In this renewal application, we propose to extend our efforts to develop novel antileukemic strategies based on the concept of disrupting/modulating the actions of differentiation-inducing agents, primarily histone deacetylase inhibitors (HDACIs), to promote mitochondrial injury and apoptosis in leukemia cells. In the preceding application, we demonstrated that the CDK inhibitor flavopiridol triggered multiple perturbations in leukemia cells, including down-regulation of p21CIP1, XIAP, Mcl-1, and NF-kappaB, that collectively blocked HDACI-mediated maturation and reciprocally potentiated apoptosis, resulting in pronounced antileukemic synergism. These studies resulted in several multi-institutional Phase I trials in patients with hematologic and non-hematologic malignancies. Insights generated during the preceding funding period have led us to the hypothesis that NF-kappaB/p65 acetylation/nuclear translocation/activation plays a pivotal role in protecting leukemic cells from HDACI-mediated lethality, and that interference with these events at multiple levels (e.g., through inhibition of IKKs, particularly IKKbeta, proteasome inhibition, or activation of the SIRT1 HDAC by resveratrol) potently trigger leukemic cell apoptosis through the selective induction of oxidative injury.
The specific aims of this proposal are a) to elucidate, through both pharmacologic and genetic strategies, the functional roles of disruption of p65 acetylation/phosphorylation, nuclear translocation, and activation in synergistic antileukemic interactions between these agents;b) to determine whether and to what extent downregulation/inactivation of NF-kappaB antioxidant target genes, particularly MnSOD, Trx/TrxR, and GPx1, culminate in oxidative injury and contribute to antileukemic activity and selectivity;c) to test the hypothesis that sustained activation of the stress-related JNK pathway plays a critical role in mediating the antileukemic activity of these regimens;and d) to perform parallel studies in primary leukemic and leukemia stem cells (LSC), and to employ xenograft and NOD/SCID murine models, to establish a basis for the selectivity of this strategy. The relevance of this proposal is that the information generated may provide a rational foundation for the development of entirely novel antileukemic regimens combining inhibitors of an important survival pathway (NF-kappaB) and a promising new class of antileukemic agents (HDAC inhibitors) in the treatment of acute leukemia and potentially other hematologic malignancies in humans.
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