Cellular zinc fluxes and the regulation of apoptosis - gene-directed cell death
The maintenance of discrete subcellular pools of zinc (Zn) is critical for the functional and structural integrity of cells. Among the important biological processes influenced by Zn is apoptosis, a process that is important in cellular homeostasis (an important cellular homeostatic process). It has also been identified as a major mechanism contributing to cell death in response to toxins and in disease, offering hope that novel therapies that target apoptotic pathways may be developed. Because Zn levels in the body can be increased in a relatively nontoxic manner, it may be possible to prevent or ameliorate degenerative disorders that are associated with high rates of apoptotic cell death. This review begins with brief introductions that address, first, the cellular biology of Zn, especially the critical labile Zn pools, and, second, the phenomenon of apoptosis.
Gene disruption using zinc finger nuclease technology
Zinc finger nucleases are reagents that induce DNA double-strand breaks at specific sites that can be repaired by nonhomologous end joining, inducing alterations in the genome. This strategy has enabled highly efficient gene disruption in numerous cell types and model organisms opening a door for new therapeutic applications. Here, we describe the disruption of CD147/basigin by this technique in a human cancer cell line.
Effects of Zinc Supplementation on Clinical Outcomes in Patients Receiving Radiotherapy for Head and Neck Cancers: A Double-Blinded Randomized Study
One impact seen was that zinc supplementation improved LFS at 3 years after beginning treatment for patients with Stages III–IV disease. It is imperative that these patients be followed up for a longer period to draw a definite conclusion
Zinc sensitizes prostate cancer cells to sorafenib and regulates the expression of Livin
In prostate carcinogenesis, normal zinc-accumulating epithelial cells are transformed into malignant cells that do not accumulate zinc. Increased levels of zinc have been shown to induce apoptosis through a caspase-dependent mechanism with down-regulated anti-apoptotic proteins in prostate cancer cells. We also found that, unlike its counterparts Survivin and cIAP2, Livin was not decreased all the time; instead, it was compensatorily increased in zinc-mediated apoptosis at 48 h in prostate cancer cells. Our results offer potential treatment combinations that may augment the effect of sorafenib, and also reveal, for the first time, that increased Livin expression may play a role in the early cell death response of prostate cancer cells to zinc.
An in vitro and in vivo study of a novel zinc complex, zinc N-(2-hydroxyacetophenone)glycinate to overcome multidrug resistance in cancer
Intraperitoneal application of ZnNG in mice does not show any systemic toxicity in preliminary trials in normal mice. To conclude, a novel metal chelate of zinc viz., ZnNG, may be a promising therapeutic agent against sensitive as well as drug resistant cancers.
Superoxide dismutases in malignant cells and human tumors
Reactive oxygen metabolites have multifactorial effects on the regulation of cell growth and the capacity of malignant cells to invade. Overexpression of the superoxide dismutases (SODs) in vitro increases cell differentiation, decreases cell growth and proliferation, and can reverse a malignant phenotype to a nonmalignant one. Administering high concentrations of SOD to cells in vitro is usually associated with a non- or less malignant phenotype, whereas secondary induction of SOD in tumors in vivo can be associated with an aggressive malignant transformation probably due to the altered (oxidative) redox state in the malignant cells. This concept suggests that for many types of tumors antioxidants could be used to diminish the invasive capability of malignant cells.
Overexpression of copper zinc superoxide dismutase suppresses human glioma cell growth
Currently, ROS are being implicated in the pathogenesis of a growing number of disease processes. Carcinogenesis, neurodegeneration, and aging are all thought to have a ROS component in their pathogenesis. Copper zinc superoxide dismutase (CuZnSOD) is an essential primary antioxidant enzyme that converts superoxide radical to hydrogen peroxide and molecular oxygen in the cytoplasm. Cytosolic glutathione peroxidase (GPx) converts hydrogen peroxide into water. The overall goal of the present study was to explore the possible role of the antioxidant enzyme CuZnSOD in expression of the malignant phenotype. This work suggested that CuZnSOD is a new tumor suppressor gene. Increased intracellular ROS levels were found in cells with high activity ratios of CuZnSOD:GPx. Change in the cellular redox status, especially change attributable to the accumulation of hydrogen peroxide or other hydroperoxides, is a possible reason to explain the suppression of tumor growth observed in CuZnSOD-overexpressing cells.
