Loss of NF-kappa B Enhances Apoptosis by HDAC inhibitors

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): Eighty percent of all lung cancers are non-small cell lung cancers (NSCLC) and the majority present in advanced stages. Current chemotherapy modalities are rarely effective in treating NSCLC, in large part due to the chemoresistance of these tumors. Our laboratory and others have demonstrated that chemoresistance in NSCLC is partially dependent on the activation of NF-kappaB. Inhibition of NF-kappaB greatly enhances apoptosis rates following treatment with chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have demonstrated efficacy in treating some malignancies. Preliminary data in this proposal demonstrates that combined inhibition of NF-kappaB and HDAC's appears to have synergistic effects in inducing apoptosis in NSCLC cells lines. We propose to investigate intracellular signaling pathways responsible for the observed induction of apoptosis following concomitant inhibition of HDAC's and NF-kappaB. Additionally, we will investigate whether similar apoptosis rates occur in athymic nude mice xenografted with either cultured NSCLC cell lines or human tissue acquired from fresh pathological specimens. This ultimately will relate to whether HDAC inhibitors can effectively treat NSCLC in patients when administered in combination with other agents.