Inhibition of Glucocorticoid-Induced Apoptosis with 5-Aminoimidazole-4-carboxamide Ribonucleoside, a Cell-Permeable Activator of AMP-Activated Protein Kinase

Stefanelli, Claudio; Stanic, Ivana; Bonavita, Francesca; Flamigni, Flavio; Pignatti, Carla; Guarnieri, Carlo; Caldarera, Claudio Marcello

doi:10.1006/bbrc.1998.8154

Cited by 80 publications

(52 citation statements)

References 32 publications

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“…Several recent reports showed that AICAR exhibited both antiapoptotic and proapoptotic effects in different cell types (12,15,25). Moreover, AICAR was also shown to suppress cell proliferation (16,26).…”

Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Chao

Chen

et al. 2007

Molecular Cancer Therapeutics

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Death receptor-mediated tumor cell death, either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. In this study, we have investigated the effects and molecular mechanisms of 5-aminoimidazole-4-carboxamide riboside [AICAR; a pharmacologic activator of AMP-activated protein kinase (AMPK)] in sensitizing tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) -and TNFA-induced apoptosis of human colon cancer HCT116 cells. The cytotoxic action of AICAR requires AMPK activation and may occur at various stages of apoptotic pathways. AICAR cotreatment with either TRAIL or TNFA enhances activities of caspase-8, caspase-9, and caspase-3; down-regulates the antiapoptotic protein Bcl-2; increases the cleavage of Bid and results in the decrease of mitochondrial membrane potential; potentiates activation of p38 and c-Jun NH 2 -terminal kinase; and inhibits nuclear factor-KB activity. In addition, this sensitized cell apoptosis was neither observed in p53-null HCT116 cells nor affected by the cotreatment with mevalonate. In summary, we have developed a novel strategy of combining AICAR with TRAIL for the treatment of colon cancer cells. The sensitization effect of AICAR in cell apoptosis was mediated through AMPK pathway, requires p53 activity, and involves mitochondria-dependent apoptotic cascades, p38 and c-Jun NH 2 -terminal kinase. [Mol Cancer Ther 2007;6(5):1562 -71]

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Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Chao

Chen

et al. 2007

Molecular Cancer Therapeutics

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“…AICAR has previously been shown to inhibit apoptosis in fibroblasts deprived of growth factors (24) and thymocytes exposed to glucocorticoids (23) and in cardiomyocytes (40) and astrocytes (41) exposed to fatty acids. The multiplicity of situations in which it acts suggests that AICAR affects a common initial or terminal event in the apoptotic pathway (e.g., oxidative stress generation, Akt activation, Ca 2ϩ regulation, or possibly the generation of inhibitory factors such as IGF).…”

Section: Discussionmentioning

confidence: 99%

Hyperglycemia-Induced Apoptosis in Human Umbilical Vein Endothelial Cells

Carling²,

2002

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Apoptosis has been observed in vascular cells, nerve, and myocardium of diabetic humans and experimental animals, although whether it contributes to or is a marker of complications in these tissues is unclear. Previous studies have shown that incubation of human umbilical vein endothelial cells (HUVECs) with 30 vs. 5 mmol/l glucose for 72 h causes a significant increase in apoptosis, possibly related to an increase in oxidative stress. We report here that this increase in apoptosis (assessed morphologically by TdT-mediated dUTP nickend labeling staining) is preceded (24 h of incubation) by inhibition of fatty acid oxidation, by increases in diacylglycerol synthesis, the concentration of malonyl CoA, and caspase-3 activity, and by decreases in mitochondrial membrane potential and cellular ATP content. In addition, the phosphorylation of Akt in the presence of 150 U/ml insulin was impaired. No increases in ceramide content or its de novo synthesis were observed. AMP-activated protein kinase (AMPK) activity was not diminished; however, incubation with the AMPK activator 5-aminoimidazole-4-carboxamideriboside increased AMPK activity twofold and completely prevented all of these changes. Likewise, expression of a constitutively active AMPK in HUVEC prevented the increase in caspase-3 activity. The results indicate that alterations in fatty-acid metabolism, impaired Akt activation by insulin, and increased caspase-3 activity precede visible evidence of apoptosis in HUVEC incubated in a hyperglycemic medium. They also suggest that AMPK could play an important role in protecting the endothelial cell against the adverse effects of sustained hyperglycemia. Diabetes 51:159 -167, 2002 V ascular disease that affects both the micro-and macrovasculature is the principal cause of morbidity and mortality in patients with diabetes (1). A wide variety of studies suggest that an early site at which these vascular complications develop is the endothelium. In particular, early abnormalities such as increases in renal and retinal blood flow, impaired vasodilation in response to physiological and pharmacological stimuli, and increased vascular permeability have been attributed to endothelial cell damage (1). Morphological correlates of these functional abnormalities were not initially identified; however, recent studies have shown an increase in apoptosis in various organs affected by diabetes, including the eye (2,3), heart (4,5), and vascular endothelium (5).The Diabetes Control and Complications Trial (6) and the U.K. Prospective Diabetes Study (7,8) have linked hyperglycemia to the occurrence of microvascular disease in patients with diabetes. Although less clear-cut, a relationship between hyperglycemia and macrovascular disease (9) has also been reported. That hyperglycemia increases apoptosis in cultured endothelium was first demonstrated by in HUVECs and since then by many others (11-13). It is well-established that apoptosis can be induced by internal signals, such as cytochrome C and apoptosis-inducing factors released from ...

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“…Moreover, an activator of cAMP-activated protein kinase has been reported to block dexamethasone-induced apoptosis and caspase-3 activation. 53 T cell receptor signaling can also regulate corticosteroidinduced apoptosis. Engagement of the T cell receptor (TCR) induces apoptosis by a mechanism that involves induction of Fas ligand, which in turn interacts with its receptor and activates caspase-8.…”

Section: Signaling Pathway Crosstalkmentioning

confidence: 99%

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

2002

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Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents. This review examines many facets of the process by which glucocorticoids induce apoptosis. This process is divided into three stages, an initiation stage that involves glucocorticoid receptor-mediated gene regulation, a decision stage that involves the counterbalancing influence of prosurvival and proapoptotic factors, and the execution stage which involves caspase and endonuclease activation. Many aspects of glucocorticoid-induced apoptosis, such as mitochondrial dysfunction and caspase activation, are important steps in virtually all forms of apoptosis. But the process glucocorticoid-induced apoptosis differs from other forms of apoptosis in terms of initiation at the transcriptional level and involvement of the multicatalytic proteasome and calcium. Moreover, the abundant opportunity for crosstalk between the glucocorticoid receptor and other signaling pathways increases the complexity of glucocorticoid-induced apoptosis and its regulation.

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Inhibition of Glucocorticoid-Induced Apoptosis with 5-Aminoimidazole-4-carboxamide Ribonucleoside, a Cell-Permeable Activator of AMP-Activated Protein Kinase

Cited by 80 publications

References 32 publications

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNFα-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling

Hyperglycemia-Induced Apoptosis in Human Umbilical Vein Endothelial Cells

Recent insights into the mechanism of glucocorticosteroid-induced apoptosis

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