ABSTRACT
PURPOSE: Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC. METHODS: The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival. RESULTS: Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase. CONCLUSIONS: The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms, Experimental/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Phosphorylcholine/analogs & derivatives , Proto-Oncogene Proteins p21(ras)/genetics , RNA, Small Interfering/genetics , Tumor Suppressor Protein p53/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Carcinoma, Hepatocellular/blood supply , Carcinoma, Hepatocellular/pathology , Caspase 3/metabolism , Caspase 9/metabolism , Cell Proliferation/drug effects , DNA Transposable Elements , Drug Synergism , Liver Neoplasms, Experimental/blood supply , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neovascularization, Pathologic/drug therapy , Niacinamide/therapeutic use , Phosphorylcholine/therapeutic use , Poly(ADP-ribose) Polymerases/metabolism , SorafenibABSTRACT
Histamine is mainly produced by microorganisms that are found in fermented foods, and is frequently involved in food poisoning. Two histamine-producing bacteria were isolated from fermented fish products, anchovy sauce, and sand lance sauce by using a histidine decarboxylating medium. The species were identified as Bacillus licheniformis A7 and B. coagulans SL5. Multiplex PCR analysis showed the presence of the conserved histidine decarboxylase (hdc) gene in the chromosome of these bacteria. B. licheniformis A7 and B. coagulans SL5 produced the maximum amount of histamine (22.3±3.5 and 15.1±1.5 mg/L, respectively). As such, they were determined to be potential histamine-producing bacteria among the tested cultures.
Subject(s)
Bacillus/isolation & purification , Bacillus/metabolism , Fish Products/microbiology , Histamine/biosynthesis , Animals , Bacillus/classification , Bacillus/genetics , Fermentation , Fishes , Molecular Sequence Data , PhylogenyABSTRACT
Biogenic amines (BAs) are produced primarily by microorganisms found in fermented foods and are often implicated in food poisoning. BA-producing bacteria found in fermented soybean pastes were isolated and characterized using a decarboxylating medium and multiplex PCR analysis. Two BA-producing bacteria were isolated from traditional soybean pastes: one was a histamine-producing Clostridium strain, and the other was a tyramine-producing Pseudomonas strain. The Clostridium strain was determined to be a potent histamine producer among the cultures tested. Synthesis of tyramine by Pseudomonas sp. T1 was observed for the first time in this study.
