Abstract:

Chemical biology is a scientific interdiscipline spanning the fields of chemistry and biology that involves the application of chemical tools, often compounds, to the study and manipulation of biological systems. Remarkable achievements have been obtained on chemical biology which aims to study important biological events by using small molecular active compounds as a probe thus small active compound has become effective tools in the research of biomedicine. Our research group has achieved a series of results in the molecular mechanism study of leukemic cell differentiation and apoptosis through using small molecular active compounds. We discovered that adenanthin, a diterpenoid compound extracted from Rabdosia adenantha, induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. The chemical probe biotin-tagged adenanthin was designed on the basis of structure-activity relationship data. Further study demonstrated adenanthin directly targets the conserved resolving cysteines of PrxⅠ and Prx Ⅱ and inhibits their peroxidase activities. Consequently, cellular H2O2 is elevated, leading to the activation of extracellular signal regulated kinases and increased transcription of C/EBPβ, which contributes to adenanthin-induced differentiation. In another study we identified a novel natural ent-kaurene diterpenoid derived from I. pharicus leaves called pharicin B that can rapidly stabilize RARα as well as PML-RARα protein and enhances ATRA-dependent transcriptional activity of RARα. Additionally, pharicin B enhances differentiation-enhancing effect of ATRA in AML cell lines, some primary leukemic cells and overcomes retinoid resistance in ATRA-resistant subclones. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients.Based on our previous study that NSC606985, a novel camptothecin analog, could effectively induce apoptosis in AML cells in a time- and concentration-dependent manner, sequentially through proteolytic activation of protein kinase Cδ (PKCδ), loss of mitochondrial Δψm and caspase-3 activation, we further employed NSC606985 as a molecule probe and systemically investigated the mechanisms of apoptotic induction in AML cells and the prospects of its clinical application in vitro and in vivo. We analyzed protein expression profiles of NSC606985-induced apoptotic AML cells by systematically using phosphoproteomics, quantitive proteomics as well as subcellular proteomics analytical strategy. As a result, we uncovered a series of deregulated proteins including translocated ones during apoptosis, most of which had not been reported previously. Among these apoptotic proteins we identified, the function of ANP32B as well as NDRG1 and their relationship with NSC606985-triggered AML cell apoptosis were further investigated respectively. Moreover, the in vivo study demonstrated that NSC606985 rapidly induced apoptosis of leukemic cells in peripheral blood, bone marrow, liver and spleen, and administration of NSC606985 significantly prolonged the survival of AML mice. The above results provide new leading compound for the acute leukemia therapy. The study of "New Mechanism for Differentiation and Apoptosis of Leukemic cell" wins the National Awards of Natural Sciences (Second prize) in 2010.

Key words: chemical biology, leukemia, differentiation, apoptosis