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Inhibitor of apoptosis proteins (IAPs) is a family of highly-conserved anti-apoptotic proteins. One of the functions of IAPs is negative regulation of caspases. It has also been shown that over-expression of some of IAPs is one of the mechanisms cancer cells employ to counteract the effects of pro-apoptotic stimuli such as ionizing radiation and chemotherapeutic agents.

Smac/DIABLO, a protein released from the mitochondria in response to apoptotic stimuli, has been shown to promote apoptosis by directly binding to and displacing caspase-9 from X-linked IAP (XIAP) and other IAPs. In this study, a non-peptide, small molecule Smac mimetic compound was evaluated in its efficacy as a radiosensitizer. This compound, which was designed to bind to the BIR3 domain of the XIAP molecule, has been shown previously to promote apoptosis in a variety of human cancer cell lines.

Radiation plays an important role in the treatment of patients with Hodgkins Disease (HD) as well as low-to-intermediate grade non-Hodgkins Lymphoma (NHL). Combined modality therapy, a sequential combination of chemotherapy followed by radiation therapy, is the standard of care for many patients with HD as well as aggressive NHL. Despite initial response to chemotherapy and/or radiation therapy, disease recurrence continues to be a major cause of morbidity and mortality among many patients with HD and NHL. Also, despite advances in development of new systemic agents and their optimal use, overall toxicities of combination chemotherapy regimen followed by radiation therapy continues to be problematic in many cases.

We have been studying the effect of small molecule, non-peptide mimetic of Smac/DIABLO as a potent and specific inhibitor of XIAP as well as other IAPs. Our previous work on human breast cancer cell lines showed that high affinity Smac mimetics can in fact enhance the level of radiation induced cell death. We also showed that this enhancement occurs concurrently with enhancement of radiation induced apoptosis.

Here, we show that a high affinity Smac peptidomimetic acts as a potent in vitro radiosensitizer in a panel of human non-Hodgkins lymphoma cell lines. Our preliminary data shows that this compound increases the level of apoptosis and reduces the survival of irradiated lymphoma cells. More interestingly, this level of enhancement appears to occur even at a very low doses of this compound, a dose at which none of our cells show appreciable change in growth characteristics.

We propose that targeting of IAP via introduction of potent small molecule Smac peptidomimetics is a powerful strategy to enhance radiation induced cell death in non-Hodgkin lymphomas cells. Such Smac mimetics may have the therapeutic potential to be developed as a novel class of biologically targeted anticancer agents to be used in combination with radiation therapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA