: The diterpene triepoxide triptolide is a major active component of Tripterygium wilfordii Hook F, a popular Chinese herbal medicine with the potential to treat hematologic malignancies. In this study, we investigated the roles of triptolide in apoptosis and cell signaling events in human leukemia cell lines and primary human leukemia blasts. Triptolide selectively induced caspase-dependent cell death that was accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. Furthermore, we found that triptolide dramatically induced ROCK1 cleavage/activation and MLC and MYPT phosphorylation. ROCK1 was cleaved and activated by caspase-3, rather than RhoA. Inhibiting MLC phosphorylation by ML-7 significantly attenuated triptolide-mediated apoptosis, caspase activation, and cytochrome c release. In addition, ROCK1 inhibition also abrogated MLC and MYPT phosphorylation. Our in vivo study showed that both ROCK1 activation and MLC phosphorylation were associated with the tumor growth inhibition caused by triptolide in mouse leukemia xenograft models. Collectively, these findings suggest that triptolide-mediated ROCK1 activation and MLC phosphorylation may be a novel therapeutic strategy for treating hematological malignancies.
authors: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors: L
authors: L
authors: Liu
authors: G
authors: G
authors: Li
authors: Q
authors: Q
authors: Li
authors: Z
authors: Z
authors: Jin
authors: L
authors: L
authors: Zhang
authors: J
authors: J
authors: Zhou
authors: X
authors: X
authors: Hu
authors: T
authors: T
authors: Zhou
authors: J
authors: J
authors: Chen
authors: N
authors: N
authors: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D007938:Leukemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein