ArticlePloS one2012
General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It carries an expression of concern. Cited by 36 papers.
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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.
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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
36 citing papers in PubMed, 64 citations in OpenAlex.
- Therapeutic Potential of Scorpion Venom Proteins: Innovations in Cancer Treatment and Future Directions.Current drug targets · 2026Review
- Absolute Membrane Potential Recording with ASAP-Type Genetically Encoded Voltage Indicators Using Fluorescence Lifetime Imaging.ACS chemical neuroscience · 2025Article
- Intermediate Conductance Calcium-Dependent Potassium Channel (KJournal of cellular physiology · 2025Article
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- CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development.Cancers · 2022Review
- Functional expression of mitochondrial KPflugers Archiv : European journal of physiology · 2022Article
- Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges.Reviews of physiology, biochemistry and pharmacology · 2022Review
- The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer.International journal of molecular sciences · 2021Review
- Membrane Transporters and Channels in Melanoma.Reviews of physiology, biochemistry and pharmacology · 2021Review
- Ion Channels in Glioma Malignancy.Reviews of physiology, biochemistry and pharmacology · 2021Review
- Antibodies Targeting KBioelectricity · 2019Article
- Countering TRAIL Resistance in Melanoma.Cancers · 2019Review
- Review
- Cancer-Associated Intermediate Conductance CaCancers · 2019Review
- Gas Signaling Molecules and Mitochondrial Potassium Channels.International journal of molecular sciences · 2018Review
- Targeting Mitochondrial Ion Channels to Fight Cancer.International journal of molecular sciences · 2018Review
- KCa3.1 Channels and Glioblastoma: In Vitro Studies.Current neuropharmacology · 2018Review
- Functional Roles of the Ca2+-activated K+ Channel, KCa3.1, in Brain Tumors.Current neuropharmacology · 2018Review
- Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells.Cell death & disease · 2017Article
Corrections and comments
- Expression of concern
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable.
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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.