Cellular Uptake of the ATSM-Cu(II) Complex under Hypoxic Conditions

ChemistryOpen. 2021 Apr;10(4):486-492. doi: 10.1002/open.202100044.


The Cu(II)-diacetyl-bis (N4-methylthiosemicarbazone) complex (ATSM-Cu(II)) has been suggested as a promising positron emission tomography (PET) agent for hypoxia imaging. Several in-vivo studies have shown its potential to detect hypoxic tumors. However, its uptake mechanism and its specificity to various cancer cell lines have been less studied. Herein, we tested ATSM-Cu(II) toxicity, uptake, and reduction, using four different cell types: (1) mouse breast cancer cells (DA-3), (2) human embryonic kidney cells (HEK-293), (3) breast cancer cells (MCF-7), and (4) cervical cancer cells (Hela) under normoxic and hypoxic conditions. We showed that ATSM-Cu(II) is toxic to breast cancer cells under normoxic and hypoxic conditions; however, it is not toxic to normal HEK-293 non-cancer cells. We showed that the Cu(I) content in breast cancer cell after treatment with ATSM-Cu(II) under hypoxic conditions is higher than in normal cells, despite that the uptake of ATSM-Cu(II) is a bit higher in normal cells than in breast cancer cells. This study suggests that the redox potential of ATSM-Cu(II) is higher in breast cancer cells than in normal cells; thus, its toxicity to cancer cells is increased.

Keywords: ATSM−Cu(II); cancer; copper homeostasis; copper toxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Coordination Complexes
  • Copper Radioisotopes / chemistry
  • Copper Radioisotopes / metabolism
  • Copper Transporter 1 / metabolism
  • HEK293 Cells
  • Humans
  • Hypoxia / metabolism*
  • Mice
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / metabolism*
  • Organometallic Compounds / toxicity
  • Oxidation-Reduction
  • Thiosemicarbazones / chemistry
  • Thiosemicarbazones / metabolism*
  • Thiosemicarbazones / toxicity


  • Coordination Complexes
  • Copper Radioisotopes
  • Copper Transporter 1
  • Copper-64
  • Organometallic Compounds
  • SLC31A1 protein, human
  • Slc31a1 protein, mouse
  • Thiosemicarbazones
  • copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)