ArticleThe Journal of clinical investigation2016
Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
What it found
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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.
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Who cites it
46 citing papers in PubMed, 77 citations in OpenAlex.
- Combating VEGFA-siRNA-Induced Metabolic Reprogramming via Glucose Utilization Deprivation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Endolysosomal trafficking regulator SH-BC-893 inhibits coronavirus entry in vitro and in vivo.Scientific reports · 2026Article
- Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A.The EMBO journal · 2025Article
- Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-CaBasic research in cardiology · 2024Article
- PIKfyve controls dendritic cell function and tumor immunity.bioRxiv : the preprint server for biology · 2024Article
- PIKfyve, expressed by CD11c-positive cells, controls tumor immunity.Nature communications · 2024Article
- Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.Current medical science · 2024Article
- Unexpected inhibition of the lipid kinase PIKfyve reveals an epistatic role for p38 MAPKs in endolysosomal fission and volume control.Cell death & disease · 2024Article
- Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells.Nature communications · 2023Article
- Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer.Experimental & molecular medicine · 2023Article
- Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics.Nucleic acids research · 2023Article
- Pacritinib inhibits glucose consumption in squamous cell lung cancer cells by targeting FLT3.Scientific reports · 2023Article
- Kir2.1-mediated membrane potential promotes nutrient acquisition and inflammation through regulation of nutrient transporters.Nature communications · 2022Article
- A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy.Nano-micro letters · 2021Article
- Biomimetic Cascade Polymer Nanoreactors for Starvation and Photodynamic Cancer Therapy.Molecules (Basel, Switzerland) · 2021Article
- ONC212 is a Novel Mitocan Acting Synergistically with Glycolysis Inhibition in Pancreatic Cancer.Molecular cancer therapeutics · 2021Article
- Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity.EMBO molecular medicine · 2021Article
- Fuse your mitochondria, lose appetite: an anorexic, anti-obesity sphingolipid.EMBO molecular medicine · 2021Article
- Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex.Cancer research · 2021Article
- Metabolism of HSAN1- and T2DM-associated 1-deoxy-sphingolipids inhibits the migration of fibroblasts.Journal of lipid research · 2021Article
Corrections and comments
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Authors and funding
24 authors at 3 institutions in 2 countries.
Funding
Abstract
Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity.
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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.