Necrosulfonamide Selectively Induces DNA Double-Strand Breaks in Acute Myeloid Leukemia Cells

Eliciting regulated cell death, like necroptosis, is a potential cancer treatment. However, pathways eliciting necroptosis are poorly understood. It has been reported that prolonged activation of acid-sensing ion channel 1a (ASIC1a) induces necroptosis in mouse neurons. Glioblastoma stem cells (GSCs) also express functional ASIC1a, but whether prolonged activation of ASIC1a induces necroptosis in GSCs is unknown. Here we used a tumorsphere formation assay to show that slight acidosis (pH 6.6) induces necrotic cell death in a manner that was sensitive to the necroptosis inhibitor Nec-1 and to the ASIC1a antagonist PcTx1. In addition, genetic knockout of ASIC1a rendered GSCs resistant to acid-induced reduction in tumorsphere formation, while the ASIC1 agonist MitTx1 reduced tumorsphere formation also at neutral pH. Finally, a 20 amino acid fragment of the ASIC1 C-terminus, thought to interact with the necroptosis kinase RIPK1, was sufficient to reduce the formation of tumorspheres. Meanwhile, the genetic knockout of MLKL, the executive protein in the necroptosis cascade, did not prevent a reduction in tumor sphere formation, suggesting that ASIC1a induced an alternative cell death pathway. These findings demonstrate that ASIC1a is a death receptor on GSCs that induces cell death during prolonged acidosis. We propose that this pathway shapes the evolution of a tumor in its acidic microenvironment and that pharmacological activation of ASIC1a might be a potential new strategy in tumor therapy.

show abstract

“…3i ). Although this effect was unexpected, it had previously been observed [ 32 , 33 ] and characterized [ 34 ] by others.…”

Section: Resultssupporting

confidence: 51%

Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a

et al. 2022

View full text Add to dashboard Cite

show abstract

“…We now report that NSA acts as a potent redox cycler, impacting ciliogenesis and autophagy via ROS independently of MLKL. These results support the recent description that NSA drives ROS generation in monocytic cell lines 38 . Our data demonstrate rapid aggregation of PCM1, several centriolar satellite components, and the established redox protein p62 upon NSA exposure.…”

Section: Discussionsupporting

confidence: 92%

Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy

Nicolau

Renaud

Maghe

et al. 2023

Preprint

View full text Add to dashboard Cite

(PCM1) protein, that gravitate as particles around the centrosome. Centriolar satellites have been linked to key cellular processes including the formation of primary cilia and GABARAP-mediated autophagy. However, to date, there is no pharmacological inhibitor of centriolar satellites. Here, we report that necrosulfonamide (NSA), a compound previously shown to target the cell death effector MLKL, induced non-degradative ubiquitination of PCM1. This also caused a defect in ciliogenesis and an accumulation of autophagy markers such as P62 and GABARAPL1, although the overall architecture and distribution of centriolar satellites were maintained. We further found that the depletion of PCM1 lessened the impact of NSA on autophagy. Altogether, NSA may be a valuable tool to study centriolar satellites and provide further insights into their interplay with autophagy.

show abstract

“…The pUC19 plasmid DNA has a compact supercoiled (SC) conformation (form I), and when subjected to electrophoresis, it migrates relatively fast. Single-strand scission of this SC form of DNA generates a slower moving nicked circular (NC) form (form II), and on double-strand scission, a linear form (form III) that migrates between SC and NC forms is generated. , Generally, DNA cleavage − can occur by three ways, namely, (i) DNA hydrolysis, (ii) oxidative cleavage, and (iii) photochemical cleavage, of which the last two categories are closely related. In the oxidative cleavage pathway, the target is either a sugar moiety or the base of the DNA strands and is comparatively easier.…”

Section: Resultsmentioning

confidence: 99%

Mixed Ligand Mononuclear Copper(II) Complex as a Promising Anticancer Agent: Interaction Studies with DNA/HSA, Molecular Docking, and In Vitro Cytotoxicity Studies

et al. 2022

View full text Add to dashboard Cite

The isolated copper(II) complex [CuL( o -phen)]·H 2 O ( 1 ) [H 2 L = o -HO-C 6 H 4 C(H)=N-C 6 H 4 -SH- o , o -phen = 1,10-phenanthroline] was structurally characterized using single-crystal X-ray crystallography. 1 in CH 3 CN at liquid nitrogen temperature displayed a characteristic monomeric X-band electron paramagnetic resonance spectrum having a tetragonal character with g ∥ = 2.1479 and g ⊥ = 2.0691 and A ∥ ≈ 18.0 mT and A ⊥ ≤ 3.9 mT, respectively. 1 showed a strong binding affinity toward calf thymus DNA as reflected from its intrinsic binding constant ( K b = 7.88 × 10 5 M –1 ), and its competitive displacement of ethidium bromide suggested an intercalative DNA-binding mode ( K app = 1.32 × 10 6 M –1 ). This was confirmed from the viscosity study that showed an increase in the viscosity of DNA with an increasing concentration of 1 . Complex 1 is highly efficient in promoting oxidative and hydrolytic DNA cleavage ( k obs = 1.987 h –1 ). 1 showed a strong binding affinity with the carrier protein human serum albumin (HSA) ( K a = 5.22 × 10 5 M –1 ). A high bimolecular quenching constant k q = 2.29 × 10 13 M –1 s –1 indicated a static quenching mechanism involved in the fluorescence quenching of HSA by 1 . Fluorescence resonance energy transfer theory suggested that the distance ( r = 3.52 nm) between 1 and HSA is very close. Molecular docking studies suggested that 1 primarily binds to HSA in subdomain IIA. A protein–ligand interaction profiler was used to visualize hydrophobic, hydrogen bonds, and π–cation interactions between HSA and 1 . A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa and MDA-MB-231 cells showed a significant in vitro anticancer activity of 1 (IC 50 2.63 and 2.68 μM, respectively). Nuclear staining assays suggested apoptotic cell death in HeLa cells treated with 1 . The effect of 1 on the cytoskeletal actin filaments vis...

show abstract

Necrosulfonamide Selectively Induces DNA Double-Strand Breaks in Acute Myeloid Leukemia Cells

Cited by 7 publications

References 29 publications

Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a

Acidosis induces RIPK1-dependent death of glioblastoma stem cells via acid-sensing ion channel 1a

Necrosulfonamide causes oxidation of PCM1 and impairs ciliogenesis and autophagy

Mixed Ligand Mononuclear Copper(II) Complex as a Promising Anticancer Agent: Interaction Studies with DNA/HSA, Molecular Docking, and In Vitro Cytotoxicity Studies

Contact Info

Product

Resources

About