ABSTRACT
PURPOSE: Angiogenin (ANG) undergoes nuclear translocation and stimulates rRNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG. EXPERIMENTAL DESIGN: The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression. RESULTS: Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of ANG and inhibits rRNA transcription, cell proliferation, and angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in murine prostate-restricted AKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis and an increase in prostate epithelial cell apoptosis. CONCLUSION: We confirmed that ANG is a molecular target for cancer drug development and that blocking nuclear translocation of ANG is an effective means to inhibit its activity. Our results also suggested that neamine is a lead compound for further preclinical evaluation.
Subject(s)
Antineoplastic Agents/pharmacology , Framycetin/pharmacology , Prostatic Neoplasms/drug therapy , RNA, Ribosomal/genetics , Ribonuclease, Pancreatic/antagonists & inhibitors , Transcription, Genetic/drug effects , Angiogenesis Inhibitors/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Mice , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-akt/physiology , Ribonuclease, Pancreatic/physiology , Xenograft Model Antitumor AssaysABSTRACT
PURPOSE: We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity. EXPERIMENTAL DESIGN: The effect of neamine on the nuclear translocation of angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models. RESULTS: Neamine effectively blocked the nuclear translocation of angiogenin in endothelial cells and inhibited angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine. CONCLUSION: These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of angiogenin and may serve as an inhibitor for angiogenin-induced angiogenesis and cancer progression.
Subject(s)
Aminoglycosides/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Cell Nucleus/metabolism , Framycetin/therapeutic use , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Ribonuclease, Pancreatic/metabolism , Active Transport, Cell Nucleus/drug effects , Animals , Cell Nucleus/drug effects , Cell Proliferation/drug effects , Endothelial Cells/drug effects , Humans , Mice , Mice, Nude , Neoplasms/blood supply , Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , Umbilical Veins/cytology , Xenograft Model Antitumor AssaysABSTRACT
Angiogenin is an angiogenic protein known to play a role in rRNA transcription in endothelial cells. Nuclear translocation of angiogenin in endothelial cells decreases as cell density increases and ceases when cells are confluent. Here we report that angiogenin is constantly translocated to the nucleus of HeLa cells in a cell density-independent manner. Down-regulation of angiogenin expression by antisense and RNA interference results in a decrease in rRNA transcription, ribosome biogenesis, proliferation, and tumorigenesis both in vitro and in vivo. Exogenous angiogenin rescues the cells from antisense and RNA interference inhibition. The results showed that angiogenin is constitutively translocated into the nucleus of HeLa cells where it stimulates rRNA transcription. Thus, besides its angiogenic activity, angiogenin also plays a role in cancer cell proliferation.
