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

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.

Copper as the Target for Anticancer Nanomedicine

“…The self-assembly of this conjugate formed DSF-loaded nanoparticles (LDNPs) that could be taken up by tumor cells efficiently via receptor-mediated endocytosis and then release diethyldithiocarbamate (ET), resulting in the formation of CuET complex. [137,138] Karmakar et al used chitosan-based nanoparticles for the delivery of copper-diketo complex, such as bis(acetylacetonate)Cu(II) [139] and bis(2,4-pentanedionato)Cu(II). [135] Adv.…”

“…Wehbe et al. developed liposomal CuET complex that exhibited potent anticancer activity in vivo regardless of platinum sensitivity status . Karmakar et al.…”

What Drives Innovation: The Canadian Touch on Liposomal Therapeutics

“…Furthermore, these nanoparticles can be suspended in biocompatible aqueous buffers for parenteral administration into relevant preclinical models. The Bally group and Cuprous validated the concept of metal-dependent anticancer activity for copper-coordinating compounds through an in vitro screen on platinum-sensitive and platinum-resistant cell lines and prepared injectable copper-based formulations of DDC and clioquinol [80,89,90]. The Metaplex technology can also be used to reformulate sparingly soluble compounds that have metal-binding properties with the goal of either reducing toxicity or improving therapeutic activity.…”

A new parameter of growth inhibition for cell proliferation assays

“…We emphasize that, using these parameters to compare drug efficacy between distinct cell populations (such as cell lines), cells that grow “faster” in culture will be inferred more sensitive than “slower” ones, and therefore these parameters lead to a misinterpretation of the results because of their dependency to the unique growth properties of each cell population. Despite PG partially overcomes this limitation, we provide in the first section of the results a detailed description of the dependency of R , and consequently the IC 50 , to cell proliferation rate because of its frequent usage in current anticancer drug discovery research (as few recent examples (Ben et al, ; Cabrera et al, ; Esposito et al, ; Hamed, Darwish, Herrmann, Abadi, & Engel, ; Indovina et al, ; Koul et al, ; Mathema, Chaijaroenkul, Karbwang, & Na‐Bangchang, ; Menderes et al, ; Mukunthan, Satyan, & Patel, ; Muñoz, Rosso, & Coveñas, ; Potenza et al, ; Ravi, Ramesh, & Pattabhi, ; Rimoldi et al, ; Said, Brouard, Quintana, & Estévez, ; Venkataramana Reddy et al, ; Wehbe et al, ; Zamora et al, ; Zhu et al, )). Subsequently, in the second section of the results, we show that PG is also dependent on the growth properties of the cells, because of their exponential and not linear proliferation in culture.…”