ArticleMolecular cancer therapeutics2014
Leelamine mediates cancer cell death through inhibition of intracellular cholesterol transport.
Article in Molecular cancer therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 75 citations in OpenAlex.
- A Direct-to-Biology Amine-Acid Amination for Rapid Phenotypic Profiling of Lysosomotropic Natural Products.Journal of the American Chemical Society · 2026Article
- StarD5 Regulates Cholesterol Homeostasis to Promote Colorectal Cancer Progression and the Cancer Stem Cell Phenotype.Molecular cancer research : MCR · 2026Article
- Decoding the Role of Lipid Metabolism and Membrane Dynamics in Melanoma.International journal of molecular sciences · 2026Review
- The SOX10-ACAT2-Cholesterol Synthesis Axis Is Required for Melanoma Proliferation.International journal of biological sciences · 2026Article
- Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism.Nature communications · 2025Article
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- Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.Carcinogenesis · 2024Article
- Targeting endocytosis to sensitize cancer cells to programmed cell death.Biochemical Society transactions · 2024Review
- Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities.International journal of biological sciences · 2024Review
- In Vitro Cytotoxic Effects of Ferruginol Analogues in Sk-MEL28 Human Melanoma Cells.International journal of molecular sciences · 2023Article
- Review
- The Finally Rewarding Search for A Cytotoxic Isosteviol Derivative.Molecules (Basel, Switzerland) · 2023Article
- The role of lysosomal peptidases in glioma immune escape: underlying mechanisms and therapeutic strategies.Frontiers in immunology · 2023Review
- The role of cholesterol metabolism in tumor therapy, from bench to bed.Frontiers in pharmacology · 2023Review
- Potential Application of Leelamine as a Novel Regulator of Chemokine-Induced Epithelial-to-Mesenchymal Transition in Breast Cancer Cells.International journal of molecular sciences · 2022Article
- Antiviral Profiling of C-18- or C-19-Functionalized Semisynthetic Abietane Diterpenoids.Journal of natural products · 2022Review
- Repurposing autophagy regulators in brain tumors.International journal of cancer · 2022Review
- Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development.International journal of molecular sciences · 2022Article
- Leelamine Modulates STAT5 Pathway Causing Both Autophagy and Apoptosis in Chronic Myelogenous Leukemia Cells.Biology · 2022Article
- Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation.Molecular oncology · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Leelamine is a promising compound for the treatment of cancer; however, the molecular mechanisms leading to leelamine-mediated cell death have not been identified. This report shows that leelamine is a weakly basic amine with lysosomotropic properties, leading to its accumulation inside acidic organelles such as lysosomes. This accumulation leads to homeostatic imbalance in the lysosomal endosomal cell compartments that disrupts autophagic flux and intracellular cholesterol trafficking as well as receptor-mediated endocytosis. Electron micrographs of leelamine-treated cancer cells displayed accumulation of autophagosomes, membrane whorls, and lipofuscin-like structures, indicating disruption of lysosomal cell compartments. Early in the process, leelamine-mediated killing was a caspase-independent event triggered by cholesterol accumulation, as depletion of cholesterol using β-cyclodextrin treatment attenuated the cell death and restored the subcellular structures identified by electron microscopy. Protein microarray-based analyses of the intracellular signaling cascades showed alterations in RTK-AKT/STAT/MAPK signaling cascades, which was subsequently confirmed by Western blotting. Inhibition of Akt, Erk, and Stat signaling, together with abnormal deregulation of receptor tyrosine kinases, was caused by the inhibition of receptor-mediated endocytosis. This study is the first report demonstrating that leelamine is a lysosomotropic, intracellular cholesterol transport inhibitor with potential chemotherapeutic properties leading to inhibition of autophagic flux and induction of cholesterol accumulation in lysosomal/endosomal cell compartments. Importantly, the findings of this study show the potential of leelamine to disrupt cholesterol homeostasis for treatment of advanced-stage cancers.
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Registered trials
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