title: Tumor-targeting novel manganese complex induces ROS-mediated apoptotic and autophagic cancer cell death.
abstract: In this study, the antitumor activity of the novel manganese (II) compound, Adpa-Mn {[(Adpa)Mn(Cl)(H(2)O)] (Adpa=bis(2-pyridylmethyl)amino-2-propionic acid)}, and its possible mechanisms of action were investigated. In vitro, the growth inhibitory effects of Adpa-Mn (with IC(50) values lower than 15 µM) on tumor cell lines were examined by MTT assay. We found that this compound was more selective against cancer cells than the popular chemotherapeutic reagent, cisplatin. We then found that Adpa-Mn achieved its selectivity against cancer cells through the transferrin (Tf)-transferrin receptor (TfR) system, which is highly expressed in tumor cells. Furthermore, Adpa-Mn induced both apoptosis and autophagy, as indicated by chromatin condensation, the activation of poly(ADP-ribose) polymerase (PARP), Annexin V/propidium iodide staining, an enhanced fluorescence intensity of monodansylcadaverine (MDC), as well as the elevated expression of the autophagy-related protein, microtubule-associated protein 1 light chain 3 (LC3). In addition, Adpa-Mn induced the generation of intracellular reactive oxygen species (ROS) and its anticancer effects were significantly reduced following pre-treatment with the antioxidant, N-acetyl cysteine, indicating that ROS triggered cell death. In vivo, the induction of apoptosis and autophagy in tumor tissue was confirmed following treatment with Adpa-Mn, which contributed to its significant antitumor activity against hepatocellular carcinoma (Hep-A cell) xenografts at 10 mg/kg. Taken together, these data suggest the possible use of Adpa-Mn as a novel anticancer drug.
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Geng
authors.affiliation: School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008345:Manganese / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D008345:Manganese