Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors.

Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC50 values 3-10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC50 values 9-17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.

Retrospective analysis of 119 cases of pediatric acute promyelocytic leukemia: Comparisons of four treatment regimes.

Clinical trials have demonstrated that pediatric acute promyelocytic leukemia (APL) is highly curable. Small-scale studies have reported on the treatment of APL using one or two treatment regimes. Here, we report a multiple center-based study of 119 cases of pediatric APL treated with four regimes based on all-trans-retinoic acid (ATRA). We retrospectively analyzed the clinical characteristics, laboratorial test results and treatment outcome of the pediatric APL patients. Regime 1 used an in-house developed protocol, regime 2 was modified from the PETHEMA LPA99 protocol, regime 3 was modified from the European-APL93 protocol, and regime 4 used a protocol suggested by the British Committee for Standards in Haematology. The overall complete remission rates for the four regimes were 88.9, 87.5, 97.1 and 87.5%, respectively, which exhibited no statistical difference. However, more favorable results were observed for regimes 2 and 3 than regimes 1 and 4, in terms of the estimated 3.5-year disease-free survivals, relapse rates, drug toxicity (including hepatotoxicity, cardiac arrhythmia, and differentiation syndrome) and sepsis. In conclusion, the overall outcomes were more favorable after treatment with regimes 2 and 3 than with regimes 1 and 4, and this may have been due to the specific compositions of regimes 2 and 3.

Signal pathways in ouabain-induced proliferation of leukemia cells.

BACKGROUND: Cardiotonic steroids (CTSs) can bind to Na(+)/K(+)-ATPase and activate protein kinase cascades, resulting in changes in cell proliferation, differentiation or apoptosis in a cell-specific manner. We explored the participation of ouabain-activated signaling pathways in growth regulation of leukemia cells. METHODS: Lymphocytic leukemia Jhhan cells and megakaryocytic leukemia M07e cells were incubated at different concentrations of ouabain (0, 1 and 10 nmol) for 24 hours. Cell proliferation was measured by methyl thiazolyl tetrazolium (MTT) assay. To probe the role of ouabain-induced signaling in control of cell growth, we employed Src kinase inhibitor PP2 and the MEK inhibitor PD98059, respectively. The expression of Na(+)/K(+)-ATPase alpha1 subunit of leukemia cells was evaluated by RT-PCR and Western blotting. RESULTS: One nmol and 10 nmol ouabain promoted proliferation of both Jhhan and M07e cells. Ouabain also up-regulated the expression of Na(+)/K(+)-ATPase alpha1 subunit. Addition of either PP2 or PD98059 blocked the effects of ouabain on cell proliferation. CONCLUSION: Ouabain activates Src and ERK1/2 pathways and regulates the proliferation of leukemia cells.