ABSTRACT
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 p53 protein 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.
Subject(s)
Humans , Apoptosis , Blotting, Western , Caspase 3 , Down-Regulation , Flow Cytometry , Growth Inhibitors , Indoles , Lung , Lung Neoplasms , Molecular Targeted Therapy , Piperazines , Protein-Tyrosine Kinases , Puma , Sulfonamides , Transplantation, Heterologous , Tumor Burden , Tumor Suppressor Protein p53 , Up-RegulationABSTRACT
OBJECTIVE: To identify a characteristic chemical marker of Ranunculi Ternati Radix and establish a HPLC method for determination of its content. METHODS: Various chromatographic methods were applied to isolate the marker 4-[formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid, and its structure was elucidated by spectroscopic methods. The HPLC was performed on Agilent TC-C18 column (4.6 mm × 250 mm, 5 μm) using CH3OH-H2O (containing 0.4% acetic acid) as the mobile phase. The flow rate was 1.0 mL · min-1 and the detection wavelength was set at 292 nm. RESULTS: 4-[formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid was isolated and identified as the chemical marker. The HPLC method showed good linearity within the range of 0.372-1.302 μg (r2=0.9998). The average recovery of 4-[formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoic acid was 100.89% (n=6, RSD=0.83%). CONCLUSION: This method is simple, rapid and reliable for the quality control of Ranunculi Ternati Radix. Copyright 2012 by the Chinese Pharmaceutical Association.
ABSTRACT
Os antiinflamatórios não-esteróides (AINEs) estão entre os fármacos mais prescritos e utilizados do mundo. Estes fármacos inibem as ciclooxigenases, enzimas responsáveis pela transformação do ácido araquidônico em prostaglandinas flogísticas, pela ação da fosfolipase A2. A síntese de compostos antiinflamatórios contendo núcleo pirrólico em suas estruturas vem sendo um tópico muito atrativo e bastante estudado, que somado ao conhecimento do sítio de interação do fármaco ao receptor possibilita o planejamento de estruturas de novas substâncias candidatas a protótipos de novos fármacos, por meio da modificação molecular. Nesse contexto, o presente trabalho teve como objetivo o planejamento, síntese e avaliação biológica de derivados pirrólicos com potencial atividade antiinflamatória, com base nas estruturas da indometacina, protótipo da classe dos derivados de ácido arilalcanóico e dos diarilheterociclos (COXIBES). Sendo assim, foram obtidos cinco compostos em rendimentos satisfatórios, a partir de acetoacetato de etila, via metodologia de Hantzsch e ciclofuncionalização, utilizando ultrassom, que resultou na redução do tempo de reação e do consumo de solvente, seguindo os princípios da Química Verde. Os compostos 5a e 5b mostraram-se promissores, a partir de ensaios "in vitro"
The nonsteroidal antiinflammatory drugs (NSAIDs) are among the most prescribed and used drugs in the world. These drugs inhibit the cyclooxygenases, enzymes responsible for conversion of arachidonic acid into phlogistic prostaglandins, by the action of phospholipase A2. The synthesis of compounds containing pyrrole nucleus in their structures has been a topic very attractive and well studied, that knowledge added to the site of interaction of the drug to the receptor enables the planning of new structures of substances candidates for prototypes of new drugs through of molecular modification. In this context, this work aimed at the design, synthesis and biological evaluation of pyrrole derivatives with potential antiinflammatory activity, based on the structures of indomethacin, the prototype of arylalkanoic acid class and diarylheterocycles (coxibs). Thus, five compounds were obtained in good yields from ethyl acetoacetate, route of Hantzsch and cyclofunctionalization methods, using ultrasound, which resulted in the reduction of the reaction time and consumption of solvent, following the principles of Green Chemistry. The 5a and 5b compounds were shown to be promising, from tests in vitro