Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)-or oxidative stress-impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC 50 of approximately 30 nM and 200 nM, respectively. CSE caused a reduction in HDAC2 protein expression that was restored by curcumin. This decrease in HDAC2 protein expression was reversed by curcumin even in the presence of cycloheximide, a protein synthesis inhibitor. The proteasomal inhibitor, MG132, also blocked CSE-induced HDAC2 degradation, increasing the levels of ubiquitinated HDAC2. Biochemical and gene chip analysis indicated that curcumin at concentrations up to 1 mM propagates its effect via antioxidant-independent mechanisms associated with the phosphorylation-ubiquitin-proteasome pathway. Thus curcumin acts at a post-translational level by maintaining both HDAC2 activity and expression, thereby reversing steroid insensitivity induced by either CSE or oxidative stress in monocytes. Curcumin may therefore have potential to reverse steroid resistance, which is common in patients with COPD and asthma.

The ATM/p53-dependent DNA damage response pathway plays an important role in the progression of lymphoid tumors. Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease. Although the ATM and p53 pathways overlap, they are not congruent, and it is unclear how the mechanism of tumor progression differs between ATM-and p53-deficient tumors. Using microarray analysis of ATM-mutant, TP53-mutant, and ATM/TP53 wild-type B-CLLs, we show that after exposure to DNA damage transcriptional responses are entirely dependent on ATM function. The p53 proapoptotic responses comprise only a part of ATMregulated transcription; additionally, ATM regulates prosurvival responses independently of p53. Consequently, the greater severity of the TP53-mutant B-CLLs compared with ATM-mutant B-CLLs is consistent with the additive effect of defective apoptotic and elevated survival responses after DNA damage in these tumors. We also show that transcription expression profiles of ATM-deficient, TP53-deficient, and wild-type B-CLLs are indistinguishable before irradiation. Therefore, damage-induced transcriptional fingerprinting can be used to stratify tumors according to their biologic differences and simultaneously identify potential targets for treating refractory tumors. IntroductionChronic B-cell lymphocytic leukemia (B-CLL) is the most common leukemia in western countries and is characterized by the proliferation of mature B cells. 1 Considerable clinical heterogeneity exists among patients with B-CLL. Some patients have stable disease for many years, whereas others have rapidly progressing disease and short life expectancy. Recently, a number of genetic markers have been identified that directly influence the progression of disease. The mutational status of the immunoglobulin heavy chain (V H ) gene distinguishes biologically distinct B-CLL subtypes, 2,3 and B-CLL tumors with unmutated V H genes are generally associated with rapid clinical progression, whereas those that have accumulated somatic mutations in the V H gene characteristically have a more indolent outcome. However, it is now clear that this simple subdivision does not always adequately predict clinical behavior, and the mutational state of genes associated with the DNA damage response pathway has been shown to provide more powerful predictive information. 4 The DNA damage response pathway plays a crucial role in the etiology and clinical behavior of malignant cells. Inducing tumor cell death by ionizing radiation (IR) and many cytotoxic drugs causes DNA double-strand breaks (DSBs), 5 and the inactivation of genes that regulate the response to DSBs is commonly found in human cancer. The ATM protein is the principal integrator of the various cellular responses to DSBs. 6 Critically, ATM is responsible for activating the p53 tumor-suppressor protein, leading to the up-regulation of p53-responsive genes that promote cell-cycle arrest and apoptosis. Outcomes of p53 activation, however, depend on the cellular contex...