Copper may be key in anti-cancer mechanism of isoflavone: Study

The research suggests that genistein blocks the growth and development of cancer cell lines in a dose- and time-dependent manner due to its ability to target copper and generate pro-oxidant signaling cascades that target cancer cells.

“Copper levels are known to be considerably elevated in almost all types of cancers, in this proof-of-concept study we show that genistein is able to target endogenous copper leading to pro-oxidant signaling and consequent cell death,”​ said the researchers, led by Dr Mohammad Ullah from the Faculty of Life Sciences, at the Aligarh Muslim University (AMU), India.

“We believe that such a mechanism explains the anti-cancer effect of genistein and also its preferential cytotoxicity towards cancer cells,”​ added the authors, writing in the journal Molecular Nutrition & Food Research.​

Anti-cancer​

“It has been estimated that more than two-third of human cancers could be prevented through appropriate lifestyle modification including dietary habits,”​ said Ullah and co workers.

Epidemiological studies have suggested that populations with high isoflavone intake, through soy consumption, have lower rates of breast, prostate, and colon cancer.

Isoflavone genistein in soybean is considered a potent chemo-preventive agent against cancer. The researchers noted that the anti-cancer effects of genistein have been demonstrated against cancer models, both in vitro​ and in vivo​.

“Although several mechanisms have been proposed, a clear anticancer action mechanism of genistein is still not known,”​ said the authors.

Previous studies have proposed that the preferential cytotoxicity of genistein toward cancer cells may be explained by the elevated levels of copper in cancer tissues and cells. The authors suggested that such a mechanism may involve the mobilization of endogenous copper, and possibly chromatin-bound copper, resulting in pro-oxidant action.

It is known that copper transporters are over-expressed in malignant cells, which aid the uptake and accumulation of excess of copper. Ullah and co-workers said the reason for increased copper concentration in tumors is not clearly understood. But, noted that copper might be required for the expression of ceruloplasmin – a major copper-binding protein also elevated in cancer cells – which has been proposed to be an angiogenic stimulator.

“In this proof-of-concept study, we show that genistein-induced cytotoxicity against breast cancer cells involves mobilization of endogenous copper and the consequent pro-oxidant action,”​ said Ullah and colleagues.

Study details​

The authors reported that genistein caused a dose- and time-dependent inhibition of the development of human breast cancer cells (MDA-MB-231 and MDA-MB-468 cancer cell lines)

They observed that genistein’s inhibitory effect on the growth and development of ‘normal’ breast epithelial cells (MCF-10A) was non-significant, “thus verifying a cancer cell-specific anticancer effect,” ​they said.

Further, when breast cancer cells were treated with genistein in the presence of a copper-specific binder (chelator) known as neocuproine, no such inhibition of cancer cell development was observed.

“These results suggest the involvement of endogenous copper … as essential element, in the pathway that leads to cell growth inhibition by genistein,”​ said Ullah and co workers.

They added that whereas the copper specific chelator neocuproine was found to inhibit the anti-cancer potential of genistein, molecules which specifically bind iron (desferroxamine mesylate) and zinc (histidine) were relatively ineffective in causing such inhibition.

“This study identifies endogenous copper as a novel molecular target for cytotoxic action of genistein against cancer cells,”​ concluded the researchers.

Source: Molecular Nutrition & Food Research​
Published online ahead of print, doi: 10.1002/mnfr.201000329
“Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species”​
Authors: M.F. Ullah, A. Ahmad, H. Zubair, H.Y. Khan, Z. Wang, F.H. Sarkar, S.M. Hadi