Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action

Abstract

Scope: Anticancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as antioxidants, but can be prooxidants in the presence of copper ions. We earlier proposed a mechanism for such activity of polyphenols and now we provide data in multiple cancer cell lines in support of our hypothesis. Methods and results: Through multiple assays, we show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition. Conclusion: Since the concentration of copper is significantly elevated in cancer cells, our results strengthen the idea that an important anticancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this prooxidant chemopreventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.

Effect of the polyphenol composition BP‑C3 on haematological and intestinal indicators of 5‑fluorouracil toxicity in mice

“…In the presence of copper ions, of which there are more in cancer cells than in normal cells (31), at least some polyphenols (luteolin, apigenin, epigallocatechin-3-gallate and resveratrol) act as pro-oxidants. The anti-tumour effect of these polyphenols decreases significantly in the presence of copper chelators (32).…”

Antiproliferative and pro-apoptotic effects of Andean berry juice (Vaccinium meridionale Swartz) on human colon adenocarcinoma SW480 cells

“…Recently, Khan et al (2014) proposed that the fact that carcinogenic cells have higher levels of copper compared with non-malignant cells and may be more susceptible to the transfer of electrons with antioxidants to generate ROS, so damage to DNA by copper may be an important route by which carcinogenic cells can die in the presence of polyphenols, while normal cells can survive (Azmi et al, 2006).…”

Epicatechin acts synergistically with curcumin-induced cytogenotoxic effect in acute promyelocytic leukemia HL-60 cell line

“…Furthermore, MPO activity is high in HL-60 cells [37] . Khan et al [38] found that the use of neocuproine, a chelator of Cu 2+ ions, inhibits polyphenol-induced apoptosis in cancer cell lines.…”