Mimicry of a Cellular Low Energy Status Blocks Tumor Cell Anabolism and Suppresses the Malignant Phenotype

Abstract

Aggressive cancer cells typically show a high rate of energyconsuming anabolic processes driving the synthesis of lipids, proteins, and DNA. Here, we took advantage of the ability of the cell-permeable nucleoside 5-aminoimidazole-4-carboxamide (AICA) riboside to increase the intracellular levels of AICA ribotide, an AMP analogue, mimicking a low energy status of the cell. Treatment of cancer cells with AICA riboside impeded lipogenesis, decreased protein translation, and blocked DNA synthesis. Cells treated with AICA riboside stopped proliferating and lost their invasive properties and their ability to form colonies. When administered in vivo, AICA riboside attenuated the growth of MDA-MB-231 tumors in nude mice. These findings point toward a central tie between energy, anabolism, and cancer and suggest that the cellular energy sensing machinery in cancer cells is an exploitable target for cancer prevention and/or therapy. (Cancer Res 2005; 65(6): 2441-8)

AMP-activated protein kinase and human cancer: cancer metabolism revisited

“…Although intact LKB1/AMPK signaling in normal tissues may protect against the development of cancer, in transformed cells, AMPK activation has been shown to be substantially cytotoxic to a variety of human cancer cell lines in vitro including lung, 30 prostate, 31,32 stomach, 33 liver, 34 breast 32,35 and glial. 32 In addition, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside, an activator of AMPK, reduced tumor growth in vivo in a rat C6 glioma allograft, 32 and in MDA-MB-231 human breast cancer xenografts.…”

“…32 In addition, 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside, an activator of AMPK, reduced tumor growth in vivo in a rat C6 glioma allograft, 32 and in MDA-MB-231 human breast cancer xenografts. 35 The precise mechanism whereby AMPK activation induces apoptosis or growth arrest in cancer cells is complex and its understanding is incomplete. However, a picture is emerging that AMPK activation may interfere with cancer cell metabolism mediated, perhaps in large part, through the Akt oncogene.…”

Methotrexate and 5-aminoimidazole-4-carboxamide riboside exert synergistic anticancer action against human breast cancer and hepatocellular carcinoma

“…Combination therapy can reduce side effects and prevent the emergence of resistance to anticancer drugs when drugs with different mechanisms of action are used in combination [21,22] . MTX is a classical folic acid antagonist [19] , whereas AICA riboside activates AMPK and subsequently inhibits energy-consuming processes, such as DNA synthesis, protein translation and lipogenesis [15] . The antitumor mechanisms of MTX and AICA riboside are complementary.…”

“…This is believed to be the first study to demonstrate that the combination of MTX and AICA riboside synergistically inhibits cancer cell growth in vitro and in vivo, and MTX increases AICA riboside and its active metabolite concentration in tumors. Although AICA riboside is well tolerated [18] , the clinical use of AICA riboside is limited by the large amount needed to exert its effects [15] and its poor pharmacokinetic profile. These shortcomings are associated in part with the rapid metabolism of AICA ribotide, which is converted to 10-formyl AICA ribotide by AICA ribotide transformylase.…”

“…AICA riboside has an inhibitory effect on the proliferation of a variety of human cancer cell lines such as B-cell chronic lymphocytic leukemia cells [9] , chronic myelogenous leukemia cells [10] , gastric cancer cells [11] , cervical cancer cells [12] , prostate cancer cells [13] and hepatocellular carcinoma cells [14] . AICA riboside also has www.nature.com/aps Cheng XL et al Acta Pharmacologica Sinica npg potent antitumor activity in nude mice bearing MDA-MB-231 and C6 cell xenografts [15,16] . The first patient was enrolled in a phase I/II trial of AICA riboside treatment for B-cell chronic lymphocytic leukemia in 2008 [17] .…”