5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells

Mukhopadhyay, Suman; Chatterjee, Amrita; Kogan, Diane; Patel, Deven; Foster, David A.

doi:10.1080/15384101.2015.1087623

Cited by 41 publications

(47 citation statements)

References 31 publications

(81 reference statements)

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“…In the CA1, there were 1 upregulated and 1 downregulated metabolite compared to the CA3. 4-Amino-5-imidazole carboxamide, a purine metabolite upregulated in the CA1 after 72 hours of tGCI, was reported to have apoptotic effects 49,50 , therefore its decrease in the CA3 compared to the CA1 may represent a mechanism by which the CA3 evades apoptosis. However, Deoxyuridine-5'-triphosphate, downregulated in CA1 vs CA3, is another metabolite which accumulation is linked to a commitment to apoptosis and cell growth retardation 51 .…”

Section: Discussionmentioning

confidence: 99%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.Metabolomics is the study of metabolite composition of cells, tissues or biological fluids. Recent technological advances in this field has allowed the discovery of new biomarkers of diseases such as coronary artery disease, septic shock and brain tumors as well as the discovery of new drugs 1-5 . Metabolomic analysis has also deepened our understanding of several disease models, leading to the discovery of new pathways or targets for drug therapies that could later be applied to the treatment of various diseases [6][7][8][9][10][11] . Indeed, metabolomics are closer to the phenotype of a given disease compared with transcriptomic or proteomic analysis, both of which are prone to downstream modifications and changes in activities 1,12 .Several techniques, tools and software platforms exist to study metabolomics, all of which complement each other 13 . The application of these tools has greatly enhanced our understanding of the pathophysiology of diseases in almost every field of research 14 . In the field of neuroscience, metabolomic analysis is used to study stroke 15 , brain tumors 16 , traumatic brain injury (TBI) 17,18 , neurodegenerative diseases 19 , hypoxic-ischemic encephalopathy 20 and depression 21 to name a few 22 . The application of metabolomic tools to study brain diseases have greatly enhanced our understanding of different pathologies, for example; we demonstrated the upregulation of the ceramide "Cer(d18:0/18:0)" and phosphocreatine following transient ischemia-reperfusion in mice using a mass spectrometric imaging approach 15 . Several studies have highlighted an array of small molecules, amino acids and lipids that were linked to stroke severity, progression or post-stroke cognitive deficits [23][...

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Section: Discussionmentioning

confidence: 99%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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“…3. In this regard, we just reported that reducing PLD activity by activating AMP-activated protein kinase can make mTORC2 sensitive to clinically-tolerable nano-molar doses of rapamycin (64). Thus, while there are problems associated with the use of rapamycin or rapamycin analogs, the role that mTOR plays in promoting the survival of what is likely most human cancers (1, 18, 19), the high degree of specificity of rapamycin and the versatility of differentially inhibiting different downstream targets of mTOR make rapamycin a valuable reagent in the lab and the clinic.…”

Section: Discussionmentioning

confidence: 99%

“…This could potentially be achieved through the combination of low dose rapamycin with compounds that that suppress PLD activity, which lowers the levels of rapamycin needed to suppress both mTORC1 and mTORC2, which has been shown to work in the laboratory (27, 32). In addition, it was reported that activating AMP-activated protein kinase with AICAR (5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside) suppresses PLD activity (63) and that AICAR makes mTORC2 highly sensitive to nano-molar doses of rapamycin (64). Thus, suppressing PLD activity make rapamycin cytotoxic at tolerated doses of rapamycin.…”

Section: Differential Rapamycin Sensitivity Of Mtorc1 Substratesmentioning

confidence: 99%

The Enigma of Rapamycin Dosage

Mukhopadhyay

Frías

Chatterjee

et al. 2016

Molecular Cancer Therapeutics

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The mammalian target of rapamycin (mTOR) pathway is a critical regulator of cell growth, proliferation, metabolism and survival. Dysregulation of mTOR signaling has been observed in most cancers and thus, the mTOR pathway has been extensively studied for therapeutic intervention. Rapamycin is a natural product that inhibits mTOR with high specificity. However, its efficacy varies by dose in several contexts. First, different doses of rapamycin are needed to suppress mTOR in different cell lines; second, different doses of rapamycin are needed to suppress the phosphorylation of different mTOR substrates; and third, there is a differential sensitivity of the two mTOR complexes mTORC1 and mTORC2 to rapamycin. Intriguingly, the enigmatic properties of rapamycin dosage can be explained in large part by the competition between rapamycin and phosphatidic acid (PA) for mTOR. Rapamycin and PA have opposite effects on mTOR whereby rapamycin destabilizes and PA stabilizes both mTOR complexes. In this review, we discuss the properties of rapamycin dosage in the context of anti-cancer therapeutics.

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“…22 Besides, β-Carotene induces apoptosis in esophageal squamous cell Carcinoma via the Cav-1/AKT/NF-κB signaling pathway. 23 The previous study showed that Cav-1was strongly associated with apoptosis. However, the role of Cav-1 in propofol-induced apoptosis remains unclear.…”

Section: Introductionmentioning

confidence: 97%

<p>Metformin Inhibits Propofol-Induced Apoptosis of Mouse Hippocampal Neurons HT-22 Through Downregulating Cav-1</p>

Ge¹,

Huang²,

Zhang³

et al. 2020

DDDT

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To elucidate the neuroprotective function of metformin in suppressing propofolinduced apoptosis of HT-22 cells. Methods: HT-22 cells were treated with 0, 10 or 100 μmol/L propofol, followed by determination of their proliferative ability. Subsequently, changes in proliferation and apoptosis of propofol-treated HT-22 cells induced with metformin were assessed. Apoptosisassociated genes in HT-22 cells were detected by Western blot. At last, regulatory effects of Cav-1 on propofol and metformin-treated HT-22 cells were examined. Results: Propofol treatment dose-dependently decreased proliferative ability and increased apoptosis ability in HT-22 cells, which were partially blocked by metformin administration. Upregulated Bcl-2 and downregulated Bax were observed in propofol-treated HT-22 cells following metformin administration. In addition, Cav-1 level in HT-22 cells was regulated by metformin treatment. Notably, metformin reversed propofol-induced apoptosis stimulation and proliferation decline in HT-22 cells via downregulating Cav-1. Conclusion: In our study, we found that propofol could induce apoptosis of HT-22 cells and metformin could rescue the apoptosis effect regulated by propofol. Then, we found that metformin protects propofol-induced neuronal apoptosis via downregulating Cav-1.

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5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells

Cited by 41 publications

References 31 publications

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

The Enigma of Rapamycin Dosage

<p>Metformin Inhibits Propofol-Induced Apoptosis of Mouse Hippocampal Neurons HT-22 Through Downregulating Cav-1</p>

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