PBT2 acts through a different mechanism of action than other 8-hydroxyquinolines: an X-ray fluorescence imaging study

Summers, Kelly L.; Dolgova, Natalia V.; Gagnon, Kenneth B.; Sopasis, George J.; James, Ashley K.; Lai, Barry; Sylvain, Nicole J.; Harris, Hugh H.; Nichol, Helen K.; George, Graham N.; Pickering, Ingrid J.

doi:10.1039/d0mt00222d

PBT2 acts through a different mechanism of action than other 8-hydroxyquinolines: an X-ray fluorescence imaging study

Journal Article · Tue Nov 10 00:00:00 EST 2020 · Metallomics

DOI:https://doi.org/10.1039/d0mt00222d· OSTI ID:1835301

^[1]; ^[1]; Gagnon, Kenneth B. ^[2]; Sopasis, George J. ^[3]; James, Ashley K. ^[1]; ^[4]; Sylvain, Nicole J. ^[5]; ^[3]; Nichol, Helen K. ^[1]; ^[1]; ^[6]

Univ. of Saskatchewan, Saskatoon, SK (Canada)
Univ. of Saskatchewan, Saskatoon, SK (Canada); Univ. of Louisville, KY (United States)
Univ. of Adelaide, SA (Australia)
Argonne National Lab. (ANL), Lemont, IL (United States)
Canadian Light Source Inc., Saskatoon, SK (Canada); Univ. of Saskatchewan, Saskatoon, SK (Canada)
Univ. of Saskatchewan, Saskatoon, SK (Canada); Univ. of Adelaide, SA (Australia)

8-Hydroxyquinolines (8HQs) comprise a family of metal-binding compounds that have been used or tested for use in numerous medicinal applications, including as treatments for bacterial infection, Alzheimer's disease, and cancer. Two key 8HQs, CQ (5-chloro-7-iodo-8-hydroxyquinoline) and PBT2 (2-(dimethylamino)methyl-5,7-dichloro-8-hydroxyquinoline), have drawn considerable interest and have been the focus of many studies investigating their in vivo properties. These drugs have been described as copper and zinc ionophores because they do not cause metal depletion, as would be expected for a chelation mechanism, but rather cellular accumulation of these ions. In studies of their anti-cancer properties, CQ has been proposed to elicit toxic intracellular copper accumulation and to trigger apoptotic cancer cell death through several possible pathways. In this study we used synchrotron X-ray fluorescence imaging, in combination with biochemical assays and light microscopy, to investigate 8HQ-induced alterations to metal ion homeostasis, as well as cytotoxicity and cell death. We used the bromine fluorescence from a bromine labelled CQ congener (5,7-dibromo-8-hydroxyquinoline; B2Q) to trace the intracellular localization of B2Q following treatment and found that B2Q crosses the cell membrane. We also found that 8HQ co-treatment with Cu(ii) results in significantly increased intracellular copper and significant cytotoxicity compared with 8HQ treatments alone. PBT2 was found to be more cytotoxic, but a weaker Cu(ii) ionophore than other 8HQs. Moreover, treatment of cells with copper in the presence of CQ or B2Q resulted in copper accumulation in the nuclei, while PBT2-guided copper was distributed near to the cell membrane. Furthermore, these results suggest that PBT2 may be acting through a different mechanism than that of other 8HQs to cause the observed cytotoxicity.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Canada Foundation for Innovation (CFI); Natural Sciences and Engineering Research Council of Canada (NSERC); USDOE Office of Science (SC), Basic Energy Sciences (BES); University of Saskatchewan

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1835301

Journal Information:: Metallomics, Journal Name: Metallomics Journal Issue: 12 Vol. 12; ISSN 1756-5901

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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8-hydroxyquinolines
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drug action
iron
metal homeostasis
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PBT2 acts through a different mechanism of action than other 8-hydroxyquinolines: an X-ray fluorescence imaging study

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