(HEPATOLOGY 2011;.) Hepatocellular carcinoma (also called malignant hepatoma) is one of the most common malignant tumors and the third leading cause of cancer mortality worldwide.1 Despite many efforts to develop various classes of agents, systemic chemotherapy and hormone therapy have failed to significantly increase the survival of patients with advanced hepatoma. However, recent advances in the understanding of hepatoma progression have led to the development of novel molecularly targeted therapies.2 Because angiogenesis is pivotal for the development and progression of hepatoma,

key molecules AZD2014 solubility dmso regulating angiogenesis are regarded as promising targets for treating hepatoma.3 Hypoxia inevitably develops in rapidly growing tumors and is an important microenvironment that forces changes in tumor behavior. In particular, hypoxia activates hypoxia-inducible factor-1α (HIF-1α), which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive.4, 5 The roles of

HIF-1α have been extensively investigated in cancer patients and in tumor-bearing mice.6, 7 Consequently, HIF-1α is believed to be a valid target for the treatment of aggressive tumors, and many efforts have been made to identify suitable HIF-1α inhibitors.8 Chaetocin, which is produced by Chaetomium sp., is an antibiotic having the thiodioxopiperazine structure (a disulfide-bridged see more piperazine).9 Other thiodioxopiperazines are known to have antimicrobial, antiviral, immunosuppressive, and antiinflammatory activities,10, 11 but the biological activity of chaetocin has been reported in relatively few reports. In one such report, it was suggested that chaetocin inhibits the histone methyltransferase suv39H1.12 Recently, it was also demonstrated that chaetocin induces apoptosis of myeloma cells and retards the growth of myeloma xenografts.13 Mechanistically, it was

proposed that chaetocin produces oxidative damage in myeloma cells by inhibiting the antioxidant enzyme thioredoxin reductase.14 However, little is known about the effects of chaetocin on solid tumors, and thus we tested the anticancer activity of chaetocin against solid tumors. Here we demonstrated that chaetocin has click here antiangiogenic and anticancer activities in hepatoma and fibrosarcoma grafts, and that these actions of chaetocin are due to HIF-1α down-regulation caused by the deregulation of HIF-1α premessenger RNA (pre-mRNA) splicing. ATP, adenosine triphosphate; CA9, carbonic anhydrase 9; EPO, erythropoietin; HIF, hypoxia-inducible factor; MEF, mouse embryonic fibroblast; PDK1, pyruvate dehydrogenase kinase 1; PHD, prolyl-hydroxylase domain protein; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau.