Apoptosis DNA damage

Cell cycle progression, apoptosis, DNA damage and DNA repair are cellular functions that are regulated by several mechanisms. One such important regulatory mechanism is posttranslational modification of histone and non-histone proteins. Myriad of reports have been shown that acetylation of non-histone proteins apart from histones, contributes in major to these processes. 

Niacin at cellular level has protective effects in preventing apoptosis, DNA damage and lipid metabolism. 

Hybrid NORMs are expected to induce cellular oxidative stress by release of NOjc, thiophiUc electrophiles, and through depletion of bioactivating species. High levels of oxidative stress and NO release are compatible with induction of apoptosis, DNA damage, and a role in chemotherapy, while lower levels of oxidative stress and lower rates of NO release are commensurate with induction of multiple chemopreventive pathways. 

Cell Cycle Control. Figure 3 The DNA damage checkpoint. In response to DNA damage cells activate p53 dependent and independent checkpoint pathways leading to cell cycle arrest at G1/S and G2/M allowing DNA repair. If the cellular damage cannot be repaired, cells can initiate apoptosis. 

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

Topo inhibitors are found to be the most efficient inducers of apoptosis. The main pathways leading from topo-mediated DNA damage to cell death involve activation of caspases in the cytoplasm by pro-apoptotic molecules released from mitochondria. In some cells, the apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement of these apoptotic ef-... 

A second explanation of the ability of oxidative stress to cause DNA damage is that the stress tri ers a series of metabolic events within the cell that lead to activation of nuclease enzymes, which cleave the DNA backbone. Oxidative stress causes rises in intracellular free Ca, which can fiagment DNA by activating Ca -dependent endonucleases (Orrenius etal., 1989 Farber, 1990 Ueda and Shah, 1992) in a mechanism with some of the features of apoptosis (see Wyllie, 1980). An example of apoptosis is the killing of immature thymocytes by glucocorticoid hormones, which activate a cell-destructive process that apparently involves DNA fragmentation by a Ca -dependent nuclease. 

In summary, we showed that DNA damage can elicit a variety of responses in Xenopus early embryos. While y-irradiation induces apoptosis in the embryos, DSB-containing DNA prevents initiation of DNA replication in cell-free extracts derived from eggs. 

In summary, unoxidized lycopene can act as a lipid and a DNA antioxidant at physiological concentrations but oxidized lycopene or high concentrations of lycopene, and depending upon the oxidizing conditions, may increase lipid peroxidation and oxidative DNA damage. Furthermore, the pro-oxidant effects may result in an increased apoptosis and a decreased cell viability, which should be kept in mind as studies on proliferation and apoptosis are reviewed. 

Note THF = tetrahydrofuran BHT = butylated hydroxytoluene, an antioxidant Camptothecin (CM) = causes inhibition of the DNA enzyme topoisomerase (Top 1) which induces DNA damage and apoptosis DHT = dihydrotestosterone PrEC = normal prostate stromal cells LNCaP, PC-3, DU-145 = neoplastic prostate epithelial cells (See Table 21.1). 

Bonnesen C, Eggleston I M and Hayes J D (2001), Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines , Cancer Rese, 61, 6120-6130. 

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