Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma.

Interdisciplinary Program in Molecular and Cellular Biology and Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
Free Radical Biology and Medicine (Impact Factor: 5.71). 05/2008; 44(8):1677-86. DOI: 10.1016/j.freeradbiomed.2008.01.022
Source: PubMed

ABSTRACT Increased reactive oxygen species (ROS) such as superoxide have been implicated as causal elements of oncogenesis. A variety of cancers have displayed changes in steady-state levels of key antioxidant enzymes, with the mitochondrial form of superoxide dismutase (MnSOD) being commonly implicated. Increasing MnSOD expression suppresses the malignant phenotype in various cancer cell lines and suppresses tumor formation in xenograft and transgenic mouse models. We examined the impact of MnSOD expression in the development of T cell lymphoma in mice expressing proapoptotic Bax. Lck-Bax38/1 transgenic mice were crossed to mice overexpressing MnSOD (Lck-MnSOD) as well as MnSOD+/- mice. The effects of MnSOD on apoptosis, cell cycle, chromosomal instability (CIN), and lymphoma development were determined. The apoptotic and cell cycle phenotypes observed in thymocytes from control and Bax transgenic mice were unaffected by variations in MnSOD levels. Remarkably, increased gene dosage of MnSOD significantly decreased aneuploidy in premalignant thymocytes as well as the onset of tumor formation in Lck-Bax38/1 mice. The observed effects of MnSOD support a role for ROS in CIN and tumor formation in this mouse model of T cell lymphoma.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Increasing Manganese superoxide dismutase (MnSOD) expression could suppress the malignant phenotype in various cancer cell lines and suppress tumor formation in xenograft and transgenic mouse models. Mimic of Manganese superoxide dismutase (MnSODm), synthesized by chemical method, has been shown to possess anti-tumor. However, the anti-cancer activity of MnSODm in acute myeloid leukemia (AML) is still obscure. In this study, we investigated the effects of MnSODm on the apoptosis of human leukemia HL-60 cells. The resulted showed MnSODm significantly reduced the proliferation of HL-60 cells in a concentration and a time-dependent manner. By flow cytometric analysis, we found that MnSODm treatment resulted in an increased apoptosis in HL-60 cells. Further analysis demonstrated the involvement of activation of caspase cascade, cleavage of poly (ADP-ribose) polymerase (PARP), and release of cytochrome c in MnSODm-induced apoptosis. The results also showed that the expression of anti-apoptotic Bcl-2 and Bid were dose-dependently decreased, whereas the expressions of pro-apoptotic Bax protein were increased. Thus, MnSODm-induced apoptosis in HL-60 cells via mitochondria-mediated, caspases-dependent pathways. MnSODm inhibition of Akt phosphorylation may contribute to MnSODm-mediated acute myeloid leukemia cell growth inhibition and apoptosis induction.
    Leukemia & lymphoma 07/2013; · 2.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) are generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. This work describes the role of the manganese superoxide dismutase (MnSOD) as a biomarker of different human diseases and proposes a new therapeutic application for the prevention of cancer and its treatment. The paper also describes how a new form of human MnSOD was discovered, its initial application, and its clinical potentials. The MnSOD isolated from a human liposarcoma cell line (LSA) was able to kill cancer cells expressing estrogen receptors, but it did not have cytotoxic effects on normal cells. Together with its oncotoxic activity, the recombinant MnSOD (rMnSOD) exerts a radioprotective effect on normal cells irradiated with X-rays. The rMnSOD is characterized by the presence of a leader peptide, which allows the protein to enter cells: this unique property can be used in the radiodiagnosis of cancer or chemotherapy, conjugating radioactive substances or chemotherapic drugs to the leader peptide of the MnSOD. Compared to traditional chemotherapic agents, the drugs conjugated with the leader peptide of MnSOD can selectively reach and enter cancer cells, thus reducing the side effects of traditional treatments.
    BioMed research international. 01/2014; 2014:476789.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to investigate the protective effects of Mimic of Manganese superoxide dismutase (MnSODm) against carbon tetrachloride (CCl4)-induced hepatic injury in mice. Bifendate or MnSODm was intragastrically administered per day for 7days. On the 8th day, all mice except the normal group were given 0.5% CCl4/peanut oil to induce hepatic injury model by intraperitoneal injection. Mice were sacrificed 24h after CCl4 treatment. Compared with the CCl4 group, MnSODm significantly decreased the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the serum and liver. Moreover, the contents of hepatic and serum malondialdehyde (MDA) and nitric oxide (NO) with inducible nitric oxide synthase (iNOS) activities were reduced. Histological findings also confirmed the antihepatotoxic characterization. In addition, MnSODm inhibited the pro-inflammatory mediators, such as prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Further investigation showed that the inhibitory effect of MnSODm on the pro-inflammatory cytokines was associated with the down-regulation of nuclear factor-kappa B (NF-κB). In brief, our results show that the protective effect of MnSODm against CCl4-induced hepatic injury may rely on its ability to reduce oxidative stress and suppress inflammatory responses.
    International Immunopharmacology 06/2014; · 2.71 Impact Factor

Full-text (2 Sources)

Available from
Jul 3, 2014