Cancer is a malignant tumor that occurs as a result of abnormal and uncontrolled cellular divisions. Manganese may be critical in the development of some cancers as tumor cells usually have low concentrations of SOD2 and ROS play a role in tumor formation. Also, transfection with SOD2 enhances cellular differentiation and inhibits malignant transformation.12,51
A Mn salen mimetic of superoxide dismutase and catalase (EUK-135) has been found to exert pharmacologic efficacy in cell survival following UVB irradiation.52 UVB irradiation produces both oxidative stress and DNA damage, and induces N-terminal phosphorylation of p53 protein, an important oncogene for human cancers. Pretreatment with EUK-135 before exposure to UVB reduced the concentration of p53, in a dose-dependent manner, and inhibited the mitogen-activated protein kinase (MAPK) pathway response to oxidative stress.
The loss of the malignant phenotype in melanoma from transfection of plasmid cDNA SOD2 was initially reported by Church etal.53 Since then this technique has produced similar positive findings in mouse fibrosarcoma and human cancer cells of the breast, lung, central nervous system, prostate and oral cavity (squamous).12 In human prostate cells, transfection of the cDNA increases the expression of SOD2 approximately sixfold. Although this increment is less than the normal tenfold, the elevation is sufficient to decrease tumors. Transfection of SOD2 induced apoptosis, a G1 delay in the cell cycle, and diminished tumor volume.54 The suppression of tumor growth in prostate and other cancers suggests that SOD2 is a tumor-suppressor gene.12
Recently, the transfection efficiency of SOD2 has been improved with an adenoviral vector (adenovirusMnSOD), rather than a plasmid. This complex was administered to hamster and human oral cancer cells in combination with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), a compound that inhibits glutathione peroxidase (GPX). GPX is the enzyme that catalyzes the breakdown of H2O2 that is formed by the dismutation of SOD2 on superoxide. An inhibitor of GPX was added since it is believed that it would inhibit the removal of H2O2 and the higher levels of this ROS would potentiate the killing of cancer cells.12 The combination therapy caused 80 and 50% decreases in cell viability for human and hamster oral cancer cells, respectively. The increase in cures indicates that this treatment may be effective for solid oral cavity tumors that are accessible for injection.
Evidence suggests that another manganese complex, manganese N-nicotinoyl-N'-o-hydroxythiobenzhydrazide [Mn(Notbh)(H2O)], may also be a therapeutic agent for lymphoma and other cancers. This manganese complex (as well as a copper form) prolonged survival in mice exhibiting tumors. The mechanism was believed to be the dual action of a direct annihilation of the tumor cell and a reversal of the immunosuppression observed with tumor growth.55
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