DNA binding and oxidative DNA damage induced by climacostol–copper(II) complexes: Implications for anticancer properties

Abstract

Climacostol is a natural toxin isolated from the freshwater ciliated protozoan Climacostomum virens and belongs to the group of resorcinolic lipids. Climacostol exerts a potent antimicrobial activity against a panel of bacterial and fungal pathogens. In addition it inhibits the growth of tumor cell lines in a dose-dependent manner by inducing programmed cell death via intrinsic pathway. In this work, we investigated the possibility that climacostol exerts a prooxidant effect, inducing plasmid DNA strand breakage and eukaryotic DNA damage in presence of Cu(II) ions. Inhibition of DNA breakage using SOD, catalase and neocuproine confirmed the involvement of reactive oxygen species and Cu(I) ions in the DNA damage. UV-visible absorption changes and mass spectrometric analysis identified a product of reaction as a deprotonated form of climacostol. Study of the interaction with DNA, using fluorescence spectroscopic techniques, showed that climacostol binds with DNA. Given the structure-activity relationship of this compound and the mechanism of its prooxidant effect, we propose that the Cu(II)-mediated oxidative DNA damage by climacostol could explain its antimicrobial and antiproliferative activity.

Climacostol reduces tumour progression in a mouse model of melanoma via the p53-dependent intrinsic apoptotic programme

“…These results demonstrate the pro-apoptotic effects of climacostol in melanoma cells, in agreement with previous results12. It has been shown that climacostol can effectively bind both histone protected and naked DNA, promoting their cleavage in the presence of copper(II)19. Our data revealed that climacostol triggers a Caspase 3-dependent apoptotic programme in melanomas with enzymatic degradation of DNA.…”

“…Our data revealed that climacostol triggers a Caspase 3-dependent apoptotic programme in melanomas with enzymatic degradation of DNA. This enzymatic cleavage could reinforce the non-enzymatic one, thus playing an important role in explaining the preferential cytotoxicity of climacostol towards tumour cells that usually contain higher copper levels than normal cells19.…”

“…2a). This further demonstrates that climacostol is a compound that rapidly forms adducts with DNA thus leading to DNA damage and cell death19. Induction of DNA damage has been shown to be an effective treatment of cancer and many used anti-tumoural drugs, as for instance platinum agents, act by inducing DNA damage72021.…”

Antimicrobial activity of geopolymers ion-exchanged with copper ions

“…from the geopolymer into fresh water also increased. Since oyster mushroom hyphae grow by absorbing nutrients from sawdust and water, the copper ions dissolved in the water suppressed the growth of oyster mushroom hyphae due to DNA damage [12][13][14][15].…”

“…Copper(II) ions exhibit strong antimicrobial activity [3][4][5][6][7][8][9][10][11] and can damage the DNA of organisms [12][13][14][15]. Therefore, materials that undergo a sustained release of copper ions have the potential to act as antimicrobial substances.…”