title: A novel manganese complex selectively induces malignant glioma cell death by targeting mitochondria.
abstract: Despite advances in treatment, malignant glioma commonly exhibits recurrence, subsequently leading to a poor prognosis. As manganese (Mn) compounds can be transported by the transferrin‑transferrin receptor system, the present study synthesized and examined the potential use of Adpa‑Mn as a novel antitumor agent. Adpa‑Mn time and dose‑dependently inhibited U251 and C6 cell proliferation; however, it had little effect on normal astrocytes. Apoptosis was significantly elevated following treatment with Adpa‑Mn, as detected by chromatin condensation, Annexin V/propidium iodide staining, cytochrome c release from mitochondria to the cytoplasm, and the activation of caspases‑9, ‑7 and ‑3 and poly (ADP‑ribose) polymerase. In addition, Adpa‑Mn enhanced fluorescence intensity of monodansylcadaverine and elevated the expression levels of the autophagy‑related protein microtubule‑associated protein 1 light chain 3. Pretreatment with the autophagy inhibitors 3‑methyladenine and chloroquine enhanced Adpa‑Mn‑induced cell inhibition, thus indicating that autophagy has an essential role in this process. Furthermore, evidence of mitochondrial dysfunction was detected in the Adpa‑Mn‑treated group, including disrupted membrane potential, elevated levels of reactive oxygen species (ROS) and depleted adenosine triphosphate. Conversely, treatment with the mitochondrial permeability transition inhibitor cyclosporin A reversed Adpa‑Mn‑induced ROS production, mitochondrial damage and cell apoptosis, thus suggesting that Adpa‑Mn may target the mitochondria. Taken together, these data suggested that Adpa‑Mn may be considered for use as a novel anti‑glioma therapeutic option.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Pharmacy, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Kaidi
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Applied Chemistry, 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: Department of Pharmacy, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Pharmacy, 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 / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008345:Manganese / Q000737:chemistry* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; C000620838:aquachloro(bis(2-pyridylmethyl)amino-2-propionic acid)manganese(II); D008345:Manganese