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 Acevedo, David J Hayne, Lachlan E McInnes, Asif Noor, Clare Duncan, Diane Moujalled, Irene Volitakis, Angela Rigopoulos, Kevin J Barnham, Victor L Villemagne, Anthony R White, Paul S Donnelly
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 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 ..View full abstract
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Awarded by Australian Research Council
Financial support was from the Australian Research Council (Grants FT130100204 and DP160100288). A.R.W. is supported by an NHMRC Senior Research Fellowship. Prof. Des R. Richardson (Bosch Institute, University of Sydney) kindly provided the HEK293 vector and P-gp expressing cell lines. Dr. Carleen Cullinane (Peter MacCallum Cancer Centre) kindly provided SKOV-3 cells. P.S.D. acknowledges Dr. Matthew D. Hall (NCATS) for advice on the cell lines used in this study. The ATP7A antibody used in confocal imaging was a kind gift from Prof. B. Eipper (Neuroscience and Molecular, Microbial, and Structural Biology Division Institute of Connecticut). We acknowledge the generous support of Prof. Andrew M. Scott, A/Prof. Henri Tochon-Danguy, Dr. Uwe Ackermann, Dr. FT Lee, and Stan S. Poniger of the Austin Hospital, Heidelberg, Victoria, Australia, for providing access to copper-64 and radiochemistry facilities.