Role of superoxide dismutase in cancer: a review (original) (raw)
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Overexpression of manganese or copper–zinc superoxide dismutase inhibits breast cancer growth
Free Radical Biology and Medicine, 2006
We have studied the effects of overexpression of superoxide dismutase (SOD), a tumor suppressor protein that dismutes superoxide radical to H 2 O 2 , on breast cancer cell growth in vitro and xenograft growth in vivo. No previous work has directly compared the growth-suppressive effects of manganese SOD (MnSOD) and copper-zinc SOD (CuZnSOD). We hypothesized that either adenoviral MnSOD (AdMnSOD) or adenoviral CuZnSOD (AdCuZnSOD) gene therapy would suppress the growth of human breast cancer cells. After determining the antioxidant profiles of three human breast cell lines, MCF 10A, MDA-MB231, and MCF-7, we measured the effects of MnSOD or CuZnSOD overexpression on cell growth and survival in vitro and in vivo. Results demonstrated that infection with AdMnSOD or AdCuZnSOD increased the activity of the respective enzyme in all three cell lines. In vitro, overexpression of MnSOD or CuZnSOD decreased not only cell growth but also clonogenic survival in a dose-and transgene-dependent manner. In vivo, treatment of tumors with AdMnSOD or AdCuZnSOD decreased xenograft growth compared to controls. The first direct comparison of MnSOD to CuZnSOD overexpression indicated that CuZnSOD and MnSOD were similarly effective at suppressing cancer cell growth.
Potential Mechanisms for the Inhibition of Tumor Cell Growth by Manganese Superoxide Dismutase
Antioxidants & Redox Signaling, 2001
Studies from many laboratories have shown that overexpression of manganese superoxide dismutase (MnSOD) inhibits the growth of numerous tumor cell types. The inhibition of tumor cell growth can be attributed to the increase in the steady-state levels of H 2 O 2 as a result of the increased dismuting activity of MnSOD. Here we demonstrate that overexpression of MnSOD enhances the activity of the superoxide (O 2 ? 2)-sensitive enzyme aconitase, decreases the intracellular GSH/GSSG ratio, and dose-dependently inhibits pyruvate carboxylase activity. Thus, alterations in the steady-state concentrations of mitochondrial O 2 ? 2 and H 2 O 2 as a result of MnSOD overexpression can alter the metabolic capacity of the cell leading to inhibition of cell growth. Furthermore, we propose that MnSOD overexpression can modulate the activity of nitric oxide (? NO) by preventing its reaction with O 2 ? 2. This hypothesis suggests that the redox environment of the mitochondria can be altered to favor the activity of ? NO rather than peroxynitrite (ONOO 2) and may explain the enhanced toxicity of ? NO-generating compounds toward MnSOD-overexpressing cell lines. These findings indicate that therapeutic strategies targeted at overexpressing MnSOD in tumor tissue may be more effective when used in combination with agents that deplete the oxidant-buffering and enhance the ? NO-generating capacity of the tumor and host, respectively. Antioxid. Redox Signal. 3, 361-373.
The role of manganese superoxide dismutase in the growth of pancreatic adenocarcinoma
Cancer research, 2003
Chronic pancreatitis, K-ras oncogene mutations, and the subsequent generation of reactive oxygen species (ROS) appear to be linked to pancreatic cancer. ROS have also been suggested to be mitogenic and capable of stimulating cell proliferation. Cells contain antioxidant enzymes to regulate steady state levels of ROS produced by products of metabolism. The aims of our study were to determine antioxidant enzyme activity in pancreatic cancer cells and correlate enzyme activity with tumor growth, as well as determine whether tumor cell growth could be altered with antioxidant gene transfection. Western blots, enzyme activity, and enzyme activity gels were performed for manganese superoxide dismutase (MnSOD), copper/zinc, catalase, and glutathione peroxidase in normal human pancreas and in the human pancreatic cancer cell lines BxPC-3, Capan-1, MIA PaCa-2, and AsPC-1. Cell population doubling times were determined and correlated with antioxidant enzyme activity. MnSOD was overexpressed i...
International Journal of Cancer, 2006
A cell line derived from a pleiomorphic liposarcoma, named LSA, was previously reported to secrete (a) factor(s) exhibiting oncotoxic properties. The present article describes the isolation, purification and sequence analysis of a protein released by LSA cells into conditioned culture medium. This protein proved to be a variant isoform of manganese superoxide dismutase (MnSOD), hence its designation as LSA-type-MnSOD. This LSA-type-SOD differed from conventional SODs in its secretion by producer cells, contrasting with the normal localization of SODs in the mitochondrial matrix. Interestingly, during the protein purification process, LSA-type-SOD cosegregated with a cytotoxic activity directed against a number of tumor cell lines, as determined under in vitro conditions. This cytopathic effect was most likely due to LSAtype-SOD, since it could be fully reproduced using recombinant SOD that was expressed from cDNA clones isolated from LSA cells mRNA preparations and henceforth designated L-rSOD. In addition to its manifestation in cell lines kept in tissue culture, the oncotoxicity of LSA-type-SOD was further reflected in a remarkable capacity of this protein for suppression of mammary tumors in Balb-C-FR III mice. Animals subcutaneously injected with L-rSOD in the tumor area showed a complete disruption of established mammary carcinomas, as monitored by nuclear magnetic resonance (NMR) scanning. Moreover, metastatic spreading, which was readily detected in the control group, was suppressed in the treated animals. Altogether these data suggest that LSA-type-SOD interferes with survival and spreading of neoplastically transformed cells and deserves to be future validated as a therapeutic agent against cancer, either alone or in combination with conventional treatments. ' 2006 Wiley-Liss, Inc.
