The involvement of the "Inhibitor of Apoptosis Proteins" (IAP) family has been strongly implicated in the resistance of various cancers to apoptosis (click here for our analysis of this field).

The X-linked inhibitor of apoptosis protein (XIAP) is one particularly well-defined member of the IAP family. XIAP expression is elevated in non-small cell lung cancer and acute myelogenous leukemia. With respect to the latter there is a strong correlation between expression and survival. A convincing body of evidence supports a direct role of XIAP in the resistance of cancer cells to radiation and chemotherapeutic intervention. Perhaps most convincing are recent reports that low dose gamma-irradiation upregulates XIAP in non-small cell lung carcinoma cells and as a result resistance to radiation-induced apoptosis was enhanced. On the other hand XIAP antisense sensitized cells to low dose gamma-irradiation. A similar approach was used to sensitize ovarian carcinoma cells to cisplatin-induced apoptosis. A greater understanding of the mechanisms through which XIAP confer resistance and improved strategies for targeting this phenomena will lead to better anti-cancer treatments and both of these areas have been addressed in our recent dossier.

Most recently, Japanese researchers investigated the effects of XIAP overexpression on taxol-induced cell growth arrest and apoptosis in the prostate cancer cell line (LNCaP). Although the growth rates were reduced in a dose- and time-dependent manner by taxol, these effects were significantly decreased in cell lines stably overexpressing XIAP. Taxol treatment was found to induce the cleavage of pro-caspase-3, followed by apoptosis. Overexpression of XIAP inhibited apoptosis by attenuating this pro-caspase-3 cleavage and caspase-3 activity. These results suggest that the overexpression of XIAP inhibits taxol-induced apoptosis through the decrease of caspase-3 activity and inhibition of the processing of pro-caspase-3.

Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it was estimated that approximately 1.3 million new cases of cancer would have been diagnosed and 555,500 people would have died from cancer in the United States in 2002. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" for a full analysis of current and future pharmaceutical approaches to cancer). Prostate cancer is one of the most common forms of cancer, however prognosis is often good with tumors being responsive to hormonal therapies. The development of hormone resistance does however result is a dramatic drop in prognosis and a narrowing of therapeutic options for the clinician. This results in a limited median survival of 10-12 months for the patient. While cytotoxic chemotherapy has been utilized for many years, its efficacy has been disappointing. The present study suggest that the use of XIAP inhibitors may dramatically improve the response to chemotherapeutic options such as taxol thus improving the treatment of patients with hormone resistant prostate cancer.

Entry date Tuesday, April 08, 2003

Adapted from Nomura et al, Urol Res 2003 Mar;31(1):37-44 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk