Abstract
SummaryInsensitivity 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.
Highlights
Platinum (Pt) drugs are the most successful class of inorganic medicinal compounds used to treat cancer [1, 2]
We demonstrate that a MetaplexTM formulation of copper DDC (Cu(DDC)2) was active in Scheme 2 Structures of commonly used platinum drugs. a Cisplatin and (b) Carboplatin animals bearing Pt-resistant A2780-CP xenograft tumours
CDDP and CBDCA, two commonly used Pt-based therapeutics were tested in a pair of isogenic ovarian cancer cells: A2780-S cells are the parental cells that are sensitive to CDDP while A2780-CP cells are platinum-resistant
Summary
Platinum (Pt) drugs are the most successful class of inorganic medicinal compounds used to treat cancer [1, 2]. Cisplatin (CDDP) was first used to treat leukemia in the 1960s, but through several inorganic medicinal chemistry programs, other Ptbased drugs (Carboplatin (CBDCA), Oxaliplatin, Paraplatin etc.) have been produced and approved by the FDA [2, 4]. These drugs are known to act by forming PtDNA complexes that cause DNA damage that accumulate to a point that is beyond repair, leading to cell death [3, 5]. There is a need to define drugs capable of treating Pt insensitive cancers [6]
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