ArticleCell cycle (Georgetown, Tex.)2015
5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells.
Article in Cell cycle (Georgetown, Tex.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- AICAr, a Widely Used AMPK Activator with Important AMPK-Independent Effects: A Systematic Review.Cells · 2021Pooled it
- Changes in Melanoma Cell Morphology Following Inhibition of Cell Invasion by Third-Generation mTOR Kinase Inhibitors.International journal of molecular sciences · 2025Article
- The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells.Cancers · 2025Article
- Article
- Chloroquine Enhances Chemosensitivity of Breast Cancer via mTOR Inhibition.Biomedicines · 2025Article
- Melanophilin inhibit the growth and lymph node metastasis of triple negative breast cancer via the NONO-SPHK1-S1P axis.Journal of translational medicine · 2025Article
- Molecular Basis of Oncogenic PI3K Proteins.Cancers · 2024Review
- Article
- Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer.International journal of molecular sciences · 2023Review
- Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.International journal of molecular sciences · 2023Review
- mTORC2 Is Activated under Hypoxia and Could Support Chronic Myeloid Leukemia Stem Cells.International journal of molecular sciences · 2023Article
- Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges.Biomedicines · 2023Review
- Genomic signature of MTOR could be an immunogenicity marker in human colorectal cancer.BMC cancer · 2022Article
- Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK.Biomedicines · 2022Article
- The Energy Sensor AMPKα1 Is Critical in Rapamycin-Inhibition of mTORC1-S6K-Induced T-cell Memory.International journal of molecular sciences · 2021Article
- AMPK-mTOR Signaling and Cellular Adaptations in Hypoxia.International journal of molecular sciences · 2021Review
- New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway.International journal of molecular sciences · 2021Review
- Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.International journal of molecular sciences · 2021Review
- Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer.Journal of experimental & clinical cancer research : CR · 2021Article
- Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
mTOR - the mammalian/mechanistic target of rapamycin - has been implicated as a key signaling node for promoting survival of cancer cells. However, clinical trials that have targeted mTOR with rapamycin or rapamycin analogs have had minimal impact. In spite of the high specificity of rapamycin for mTOR, the doses needed to suppress key mTOR substrates have proved toxic. We report here that rapamycin when combined with AICAR - a compound that activates AMP-activated protein kinase makes rapamycin cytotoxic rather than cytostatic at doses that are tolerated clinically. AICAR by itself is able to suppress mTOR complex 1 (mTORC1), but also stimulates a feedback activation of mTORC2, which activates the survival kinase Akt. However, AICAR also suppresses production of phosphatidic acid (PA), which interacts with mTOR in a manner that is competitive with rapamycin. The reduced level of PA sensitizes mTORC2 to rapamycin at tolerable nano-molar doses leading reduced Akt phosphorylation and apoptosis. This study reveals how the use of AICAR enhances the efficacy of rapamycin such that rapamycin at low nano-molar doses can suppress mTORC2 and induce apoptosis in human cancer cells at doses that are clinically tolerable.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.