Apoptosis disease associated with

Diseases associated with decreased apoptosis Diseases associated with increased apoptosis... 

Caspases. Table 1 Diseases associated with inappropriate caspase activation. Contribution of apoptosis (A) and inflammation (I) are indicated... 

Diseases associated with inhibition of apoptosis include autoimmune diseases, cancer, viral infection, and allergic inflammation. 

Among the diseases associated with increased apoptosis are acquired immunodeficiency syndrome (AIDS), hemopoietic diseases, heart diseases, and neurode-generative diseases. 

Apoptosis is attributed a central importance in homeostasis of tissues in an organ or a tissue, the cell number must be kept constant within narrow limits. An increase in cells due to cell division is compensated by processes to eliminate cells that are no longer functional or are old. Apoptosis is a process that helps to keep the cell number in a tissue within limits that are suitable for the development and function of the organism. If defects occur in the apoptotic program, the consequence may be a pathologic increase or decrease in cells (Fig. 15.2). Examples of diseases associated with an increased rate of cell survival are cancer and autoimmune diseases. Diseases associated with increased apoptosis include AIDS and neurodegenerative diseases (Thompson, 1995). 

Table 2. Diseases associated with defective apoptosis regulation...

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

A number of subtle dysfunctions occur at the cellular and molecular levels in the early stages of disease progression associated with the loss of cellular homeostatic functions of endothelial cells, smooth muscle cells and macrophages which constitute the major cell types in the atheroma environment. These events include the modification of the pattern of gene expression, cell proliferation and apoptosis. 

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