title: Simulating hypoxia-induced acidic environment in cancer cells facilitates mobilization and redox-cycling of genomic copper by daidzein leading to pro-oxidant cell death: implications for the sensitization of resistant hypoxic cancer cells to therapeutic challenges.
abstract: This study was conducted to investigate the mechanism of action involved in the anti-cancer activity of daidzein and identification of cancer specific micro-environment as therapeutic target of this secondary metabolite derived from soy. Our data indicated that daidzein induces cellular DNA breakage, anti-proliferative effects and apoptosis in a concentration-dependent manner. We demonstrated that such a daidzein-induced anti-cancer action involves a copper-dependant pathway in which endogenous copper is mobilized by daidzein and redox-cycled to generate reactive oxygen species which act as an upstream signal leading to pro-oxidant cell death. Further in the context of hypoxia being a resistant factor against standard therapies and that an effect secondary to hypoxia is the intracellular acidification, we show that the anticancer activity of daidzein is modulated positively in acidic pH but copper-specific chelator is still able to inhibit daidzein activity. Moreover, an experimental setup of hypoxia mimic (cobalt chloride) revealed an enhanced sensitivity of cancer cells to the cytotoxic effects of daidzein which was neutralized in the presence of neocuproine. The findings support a paradigm shift from the conventional antioxidant property of dietary isoflavones to molecules capable of initiating a pro-oxidant signaling mediated by reactive oxygen species. Further, the clinical relevance of such an action mechanism in cancer chemoprevention is also proposed. This study identified endogenous copper as a molecular target and acidic pH as a modulating factor for the therapeutic activity of daidzein against cancer. The evidence presented highlights the potential of dietary agents as adjuvants to standard therapeutic regimens.
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, India. m.ullah@ut.edu.sa.|Laboratory of Phytomedicine & Therapeutics, Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia. m.ullah@ut.edu.sa.
authors.forename: Mohammad F
authors.initials: MF
authors.lastname: Ullah
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, India.|Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Laboratory of Phytomedicine & Therapeutics, Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia.
authors.forename: Showket H
authors.initials: SH
authors.lastname: Bhat
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, India.
authors.forename: Husain Y
authors.initials: HY
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, India.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Zubair
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.affiliation: Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, 202002, India.
authors.forename: Sheikh M
authors.initials: SM
authors.lastname: Hadi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003300:Copper / Q000378:metabolism*; D053837:DNA Cleavage; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015894:Genome, Human; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007529:Isoflavones / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007529:Isoflavones; D017382:Reactive Oxygen Species; C004742:daidzein; D003300:Copper
keywords: Cancer; Cell death; Chemoprevention; DNA breakage; Daidzein; Hypoxia