title: Aminoimidazole carboxamide ribonucleotide (AICAR) inhibits the growth of retinoblastoma in vivo by decreasing angiogenesis and inducing apoptosis.
abstract: 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. Recently, we showed that AICAR-induced AMPK activation inhibits the growth of retinoblastoma cells in vitro by decreasing cyclins and by inducing apoptosis and S-phase arrest. In this study, we investigated the effects of AMPK activator AICAR on the growth of retinoblastoma in vivo. Intraperitoneal injection of AICAR resulted in 48% growth inhibition of Y79 retinoblastoma cell tumors in mice. Tumors isolated from mice treated with AICAR had decreased expression of Ki67 and increased apoptotic cells (TUNEL positive) compared with the control. In addition, AICAR treatment suppressed significantly tumor vessel density and macrophage infiltration. We also showed that AICAR administration resulted in AMPK activation and mTOR pathway inhibition. Paradoxically observed down-regulation of p21, which indicates that p21 may have a novel function of an oncogene in retinoblastoma tumor. Our results indicate that AICAR treatment inhibited the growth of retinoblastoma tumor in vivo via AMPK/mTORC1 pathway and by apoptogenic, anti-proliferative, anti-angiogenesis mechanism. AICAR is a promising novel non-chemotherapeutic drug that may be effective as an adjuvant in treating Retinoblastoma.
authors.affiliation: Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Retina Service, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sofia
authors.initials: S
authors.lastname: Theodoropoulou
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Brodowska
authors.forename: Maki
authors.initials: M
authors.lastname: Kayama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Morizane
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.forename: Evangelos S
authors.initials: ES
authors.lastname: Gragoudas
authors.forename: Demetrios G
authors.initials: DG
authors.lastname: Vavvas
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016213:Cyclins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D012175:Retinoblastoma / Q000188:drug therapy*; D012265:Ribonucleotides / Q000378:metabolism / Q000494:pharmacology*; D016196:S Phase
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide