title: Apoptosis induction through proteasome inhibitory activity of cucurbitacin D in human T-cell leukemia.
abstract: BACKGROUND
  Human T-cell leukemia is an aggressive malignancy of T lymphocytes. T-cell leukemia has a very poor prognosis, even with intensive chemotherapy, indicating the need for development of new drugs to treat the disease. Triterpenoid cucurbitacins have been shown to have antitumor activity, but the mechanism of this activity is not fully understood.
  
  
  METHODS
  The effects of cucurbitacin D on the proliferation and apoptotic induction of T-cell leukemia cells using the Cell viability assay and Annexin V staining were evaluated. To investigate the mechanisms of apoptosis, antiapoptotic protein, NF-κB, and the proteasome activity of leukemia cells treated with cucurbitacin D were evaluated by Western blotting both in vitro and in vivo.
  
  
  RESULTS
  In this study, cucurbitacin D was found to inhibit proliferation and to induce apoptosis of T-cell leukemia cells. Constitutively activated NF-κB was inhibited by cucurbitacin D in the nucleus, which resulted in accumulation of NF-κB in the cytoplasm, leading to down-regulation of the expression of antiapoptotic proteins Bcl-xL and Bcl-2. Furthermore, cucurbitacin D induced the accumulation of inhibitor of NF-κB (IκB)α by inhibition of proteasome activity. Low doses of cucurbitacin D synergistically potentiated the antiproliferative effects of the histone deacetylase inhibitor VPA. Finally, the proapoptotic and proteasome inhibitory activities of cucurbitacin D also were demonstrated using SCID mice in an in vivo study.
  
  
  CONCLUSIONS
  Cucurbitacin D induced apoptosis through suppression of proteasome activity both in vitro and in vivo, making cucurbitacin D a promising candidate for clinical applications in the treatment of T-cell leukemia.
authors.affiliation: Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.forename: Uki
authors.initials: U
authors.lastname: Yamashita
authors.forename: Hidetada
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sugiura
authors.forename: Junichi
authors.initials: J
authors.lastname: Tsukada
authors.forename: Junko
authors.initials: J
authors.lastname: Noguchi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D054875:Ubiquitination
chemical_list: D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014315:Triterpenes; C038105:cucurbitacin D