ArticleCancer research2009
Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
97 citing papers in PubMed, 144 citations in OpenAlex.
- Gene Expression Profile of the Cerebral Cortex of Niemann-Pick Disease Type C Mutant Mice.Genes · 2025Article
- One-carbon-mediated purine synthesis underlies temozolomide resistance in glioblastoma.Cell death & disease · 2024Article
- AMPK-a key factor in crosstalk between tumor cell energy metabolism and immune microenvironment?Cell death discovery · 2024Review
- Purinosomes involved in the regulation of tumor metabolism: current progress and potential application targets.Frontiers in oncology · 2024Review
- Constructing a folate metabolism gene signature for predicting prognosis in pulmonary neuroendocrine carcinomas.Journal of Cancer · 2024Article
- Purine Nucleotide Alterations in Tumoral Cell Lines Maintained with Physiological Levels of Folic Acid.International journal of molecular sciences · 2023Article
- Multitargeted 6-Substituted Thieno[2,3-ACS pharmacology & translational science · 2023Article
- Metabolites of De Novo Purine Synthesis: Metabolic Regulators and Cytotoxic Compounds.Metabolites · 2022Article
- ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease.Circulation · 2022Article
- AICAR promotes endothelium-independent vasorelaxation by activating AMP-activated protein kinase via increased ZMP and decreased ATP/ADP ratio in aortic smooth muscle.Journal of basic and clinical physiology and pharmacology · 2022Article
- Multienzyme interactions of the de novo purine biosynthetic protein PAICS facilitate purinosome formation and metabolic channeling.The Journal of biological chemistry · 2022Article
- ATIC facilitates cell growth and migration by upregulating Myc expression in lung adenocarcinoma.Oncology letters · 2022Article
- Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets.Pharmaceutics · 2021Review
- Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity.Drug safety · 2021Review
- The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance.International journal of molecular sciences · 2021Review
- Review
- A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight.ACS pharmacology & translational science · 2021Review
- Pemetrexed Hinders Translation Inhibition upon Low Glucose in Non-Small Cell Lung Cancer Cells.Metabolites · 2021Article
- Human de novo purine biosynthesis.Critical reviews in biochemistry and molecular biology · 2021Review
- AMPK: Potential Therapeutic Target for Vascular Calcification.Frontiers in cardiovascular medicine · 2021Review
37 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Pemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non-small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP.
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What OpenQuestion holds
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.