The role of apoptosis has been established in the pathogenesis of many human diseases. In the “Focus on CNS disease” section of this edition of TherapeuticAdvances we highlight the involvement of the "Inhibitor of Apoptosis Proteins" (IAP) family in a wide variety of neurodegenerative disorders. As discussed in our full analysis of this field members of the IAP family have also been strongly implicated in the resistance of various cancers to apoptosis. One of the most well known IAPs is survivin. Although not observed in adult differentiated tissue, this IAP is present in most transformed cell lines and cancers tested to date. For example almost all breast carcinomas of histological stages I to IH have been found positive for survivin, while no expression of survivin was detected in adjacent normal tissue. Survivin expression was strongly associated with reduced apoptotic index and poor survival rates. In colorectal cancer survivin expression inversely correlated with the apoptotic index and furthermore survivin expression was significantly related to an increased disease-free survival rate (77% vs 18% at 5 years in tumors with high survivin expression) and to a reduced risk for distant metastases (18% vs 78% at 5 years in tumors with high survivin expression) and local failure (6% vs 37% at 5 years in tumors with high survivin expression).

Survivin has been specifically implicated in cell cycle progression and has been shown to inhibit caspase-3 and -7 in the region of the spindle. The identification of strategies able to reduce survivin expression therefore holds much potential for the development of improved anticancer treatments. This concept is supported by studies showing that antisense targeting of survivin with antisense oligonucleotides or the use of ribozymes led to the induction of apoptosis, reduced tumor growth in mouse models of cancer, and sensitized cancer cells to chemo- and radiation- therapies. Most recently histone deacetylase has been linked to survivin. As described in the “Focus on oncology” section of this edition of TherapeuticAdvances, the field of histone deacetylation represents a major area of interest in the field of oncology. The importance of histone deacetylation centers around the now generally accepted view that chromatin structure is plastic and that histone (de)acetylation regulates genome structure and hence transcription. Modifying this process by histone deacetylase (HDAC) inhibitors can therefore regulate, potentially in a highly specific manner, transcription thereby offering a much more targeted approach to cytostasis than currently available. Information relating to histone deacetylation is emerging with breathtaking rapidity with over 1 new article currently being published every day. In response to this activity we recently published one of the most comprehensive overview of the pharmaceutical potential of HDAC inhibitors to date.

A link between survivin and HDACs was recently reported by researchers at the University of Antwerp. This group used chlamydocin as a highly potent inhibitor of cell proliferation and HDAC activity. Chlamydocin was found to cause an accumulation of cells in G(2)/M phase of the cell cycle and to induce apoptosis by activating caspase-3 driving cells from growth arrest into apoptosis. Concomitant with the activation of caspase-3, chlamydocin decreases the protein level of survivin via proteasomes. This data is important since not only does it demonstrate the involvement of histone deacetylation in survivin expression but it also raises the possibility of developing HDAC inhibitors as an alternative means of controlling survivin expression to that of antisense oligonucleotides.

Entry date February, 2003

Adapted from de Schepper et al, J Pharmacol Exp Ther 2003 Feb;304(2):881-8.

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