Toyocamycin is isolated from a culture broth of an Actinomycete strain. It inhibited ER stress-induced XBP1 activation. Toyocamycin suppressed thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation.
Toyocamycin is an adenosine analogue produced by Streptomyces diastatochromogenes and can be used as an XBP1 inhibitor.Toyocamycin blocks RNA synthesis and ribosomal function and induces apoptosis.Toyocamycin affects the IRE1α-XBP1 pathway and inhibits XBP1 mRNA. Toyocamycin affects the IRE1α-XBP1 pathway and inhibits the cleavage of XBP1 mRNA with an IC50 value of 80 nM, and also affects the autophosphorylation of IRE1α. Toyocamycin specifically inhibits CDK9 with an IC50 value of 79 nM[1][2][3] .Toyocamycin (0-0.3 μM; 4 h) inhibits ER stress-induced XBP1 mRNA splicing and selectively inhibits ER stress-induced activation of the IRE1α-XBP1 pathway[1][2][3].Toyocamycin inhibits the constitutive activation of XBP1 in MM cell lines at concentrations of 0-0.3 μM for 24 h[1] .Toyocamycin inhibited the enzymatic activity of CDK9 in colon cancer cell lines at a concentration of 250 nM for 48 hours. In contrast, at concentrations ranging from 0.05 nM to 50 μM for 48 and 72 hours, Toyocamycin did not cause immediate cytotoxicity in YB5 and HCT116 cells with cell viability greater than 50%, but resulted in eradication of the cancer cells after 2 weeks following a 10 nM treatment for 24 hours[2] .Toyocamycin induces apoptosis in PC-3 cells via the mitochondrial pathway at concentrations ranging from 0-100 nM for 24 or 48 hours[3] .At 60 nM for 0-48 h, Toyocamycin promotes p38/ERK MAPK activation and regulates ROS-mediated apoptosis by inhibiting p38 on ERK MAPK[3] .
Toyocamycin 动物研究
Animal study
Administered intravenously at doses of 0.5 mg/kg and 1.0 mg/kg twice weekly for 2 weeks, Toyocamycin showed antitumour activity in a human multiple myeloma (MM) cell xenograft model, which was potentiated by the combination of Bortezomib[1].
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