Effect of Structural Modifications to Glyoxal-bis(thiosemicarbazonato)copper(II) Complexes on Cellular Copper Uptake, Copper-Mediated ATP7A Trafficking, and P-Glycoprotein Mediated Efflux.
Karla M AcevedoDavid J HayneLachlan E McInnesAsif NoorClare DuncanDiane MoujalledIrene VolitakisAngela RigopoulosKevin J BarnhamVictor L VillemagneAnthony R WhitePaul S DonnellyPublished in: Journal of medicinal chemistry (2018)
Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293, and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway. Treatment of SKOV-3 cells with low concentrations (μM) of two of the copper complexes led to trafficking of the endogenous copper transporter ATP7A from the Golgi network to the cell membrane. Experiments in HEK293 and HEK293-P-gp cells suggest that Cu(gtsm) and Cu(gtse) are substrates for the P-gp efflux protein but the complex with a pyrrolidine functional group, Cu(gtspyr), is not. A PET experiment in mice showed that [64Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake.
Keyphrases
- positron emission tomography
- oxide nanoparticles
- induced apoptosis
- computed tomography
- cell cycle arrest
- signaling pathway
- pet ct
- pi k akt
- cell proliferation
- pet imaging
- oxidative stress
- high resolution
- metal organic framework
- squamous cell carcinoma
- adipose tissue
- endoplasmic reticulum stress
- risk assessment
- multiple sclerosis
- metabolic syndrome
- climate change
- skeletal muscle
- photodynamic therapy
- smoking cessation
- childhood cancer