Relationship between serum levels of superoxide dismutase activity and subsequent risk of cancer mortality
Relationship between serum levels of superoxide dismutase activity and subsequent risk of cancer mortality: Findings from a nested case-control study within the Japan Collaborative Cohort Study. Superoxide dismutases (SODs) are antioxidant enzymes that play a role in the defense system of the body. They may be involved in protection against carcinogenesis processes. In the present study, we investigate the association between serum SOD activity and the risk of deaths due to all cancers combined, based on a nested case-control study within the Japan Collaborative Cohort Study of 914 cancer deaths and 2,739 matched controls. Blood samples were obtained at the baseline and stored at -80 degrees C until analysis for SOD levels. Serum levels of SODs were divided into quartiles, with the first quartile used as the reference. A conditional logistic model was used to estimate odds ratios (ORs) for total cancer mortality associated with serum SOD quartile levels. The adjusted ORs and 95% confidence intervals (CIs) for the second, third and fourth SOD quartiles were 0.96 (95%CI: 0.77-1.19), 1.18 (0.92-1.51), and 1.32 (1.04-1.69), respectively. In analyses stratified by observation period, the adjusted ORs of the respective quartiles were 0.81 (95%CI: 0.60-1.08), 0.98 (0.70-1.37), and 1.28 (0.92-1.79) for the period from the baseline to 1994; and the adjusted ORs were 1.18 (95%CI: 0.85-1.63), 1.47 (1.04-2.10), and 1.41 (1.00-2.04) for the period after 1994. To conclude, we found a slightly positive association between serum SOD level and the risk of all cancer mortality in the present study. Elevated serum SOD levels might reflect a response to oxidative stress, and then may predict a state of excess reactive oxygen species in the carcinogenesis process. Detailed studies of associations between serum SOD levels and cancers in specific sites should now be performed, with attention to particular tumour types.
Suppressive effect of recombinant human Cu, Zn-superoxide dismutase on lung metastasis of murine tumor cells.
The inhibitory effect of recombinant human Cu++Zn++superoxide dismutase (rhSOD) on metastasis of tumor cells in the mouse was investigated. In an experimental pulmonary metastasis model employing Meth A cells as inoculum, significant inhibition of metastasis was obtained by intravenous pre- and post-administration of rhSOD. An inhibitory effect of rhSOD was also observed in a spontaneous pulmonary metastasis model with 3LL cells as the inoculum. rhSOD was not observed to have any significant effects on the platelet-aggregating activity of tumor cells, the adhesiveness of tumor cells to vascular components (endothelial cells, laminin and type-IV collagen), or the growth of tumor cells either in vitro or in vivo. However, rhSOD suppressed invasion of Meth A and 3LL cells into Matrigel (an artificially reconstituted basement membrane of collagen, laminin and heparan sulfate) in the presence of hypoxanthine and xanthine oxidase, in vitro producers of superoxide. Thus, the present study shows that rhSOD is able to inhibit both experimental and spontaneous pulmonary metastasis, possibly through the suppression of tumor cell invasion into the extracellular matrix.
Enhanced inhibition of experimental metastasis by the combination chemotherapy of Cu-Zn SOD and adriamycin
We previously reported that reactive oxygen species (ROS) enhance tumor cell metastasis, and by administration of recombinant human superoxide dismutase (rh SOD), an enzyme which scavenges O−2O2− successfully reduced lung metastasis of mouse MethA sarcoma and Lewis lung carcinoma. These observations suggested that rh SOD suppressed tumor cell invasion by eliminating O−2O2− , the primary source of ROS. The combination chemotherapy of SOD with anticancer drugs such as ADR can be a practical anti-metastasis strategy.
The bio-energetic theory of carcinogenesis
The altered energy metabolism of tumor cells provides a viable target for a non toxic chemotherapeutic approach. An increased glucose consumption rate has been observed in malignant cells. Warburg (Nobel Laureate in medicine) postulated that the respiratory process of malignant cells was impaired and that the transformation of a normal cell to malignant was due to defects in the aerobic respiratory pathways. Szent-Györgyi (Nobel Laureate in medicine) also viewed cancer as originating from insufficient availability of oxygen. Oxygen by itself has an inhibitory action on malignant cell proliferation by interfering with anaerobic respiration (fermentation and lactic acid production). Interestingly, during cell differentiation (where cell energy level is high) there is an increased cellular production of oxidants that appear to provide one type of physiological stimulation for changes in gene expression that may lead to a terminal differentiated state. The failure to maintain high ATP production (high cell energy levels) may be a consequence of inactivation of key enzymes, especially those related to the Krebs cycle and the electron transport system. A distorted mitochondrial function (transmembrane potential) may result. This aspect could be suggestive of an important mitochondrial involvement in the carcinogenic process in addition to presenting it as a possible therapeutic target for cancer. Intermediate metabolic correction of the mitochondria is postulated as a possible non-toxic therapeutic approach for cancer.
DNA damage and mutation. Types of DNA damage
This review outlines the basic types of DNA damage caused by exogenous and endogenous factors, analyses the possible consequences of each type of damage and discusses the need for different types of DNA repair. The mechanisms by which a minor damaging event to DNA may eventually result in the introduction of heritable mutation/s are reviewed. The major features of the role of DNA damage in ageing and carcinogenesis are outlined and the role of iatrogenic DNA damage in human health and disease (with curative intent as well as a long-term adverse effect of genotoxic therapies) are discussed in detail.