Triptolide induces apoptotic cell death of multiple myeloma cells via transcriptional repression of Mcl-1.
Triptolide, a diterpenoid trioxide purified from the Chinese herb Tripterygium wilfordii Hook F, has been used as a natural medicine in China for hundreds of years. Several reports have demonstrated that triptolide inhibits the proliferation of cancer cells in vitro and reduces the growth of several types of tumors in vivo. To address the potential of triptolide as a novel therapeutic agent for patients with multiple myeloma, we investigated the effects of triptolide on the induction of apoptosis in human multiple myeloma cells in vitro. Triptolide rapidly induces apoptotic cell death in various myeloma cell lines. Triptolide-induced apoptosis in myeloma cells is associated with the loss of mitochondrial transmembrane potential (∆ψm), the release of cytochrome c and Smac/DIABLO from mitochondria into the cytosol, and the activation of caspase-3 and caspase-9. Furthermore, triptolide induces a rapid decline in the levels of Mcl-1 protein that correlates with caspase activation and induction of apoptosis. Inhibition of Mcl-1 synthesis by triptolide occurs at the level of mRNA transcription and is associated with an inhibition of phosphorylation of RNA polymerase II CTD. These results indicate that Mcl-1 is an important target for triptolide-induced apoptosis in myeloma cells that occurs via inhibition of Mcl-1 mRNA transcription coupled with rapid protein degradation through the ubiquitin-proteasome pathway.
Department of Hematology, Yokohama Municipal Citizen's Hospital, Kanagawa 240-8550, Japan.
Tomonori
T
Nakazato
Division of Hematology, Keio University School of Medicine, Tokyo 160-0001, Japan.
Morihiko
M
Sagawa
Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan.
Masahiro
M
Kizaki
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008516:Medicine, Chinese Traditional; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics*; D010616:Phenanthrenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D004224:Diterpenes; D004852:Epoxy Compounds; D047908:Intracellular Signaling Peptides and Proteins; C579095:MCL1 protein, human; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010616:Phenanthrenes; C001899:triptolide; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9