Identification of differential anti-neoplastic activity of copper bis(thiosemicarbazones) that is mediated by intracellular reactive oxygen species generation and lysosomal membrane permeabilization

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

“…These findings are consistent with the vast majority of patients with prostate cancer (Gleason Score 7 & 9) having intratumoral copper levels well within the normal range [26]. Enhanced copper uptake by prostate cancer cell lines in vitro and in xenografts mouse models, mediated by copper transporter 1 (hCtr1) protein, elevates intracellular copper and has been suggested to underpin copper-ionophore anticancer activity [17, 18, 23]. Our results establish that surplus copper does not govern the pharmacological facility of copper-ionophores, but may heighten clinical activity in the small subset of patients found to have elevated intratumoral copper [26].…”

“…We, and others, postulated that endogenous elevated intracellular copper predisposed the cancer cells to sensitivity, by possibly underpinning a heightened state of oxidative stress [8, 14, 17, 23]. However, we recently established that only a small subset of prostate cancer patients' harbour elevated intratumoral copper [26] and thus sought to clarify whether copper is indeed the critical, and targetable, factor.…”

“…Raised intracellular ROS is a well-defined feature of human prostate cancer and clinical studies have unequivocally confirmed a role for oxidative stress in the development and progression of this disease [19–22]. Therefore, it has been postulated that elevated endogenous copper may predispose prostate cancer cells to copper-ionophore sensitivity, by possibly underpinning a heightened state of oxidative stress [8, 14, 17, 23]. However, copper ions can exert toxicity through a myriad of mechanisms, including protein iron-sulfur cluster interference, proteasome inhibition and by displacing functional metals (e.g.…”

“…The anticancer activity of Cu II (gtsm) was copper-dependent, positively correlated with milieu copper level and could be abrogated with copper chelation [tetrathiomolybdate (TTM)] [8]. Stefani and colleagues (2015) more recently demonstrated that Cu II (gtsm) generates intracellular ROS and again validated the requirement for copper for its anticancer activity [23]. Two structurally unrelated copper-ionophores, disulfiram [1-(diethylthiocarbamoyldisulfanyl)- N , N -diethyl-methanethioamide)] and clioquinol (5-chloro-7-iodo-8-quinolinol), likewise display selective pharmacological activity against prostate cancer in vitro and in mouse models [8, 16, 17].…”

Structural basis, chemical driving forces and biological implications of flavones as Cu(II) ionophores

“…As shown in Figure 3B Figure 3C), respectively. The ability of copper ionophores to promote ROS and decrease GSH as a part of their mechanism to kill cancer cells has been reported recently [39,40]. Similar to 3-HF, 3-HF-Cu alone was not cytotoxic and proapoptotic, but its potency was significantly increased in the presence of Cu(II) ( Figure 3B and C).…”