Superoxide Dismutase; structure, function and possible role in cancer prevention in living cells
The enzyme superoxide dismutase (an antioxidant) is an enzyme which catalyses the dismutation reaction of superoxide to ground state oxygen and hydrogen peroxide. This enzyme was found by Irwin Fridovich and Joe McCord. The are three types of superoxide with superoxide dismutase-1 and superoxide dismutase-3 having copper and zinc and superoxide dismutase-2 being a manganese superoxide, however, superoxide dismutase-3 differs from superoxide dismutase-1.With the help of enzymes involved, such as Catalase and Glutathione reductase, complete reaction can be carried out leaving all products which are not harmful to the body. However no clear studies have been done on whether the role of superoxide dismutase radicals have any role in aging or life span but it have been clearly shown that these radicals play an important role in carcinogenesis as they mutate cancer-related genes. Superoxide dismutase however follows a very complicated mechanism due to more enzymes being involved. Superoxide Dismutase plays a role in cancer treatment even though this is not clearly out-stated, however, the enzyme increase the rate of the dismutation reaction as dismutation reaction can occur out of the enzyme but the reaction will be relatively slow which can increase possible activation of cancer cells.
Mitochondrial Superoxide Dismutase: A Promising Target for New Anticancer Therapies
Current Medicinal Chemistry, 2004
Compelling experimental and epidemiological evidence involves oxygen radicals in carcinogenesis, acting reactive oxygen species both as endogenous genotoxins during cell initiation and as messenger molecules in mitogenesis and in tumor promotion. Moreover, oxidants stimulate neoangiogenesis, which is a prerequisite for tumor growth. However, while several natural as well as synthetic antioxidant compounds appear to be chemopreventive in mutagenicity assays, antioxidant-based treatments for the prevention or cure of cancer have led to non-conclusive if not disappointing results. This is likely due to the fact that oxygen radicals have also a major role in the natural defences against the propagation of cancer cells, i.e. tumor cell apoptosis and immune surveillance, and mediate the beneficial cytotoxic effect of both the chemo-and radio-therapy. In recent years, the mitochondrial antioxidant enzyme, Manganous Superoxide Dismutase (MnSOD), has received a growing attention as a negative modulator of cellular apoptosis and as a survival factor for cancer cells. In fact, while overexpression of this enzyme in cancer cells decreases proliferation and tumor incidence in transgenic models, it is clear that even small amounts of this enzyme are crucial for cell resistance to inflammatory stimuli and anticancer drugs, and prevent oncogene-induced apoptosis triggered by the tumor suppressor protein p53. A previously unexpected oncogenic potential of MnSOD is also suggested by the elevated levels of this enzyme in several classes of human neoplasms, in a fashion which often correlates with the degree of their malignancy. This review focuses on the debated issue of the pro-and/or anti-tumoral effect of MnSOD, with special emphasis on recent observations suggesting that pharmacological inhibition of MnSOD may represent an effective strategy to selectively kill cancer cells and to circumvent their resistance to the commonly used anticancer treatments.
Medical Journal of Indonesia
Latar belakang: Glioblastoma multiforme (GBM) merupakan tumor ganas otak primer dengan prognosis yang buruk. Tingginya resistensi terapi berbasis stres oksidatif diduga berhubungan dengan tingginya status antioksidan sel GBM. Penelitian kami sebelumnya melaporkan bahwa sel glioma derajat keganasan tinggi mengekspresikan antioksidan manganese superoxide dismutase (MnSOD) yang lebih tinggi bermakna dibandingkan dengan sel glioma derajat rendah. Penelitian ini bertujuan menganalisis dampak penekanan ekspresi MnSOD terhadap ketahanan hidup sel GBM. Metode: Desain penelitian adalah penelitian eksperimental menggunakan sel lestari glioblastoma multiforme T98G. Penekanan ekspresi MnSOD dilakukan dengan transfeksi in vitro siRNA-MnSOD. Ekspresi MnSOD dianalisis melalui pengukuran mRNA menggunakan real time RT-PCR, protein dengan ELISA dan aktivitas spesifik enzim menggunakan inhibisi xantin oksidase. Kadar reactive oxygen species (ROS) intraseluler ditentukan dengan pengukuran radikal superoksida dan hidrogen peroksida. Ketahanan hidup sel dianalisis melalui pengukuran viabilitas, proliferasi, dan apoptosis sel. Hasil: Transfeksi in vitro siRNA-MnSOD berhasil menekan mRNA, protein, dan aktivitas spesifik MnSOD. Penekanan ekspresi MnSOD tersebut menyebabkan peningkatan bermakna kadar radikal superoksida, namun tidak mempengaruhi kadar hidrogen peroksida. Selain itu, terjadi penurunan bermakna viabilitas disertai peningkatan bermakna apoptosis sel, tetapi tidak memengaruhi proliferasi sel.