Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry

Abstract

Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn “cancer-promoting” copper into anti-cancer agents.

Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas

“…Some Cu chelators have been investigated as anti-angiogenic compounds due to their ability to reduce copper levels [42]. DSF was shown to be a potent proteasome inhibitor and apoptosis inducer in vitro and in vivo only when Cu was present [43]. DSF was highly cytotoxic in glioma cells, only when it was used in combination with 1 μM of copper [44].…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…A large body of evidence documents the interactive nature of copper as a ‘switch-on' angiogenic messenger, acting downstream of major pro-angiogenic cytokines/stimuli, and so supporting the vascular response. A measure of the far-reaching impact of such findings in applicative angiogenesis research is deducible from the successful testing of copper-depriving strategies in in vitro cancer models, as well as in tumour xenograft experiments [4,5,6,7,8]. Encouraging experimental results envision the adoption of copper-reducing therapies in support of traditional approaches to starve cancer.…”

Site-specific radical formation in DNA induced by Cu(II)–H2O2 oxidizing system, using ESR, immuno-spin trapping, LC-MS, and MS/MS

“…Copper-mediated ROS damage assumes significance due to the increased evidence of elevated levels of copper in tumor growth and angiogenesis [39-41]. There have been several reports of copper concentration being significantly higher in cancer patients [39-41], whereas the concentration of other elements like zinc, iron and selenium were significantly lower [39]. Copper chelation or copper depletion is under intense investigation for therapeutic purposes [39,40].…”