生物活性

• 描述The proteasome is a catalytic enzyme complex responsible for the degradation of intracellular proteins. Bortezomib is a dipeptide boronate that potently inhibits proteasome with a Ki value of 0.6 nM. After 48-hour incubation, bortezomib at 0.1 μM completed inhibited the growth of different human multiple myeloma (MM) cell lines, including U266, IM-9 and Hs Sultan cells. In U266 and patient primary MM cells, the treatment of 0.01 μM bortezomib induced a progressive increase of sub-G₀/G₁ phase cells in a time-dependent manner from 0 – 16h. Apoptosis as indicated by DNA fragmentation was also promoted by bortezomib treatment. H460 cells treated by 0.01 – 10 μM bortezomib for 24 hours showed increased cell accumulation at G₂-M phase and cell apoptosis in a dose-dependent manner compared to control cells. Bortezomib treatment also led to concentration-dependent phosphorylation of Bcl-2 proteins. When cells were exposed to higher doses of bortezomib (0.1 – 10 μM) for 24 hours, the superphosphorylated form of Bcl-2 was detected. After the exposure to 0.01 – 0.05 μM bortezomib for 24 hours, or 0.1 μM bortezomib for 12 hours, the first cleavage fragment of Bcl-2 protein was detected. The second cleave fragment of Bcl-2 was only found in cells treated with 0.1 μM bortezomib for 12 hours. After incubating with 0.1 μM bortezomib for 24 hours, the phosphorylated Bcl-2 bands were observed in both Triton-X-100 soluble and insoluble fraction. In vivo study showed that 3 times per week injection of 2 mg/kg bortezomib for 25 days inhibited the growth of murine and human squamous cell carcinoma in mice.
• 作用机制Bortezomib inhibits proteasome by reversibly binding to the chymotrypsin-like subunit of the proteasome.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  697	-	Growth Inhibition Assay	-	IC50=1.99 nM	SANGER
  8-MG-BA	-	Growth Inhibition Assay	-	IC50=0.25 nM	SANGER
  A101D	-	Growth Inhibition Assay	-	IC50=0.225 nM	SANGER

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• 动物研究
  剂量	Mice: 0.25 mg/kg - 1 mg/kg[6] (i.v.), 1 mg/kg[7] (i.p.) Rat: 0.1 mg/kg, 0.2 mg/kg[8] (i.p.)
  给药途径	i.v., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00571493	Non-hodgkin's Lymphoma ... more >> Mantle Cell Lymphoma Collapse <<	Phase 1 Phase 2	Completed	-	United States, Nebraska ... more >> University of Nebraska Medical Center, Section of Oncology/Hematology Omaha, Nebraska, United States, 68198-7680 Collapse <<
  NCT00580320	Melanoma Soft... more >> Tissue Sarcoma Parathyroid Carcinoma Small Cell Carcinoma of the Lung Carcinoid Tumors Collapse <<	Phase 1	Completed	-	United States, New Hampshire ... more >> Dartmouth Hitchcock Medical Center Lebanon, New Hampshire, United States, 03756 United States, Virginia Massey Cancer Center/Virginia Commonwealth University Richmond, Virginia, United States, 23298 Collapse <<
  NCT02808091	Extranodal NK-T-CELL LYMPHOMA	Phase 2	Terminated(Slow recruitment)	-	Singapore ... more >> National Cancer Centre Singapore, Singapore, 169610 Collapse <<

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• 参考文献

• [1] Ludwig H, Khayat D, et al. Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. Cancer. 2005;104(9):1794-807.

  [2] Hideshima T, Richardson P, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61(7):3071-6.

  [3] Ling YH, Liebes L, et al. PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther. 2002;1(10):841-9.

  [4] Sunwoo JB, Chen Z, et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res. 2001;7(5):1419-28.

  [5] Accardi F, Toscani D, et al. Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling. Biomed Res Int. 2015.

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