The ionophore thiomaltol induces rapid lysosomal accumulation of copper and apoptosis in melanoma.
Ottis ScrivnerLong DaoM Karen Newell-RogersBabbak ShahandehFrank L MeyskensSusan Kurumi KozawaFeng Liu-SmithGermán Plascencia-VillaMiguel José-YacamánShang JiaChristopher J ChangPatrick J FarmerPublished in: Metallomics : integrated biometal science (2022)
In this report, we investigate the toxicity of the ionophore thiomaltol (Htma) and Cu salts to melanoma. Divalent metal complexes of thiomaltol display toxicity against A375 melanoma cell culture resulting in a distinct apoptotic response at submicromolar concentrations, with toxicity of Cu(tma)2 > Zn(tma)2 >> Ni(tma)2. In metal-chelated media, Htma treatment shows little toxicity, but the combination with supplemental CuCl2, termed Cu/Htma treatment, results in toxicity that increases with suprastoichiometric concentrations of CuCl2 and correlates with the accumulation of intracellular copper. Electron microscopy and confocal laser scanning microscopy of Cu/Htma treated cells shows a rapid accumulation of copper within lysosomes over the course of hours, concurrent with the onset of apoptosis. A buildup of ubiquitinated proteins due to proteasome inhibition is seen on the same timescale and correlates with increases of copper without additional Htma.
Keyphrases
- oxide nanoparticles
- oxidative stress
- cell cycle arrest
- electron microscopy
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- metal organic framework
- aqueous solution
- high resolution
- optical coherence tomography
- single molecule
- high speed
- signaling pathway
- reactive oxygen species
- basal cell carcinoma
- single cell
- raman spectroscopy
- sensitive detection