Redox cycling of endogenous copper by ferulic acid leads to cellular DNA breakage and consequent cell death: A putative cancer chemotherapy mechanism

Journal Article · Tue Dec 01 04:00:00 EST 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.09.018· OSTI ID:22687831

Sarwar, Tarique ^[1]; Zafaryab, Md ^[2]; Husain, Mohammed Amir; Ishqi, Hassan Mubarak; Rehman, Sayeed Ur ^[1]; Moshahid Alam Rizvi, M. ^[2]; Tabish, Mohammad ^[1]

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1. Department of Biochemistry, Faculty of Life Sciences, A.M. University, Aligarh, UP 202002 (India)
2. Genome Biology Lab, Department of Biosciences, Jamia Millia Islamia, Central University, New Delhi 110025 (India)

Ferulic acid (FA) is a plant polyphenol showing diverse therapeutic effects against cancer, diabetes, cardiovascular and neurodegenerative diseases. FA is a known antioxidant at lower concentrations, however at higher concentrations or in the presence of metal ions such as copper, it may act as a pro-oxidant. It has been reported that copper levels are significantly raised in different malignancies. Cancer cells are under increased oxidative stress as compared to normal cells. Certain therapeutic substances like polyphenols can further increase this oxidative stress and kill cancer cells without affecting the proliferation of normal cells. Through various in vitro experiments we have shown that the pro-oxidant properties of FA are enhanced in the presence of copper. Comet assay demonstrated the ability of FA to cause oxidative DNA breakage in human peripheral lymphocytes which was ameliorated by specific copper-chelating agent such as neocuproine and scavengers of ROS. This suggested the mobilization of endogenous copper in ROS generation and consequent DNA damage. These results were further validated through cytotoxicity experiments involving different cell lines. Thus, we conclude that such a pro-oxidant mechanism involving endogenous copper better explains the anticancer activities of FA. This would be an alternate non-enzymatic, and copper-mediated pathway for the cytotoxic activities of FA where it can selectively target cancer cells with elevated levels of copper and ROS. - Highlights: • Pro-oxidant properties of ferulic acid are enhanced in presence of copper. • Ferulic acid causes oxidative DNA damage in lymphocytes as observed by comet assay. • DNA damage was ameliorated by copper chelating agent neocuproine and ROS scavengers. • Endogenous copper is involved in ROS generation causing DNA damage. • Ferulic acid exerts cancer cell specific cytotoxicity as observed by MTT assay.

• OSTI ID: 22687831
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 289; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ABUNDANCE
ANTIOXIDANTS
APOPTOSIS
CHELATING AGENTS
CHEMOTHERAPY
CONCENTRATION RATIO
COPPER
DNA
DNA DAMAGES
IN VITRO
LYMPHOCYTES
NEOPLASMS
NERVOUS SYSTEM DISEASES
OXIDATION
OXIDIZERS
POLYPHENOLS
TOXICITY