Potent Anti-tumor Effects of an Active Site Mutant of Human Manganese-Superoxide Dismutase

Davis, Christopher A.; Hearn, Amy S.; Fletcher, Bradley S.; Bickford, Justin S.; García, Jorge; Lévêque, Vincent; Melendez, J. Andrés; Silverman, David N.; Zucali, James R.; Agarwal, Anupam; Nick, Harry S.

doi:10.1074/jbc.m310623200

Cited by 38 publications

(39 citation statements)

References 31 publications

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“…A polymorphic variant in GSTP1 has been examined in relation to oxidative damage with conflicting results (47,48). On the other hand, SOD levels have been shown to directly correlate with reactive oxygen species and damage produced by free radicals (49). SOD1, at the RNA level, is more highly expressed in the luminal cells, suggesting that persistence of free radicals is not a primary cause of the observed transitory damage response in the basal cells.…”

Section: Discussionmentioning

confidence: 99%

Isogenic Normal Basal and Luminal Mammary Epithelial Isolated by a Novel Method Show a Differential Response to Ionizing Radiation

Huper

Marks²

2007

Cancer Research

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Epithelial cells within the normal breast duct seem to be the primary target for neoplastic transformation events that eventually produce breast cancer. Normal epithelial cells are easily isolated and propagated using standard techniques. However, these techniques almost invariably result in populations of cells that are largely basal in character. Because only f20% of human breast cancers exhibit a basal phenotype, our understanding of the disease may be skewed by using these cells as the primary comparator to cancer. Further, because germ line mutations in BRCA1 yield breast cancers that are most often of the basal type, a comparison of normal basal and luminal cells could yield insight into the tissue and cell type specificity of this hereditary cancer susceptibility gene. In this report, we describe a simplified and efficient method for isolating basal and luminal cells from normal human breast tissue. These isogenic cells can be independently propagated and maintain phenotypic markers consistent with their respective lineages. Using these cultured cells, we show that basal and luminal cells exhibit distinct responses to ionizing radiation. Basal cells undergo a rapid but labile cell cycle arrest, whereas luminal cells show a much more durable arrest, primarily at the G 2 -M boundary. Molecular markers, including p53 protein accumulation, p53-activated genes, and BRCA1 nuclear focus formation all correlate with the respective cell cycle responses. Further, we show that short-term cultures of human breast tissue fragments treated with ionizing radiation show a similar phenomenon as indicated by the biphasic accumulation of p53 protein in the basal versus luminal layer. Together, these results indicate that normal basal cells have a transitory cell cycle arrest after DNA damage that may underlie their increased susceptibility to transformation after the loss of functional BRCA1. [Cancer Res 2007;67(7):2990-3001]

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Section: Discussionmentioning

confidence: 99%

Isogenic Normal Basal and Luminal Mammary Epithelial Isolated by a Novel Method Show a Differential Response to Ionizing Radiation

Huper

Marks²

2007

Cancer Research

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“…14 The LSA-type MnSOD, in fact, is secreted by LSA cells whereas native MnSOD is located in the mitochondrial matrix. 15 The molecular weight of the LSAtype MnSOD is about 30 kDa, as estimated by SDS-PAGE, 10 which is significantly higher than the value of 24 kDa calculated for human native MnSOD. 16 Finally, and more importantly, when injected in vitro or in vivo, the LSA-type MnSOD permeates and selectively kills tumour cells, provided that they express oestrogen receptors and low levels of catalase.…”

mentioning

confidence: 94%

Biophysical and biochemical characterization of a liposarcoma‐derived recombinant MnSOD protein acting as an anticancer agent

Mancini¹,

Borrelli²,

Schiattarella³

et al. 2008

Intl Journal of Cancer

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A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or 68 Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with 125 I-and 131 I-labelled proteins confirmed that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism. '

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“…DDCmediated SOD1 inhibition could serve as a screen for oxidatively damaged SOD 1 protein in the blood of acute myo cardial infarction subjects. Oxidative inactivation of red cell SOD by its product H 2 O 2 generates a modified protein which is recognised and selectively degraded by an intracellular proteolytic pathway (30). Both the loss of SOD activity and modified binding of copper by the active site appear to precede proteolytic recognition and degradation.…”

Section: Inhibition Of Antioxidant Enzymesmentioning

confidence: 99%

Complexity of free radical Metabolism in human Erythrocytes

Nikolić‐Kokić¹,

Blagojević²,

Spasić³

2010

Journal of Medical Biochemistry

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Kratak sadr`aj: Produkcija slobodnih radikala u eritrocitima uglavnom se odnosi na nastajanje superoksid anjon radikala (O 2 .-) putem autooksidacije oksihemoglobina u methemoglobin. Ljudski eritrociti izlo`eni su prooksidacionom delovanju vodonik-peroksida nastalog dismutacijom O 2 .-ili iz cirkulacije, kao i azot oksidu (NO) iz cirkulacije. Od di rektnih reakcija slobodnih radikala, reakcija O 2 .-i NO uz nastajanje peroksinitrita je reakcija sa primarno {tetnim posledicama po eritrocite. U eritrocitima se nalaze enzimi za{tite od oksidacionih o{te}enja, kao {to su superoksid dismu taza (SOD, EC 1.15.1.1), katalaza (CAT, EC 1.11.1.6), glutation peroksidaza (GSHPx, EC 1.11.1.9) i glutation reduktaza (GR, EC 1.6.4.2) kao i komponente male mo lekulske mase (glutation, vitamini E i C). Njihovim sadej stvom se kanali{u reakcije slobodnih radikala tako da di rektna o{te -}enja biomakromolekula budu {to manja. Me|u tim, kako nema de novo sinteze enzima u maturiranim eri trocitima, kapacitet ovih sistema je ograni~en, jer slobo d noradikalske vrste i direktno inhibiraju neke od enzima. Promene na enzimima i njihova inhibicija slobodnim radi kalima uti~u na kapacitet za{tite od oksidacionih o{te}enja i relativni udeo pojedinih komponenti u ukupnom antioksi da tivnom poten cijalu. To se mo`e pratiti i preko promena aktiv nosti pojedina~nih komponenti, ali i me |u sobnih odnosa izme|u komponenti antioksidativne odbrane diskrimina cio nim sta ti sti ~kim metodama, koje ukazuju na sveukupnost i kompleksnost odnosa antioksida tivnih kompo nenti u eritro citima i njihov sistemski zna~aj.

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Potent Anti-tumor Effects of an Active Site Mutant of Human Manganese-Superoxide Dismutase

Abstract: Mn

Cited by 38 publications

References 31 publications

Isogenic Normal Basal and Luminal Mammary Epithelial Isolated by a Novel Method Show a Differential Response to Ionizing Radiation

Isogenic Normal Basal and Luminal Mammary Epithelial Isolated by a Novel Method Show a Differential Response to Ionizing Radiation

Biophysical and biochemical characterization of a liposarcoma‐derived recombinant MnSOD protein acting as an anticancer agent

Complexity of free radical Metabolism in human Erythrocytes

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