title: Cytotoxicity of Manganese (III) Complex in Human Breast Adenocarcinoma Cell Line Is Mediated by the Generation of Reactive Oxygen Species Followed by Mitochondrial Damage.
abstract: Manganese (Mn) complexes are widely studied because of their important catalytic properties in synthetic and biochemical reactions. A Mn (III) complex of an amidoamine ligand was synthesized using a tetradentate amidoamine ligand. In this study, the Mn (III) complex was evaluated for its biological activity by measuring its cytotoxicity in human breast adenocarcinoma cell line (MCF-7). Cytotoxic effects of the Mn (III) complex were determined using established biomarkers in an attempt to delineate the mechanism of action and the utility of the complex as a potential anticancer drug. The Mn (III) complex induces cell death in a dose- and time-dependent manner as shown by microculture tetrazolium assay, a measure of cytotoxic cell death. Our results demonstrated that cytotoxic effects were significantly increased at higher concentrations of Mn (III) complex and with longer time of treatment. The IC50(Inhibitor concentration that results in 50% cell death) value of Mn (III) complex in MCF-7 cells was determined to be 2.5 mmol/L for 24 hours of treatment. In additional experiments, we determined the Mn (III) complex-mediated cell death was due to both apoptotic and nonspecific necrotic cell death mechanisms. This was assessed by ethidium bromide/acridine orange staining and flow cytometry techniques. The Mn (III) complex produced reactive oxygen species (ROS) triggering the expression of manganese superoxide dismutase 1 and ultimately damaging the mitochondrial function as is evident by a decline in mitochondrial membrane potential. Treatment of the cells with free radical scavenger, N, N-dimethylthiourea decreased Mn (III) complex-mediated generation of ROS and attenuated apoptosis. Together, these results suggest that the Mn (III) complex-mediated MCF-7 cell death utilizes combined mechanism involving apoptosis and necrosis perhaps due to the generation of ROS.
authors.affiliation: Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, USA.|Department of Biology, University of Diyala, Baqubah, Iraq.
authors.forename: Qudes
authors.initials: Q
authors.lastname: Al-Anbaky
authors.affiliation: Department of Biology, University of Diyala, Baqubah, Iraq.
authors.forename: Zeiyad
authors.initials: Z
authors.lastname: Al-Karakooly
authors.affiliation: Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Surya P
authors.initials: SP
authors.lastname: Kilaparty
authors.affiliation: Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Agrawal
authors.affiliation: Department of Chemistry, University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Yahya M
authors.initials: YM
authors.lastname: Albkuri
authors.affiliation: Department of Chemistry, University of Arkansas at Little Rock, Little Rock, AR, USA.
authors.forename: Ambar B
authors.initials: AB
authors.lastname: RanguMagar
authors.affiliation: Department of Chemistry, University of Arkansas at Little Rock, Little Rock, AR, USA axghosh@ualr.edu.
authors.forename: Anindya
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, USA nali@ualr.edu.
authors.forename: Nawab
authors.initials: N
authors.lastname: Ali
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D008345:Manganese / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D017382:Reactive Oxygen Species; D008345:Manganese; D013482:Superoxide Dismutase
keywords: apoptosis; breast cancer; cytotoxicity; manganese (III) complex; reactive oxygen species