Necrosis, apoptosis compared

The benzyl-substituted titanocene 3, which showed a significant higher cytotoxicity when tested in vitro against LLC-PK, was evaluated in a series of biomedical studies as well. Watson et al. tested titanocene 3 in comparison to two aryl-substituted tf .va-titanocenes on prostate cancer cells, as advanced prostate cancer is not curable up to now [37]. Therefore, it was shown that all three titanocenes induced more apoptosis (programmed cell death, in contrast to necrosis) compared with cisplatin in a dose-dependent manner. Titanocene 3 had the most significant effect on the cell cycle and apoptosis. 

Apoptosis is a potentially extremely important target in drug design. Apoptosis and necrosis are the two fundamental biochemical pathologies that cause cells to die. Necrosis is death from injury (e.g., bum injury to skin) apoptosis is predestined death from old age and degeneration. Apoptosis and necrosis may be compared as shown in table 8.1. 

Using conventional histology, it is not always easy to distinguish apoptosis from necrosis they can occur simultaneously, depending on the intensity and duration of the stimulus, the extent of ATP depletion, and so on. Table 16.2 compares some of the major morphological features of apoptosis and necrosis. 

Oesch F, Steinberg P (1987) A comparative study of drug-metabolizing enzymes present in isolated rat liver parenchymal, Kupffer and endothelial cells. Biochem Soc Trans 15 372-373 Osawa Y, Nagaki M, Banno Y, Brenner DA, Asano T, Nozawa Y, Moriwaki H, Nakashima S (2002) Tumor necrosis factor alpha-induced interleukin-8 production via NF-kappaB and phosphatidylinositol 3-kinase/Akt pathways inhibits cell apoptosis in human hepatocytes. Infect Immun 70 6294-6301... 

The actions of chemicals that cause disease or death occur at the cellular level therefore, it is necessary to conduct an array of in vitro cell culture tests to determine cytotoxicity. The bulk absorbable material is tested also, hydrolyzed products as well as extracts are assessed. The most obvious marker of toxicity is cell death. Necrosis, as compared with normal cellular apoptosis, is characterized by cellular and organelle swelling followed by rupture. Apoptosis, in contrast, is programmed cell death, which is characterized by a reduction in cell volume and basophilic staining of the chromatin. There are three common in vitro screens for toxicity — agar, direct contact, and elution assays. 

In mice administered a single 20 mg dose (per 28-30 g animal) of diterpenoids isolated from skullcap, an increase in hepatic caspases was observed as compared to controls. In one skullcap-treated mouse, apoptosis affected a few hepatocytes, while in two other skullcap-treated mice, necrosis affected a few hepatocytes. No adverse effects were observed in the 13 other skullcap-treated mice. No apoptosis or necrosis was observed in the control group, nor in a group administered skullcap and pretreated with a caspase inhibitor (Haouzi et al. 2000). 

Exposure of OK and NRK-25E cells to ochratoxin A in the presence of an inhibitor of ERK 1/2 showed that the toxicity of ochratoxin A, as measured by cell number, protein, epithelial tightness, apoptosis and necrosis, was increased. Biomarkers of inflammation, fibrosis and epithelial mesenchymal transition were also enhanced in the presence of the inhibitor of ERK 1/2, compared with ochratoxin A alone. The authors speculated that the toxicity of ochratoxin A may be influenced by the balance between the profibrotic ERK 1/2 and the antifibrotic JNK and p38, which are not affected by inhibition of ERK 1/2, and that naturally occurring inhibitors of ERK 1/2, such as anthocyanidins, may amplify the effects of ochratoxin A (Sauvant et al., 2005c). 

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