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.

The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation

“…This paradoxical down-regulation of p21 was also reported in our previous study of AICAR and metformin effects on retinoblastoma cells (Theodoropoulou et al, 2010; 2013)(unpublished data). Evidence suggesting an oncogenic function of p21 was also reported in some other tumors, including lymphoma and esophageal squamous cell carcinoma with p53 gene mutations; in these studies, p21 promoted tumor growth by inhibiting apoptosis and/or promoting cell proliferation (Gartel, 2009).…”

Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

“…Similar results were obtained by Theodoropoulou et al, who reported that aminoimidazole carboxamide ribonucleotide (AICAR) treatment decreased tumor angiogenesis in association with an increase in tumor cell apoptosis [59]. Although it is reasonable to suppose that reduced angiogenesis in the xenotransplanted tumor would increase apoptosis and eventually prevent tumor enlargement, how aflibercept treatment of retinoblastoma increases apoptosis is currently unknown.…”

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

“…AICAR acts as a cellular mimetic of adenosine monophosphate and is widely used to activate AMPK 38,39 in animals. 40,41 Furthermore, 30 μM of AICAR has previously been shown to increase AMPK phosphorylation in primary mouse cell cultures. 39 The pSNL + vehicle group and the sham + vehicle group received intrathecal injections of 10 μl saline (vehicle) in the same fashion.…”