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Invest New Drugs. 2017 Dec;35(6):682-690. doi: 10.1007/s10637-017-0488-2. Epub 2017 Jul 21.

Copper (II) complexes of bidentate ligands exhibit potent anti-cancer activity regardless of platinum sensitivity status.

Author information

1
Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada. mwehbe@bccrc.ca.
2
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada. mwehbe@bccrc.ca.
3
Experimental Therapeutics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
4
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
5
Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada.
6
Center for Drug Research and Development, Vancouver, BC, V6T 1Z4, Canada.

Abstract

Insensitivity to platinum, either through inherent or acquired resistance, is a major clinical problem in the treatment of many solid tumors. Here, we explored the therapeutic potential of diethyldithiocarbamate (DDC), pyrithione (Pyr), plumbagin (Plum), 8-hydroxyquinoline (8-HQ), clioquinol (CQ) copper complexes in a panel of cancer cell lines that differ in their sensitivity to platins (cisplatin/carboplatin) using a high-content imaging system. Our data suggest that the copper complexes were effective against both platinum sensitive (IC50 ~ 1 μM platinum) and insensitive (IC50 > 5 μM platinum) cell lines. Furthermore, copper complexes of DDC, Pyr and 8-HQ had greater therapeutic activity compared to the copper-free ligands in all cell lines; whereas the copper-dependent activities of Plum and CQ were cell-line specific. Four of the copper complexes (Cu(DDC)2, Cu(Pyr)2, Cu(Plum)2 and Cu(8-HQ)2) showed IC50 values less than that of cisplatin in all tested cell lines. The complex copper DDC (Cu(DDC)2) was selected for in vivo evaluation due to its low nano-molar range activity in vitro and the availability of an injectable liposomal formulation. Liposomal (Cu(DDC)2) was tested in a fast-growing platinum-resistant A2780-CP ovarian xenograft model and was found to achieve a statistically significant reduction (50%; p < 0.05) in tumour size. This work supports the potential use of copper-based therapeutics to treat cancers that are insensitive to platinum drugs.

KEYWORDS:

8-hydroxyquinoline; Carboplatin; Cisplatin; Clioquinol; Copper based therapeutics; Copper complexes; Diethyldithiocarbamate; Platinum drugs, platinum resistant cancer; Plumbagin; Pyrithione

PMID:
28733701
PMCID:
PMC5694505
DOI:
10.1007/s10637-017-0488-2
[Indexed for MEDLINE]
Free PMC Article

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