ArticleThe Journal of pharmacology and experimental therapeutics2013
5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- NHE1-Mediated Metabolic Reprogramming in Cancer.Metabolites · 2026Review
- A novel lipophilic amiloride derivative efficiently kills chemoresistant breast cancer cells.Scientific reports · 2024Article
- Tumor biomarkers for diagnosis, prognosis and targeted therapy.Signal transduction and targeted therapy · 2024Review
- A comprehensive pan-cancer analysis of necroptosis molecules in four gynecologic cancers.BMC cancer · 2022Article
- Necroptosis in head and neck squamous cell carcinoma: characterization of clinicopathological relevance and in vitro cell model.Cell death & disease · 2020Article
- The Microenvironment of Tongue Cancer.Advances in experimental medicine and biology · 2020Review
- Differential Exosomic Proteomic Patterns and Their Influence in Resveratrol Sensitivities of Glioblastoma Cells.International journal of molecular sciences · 2019Article
- Article
- Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation.Acta pharmacologica Sinica · 2017Article
- Exploitation of necroptosis for treatment of caspase-compromised cancers.Oncology letters · 2017Article
- Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage.BMC cancer · 2016Article
- Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy.Oncotarget · 2016Review
- Cancer and necroptosis: friend or foe?Cellular and molecular life sciences : CMLS · 2016Review
- Hexamethylene amiloride engages a novel reactive oxygen species- and lysosome-dependent programmed necrotic mechanism to selectively target breast cancer cells.Cancer letters · 2016Article
- Physiological effects of salinity on Delta Smelt, Hypomesus transpacificus.Fish physiology and biochemistry · 2016Article
- Impact of Mitochondria-Mediated Apoptosis in U251 Cell Cycle Arrest in G1 Stage and Caspase Activation.Medical science monitor : international medical journal of experimental and clinical research · 2015Article
- Mis-trafficking of endosomal urokinase proteins triggers drug-induced glioma nonapoptotic cell death.Molecular pharmacology · 2015Article
- Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway.Journal of neurochemistry · 2015Article
- The role of necroptosis in neurosurgical diseases.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2015Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
5'-Βenzylglycinyl-amiloride (UCD38B) and glycinyl-amiloride (UCD74A) are cell-permeant and cell-impermeant derivatives of amiloride, respectively, and used here to identify the cellular mechanisms of action underlying their antiglioma effects. UCD38B comparably kills proliferating and nonproliferating gliomas cells when cell cycle progression is arrested either by cyclin D1 siRNA or by acidification. Cell impermeant UCD74A inhibits plasmalemmal urokinase plasminogen activator (uPA) and the type 1 sodium-proton exchanger with potencies analogous to UCD38B, but is cytostatic. In contrast, UCD38B targets intracellular uPA causing mistrafficking of uPA into perinuclear mitochondria, reducing the mitochondrial membrane potential, and followed by the release of apoptotic inducible factor (AIF). AIF nuclear translocation is followed by a caspase-independent necroptotic cell death. Reduction in AIF expression by siRNA reduces the antiglioma cytotoxic effects of UCD38B, while not activating the caspase pathway. Ultrastructural changes shortly following treatment with UCD38B demonstrate dilation of endoplasmic reticulum (ER) and mitochondrial swelling followed by nuclear condensation within hours consistent with a necroptotic cell death differing from apoptosis and from autophagy. These drug mechanism of action studies demonstrate that UCD38B induces a cell cycle-independent, caspase-independent necroptotic glioma cell death that is mediated by AIF and independent of poly (ADP-ribose) polymerase and H2AX activation.
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