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Wu, Yong,Jin, Lu,Xue, Ying,Xie, Dai Qian,Kim, Chan Kyung,Guo, Yong,Yan, Guo Sen Wiley Subscription Services, Inc., A Wiley Company 2008 Journal of computational chemistry Vol.29 No.8
<P>The hydrolysis reaction of N,N-dimethyl-N′-(2-oxo-1, 2-dihydro-pyrimidinyl)formamidine (DMPFA), a model compound of the antivirus drug amidine-3TC (3TC = 2′, 3′-dideoxy-3′-thiacytidine), is investigated by the hybrid density functional theory B3LYP/6-31+G (d,p) method. The hydrolysis reaction of the title compound is predicted to undergo via two pathways, each of which is a stepwise process. Path A is the addition of H<SUB>2</SUB>O to the C&n.dbond;N double bond in the amidine group to form a tetrahedral structure in its first step, and then the transfer of the H atom of hydroxyl leads to the corresponding products via four possible channels. Path B simultaneously involves the nucleophilic attack of H<SUB>2</SUB>O to the C atom of the C&n.dbond;N bond and the proton transfer to the N atom of amino group leading to the cleavage of the C&n.bond;N single bond in the amidine group. The results indicate that path A is more favorable than path B in the gas phase. Moreover, to simulate the title reaction in aqueous solution, water-assisted mechanism and the cluster-continuum model, based on the SCRF/CPCM model, are taken into account in our work. The results indicate that it is rational for two water molecules served as a bridge to assist in the first step of path A and that cytosine rather than the cytosine-substituted formamide should be released from the tetrahedral intermediate via s six-membered cycle transition state (channel 2). Our calculations exhibit that the process toward the tetrahedral intermediate is the rate-determining step both in the gas phase and in aqueous solution. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008</P> <B>Graphic Abstract</B> <P> <img src='wiley_img/01928651-2008-29-8-JCC20883-gra001.gif' alt='wiley_img/01928651-2008-29-8-JCC20883-gra001'> </P>
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The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer
정해윤,주현정,박종국,김열홍 대한암학회 2012 Cancer Research and Treatment Vol.44 No.4
Purpose c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study,we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer. Materials and Methods The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry. Results SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53protein expression. Blocking c-Met signaling increased the level of p53 protein. Conclusion Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.
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