Abstract
Di-n-butyl-(2,6-difluorobenzohydroxamato)Tin(IV) (DBDFT), a potential antitumor agent against malignancies, exhibited high activities both in vitro and in vivo. Flow cytometric analysis showed that treatment with DBDFT against Human Gastric Carcinoma (SGC-7901) cells induced a concentration and time-dependent cell accumulation in the G2/M phase of the cell cycle with a parallel depletion of the percentage of cells in G0/G1, the cell apoptosis was observed by characteristic morphological changes and AnnexinV/PI dual-immunofluorescence staining. Fluorescence quantitative FQ- PCR and western blot results showed that G2/M-phase arrest was correlated with up-regulation of cyclin dependent kinase inhibitor p21, Chk2 and CyclinB1, whereas the expressions of other G2/M regulatory check-point protein, Cdc2, and feedback loop protein Cdc25C were obviously down-regulated in a p53-independent manner after the SGC-7901 cells were treated with DBDFT (2.5, 5.0, 7.5 µmol·L(-1)) compared with the control. Furthermore, the up-regulation of Bax and down-regulation of Bcl-2 as well as the activation of caspase-3 were observed, which indicated that DBDFT treatment triggered the mitochondrial apoptotic pathway with an increase of Bax/Bcl-2 ratios, resulting in mitochondrial membrane potential loss and caspase-9 activation in DBDFT treated SGC-7901 cells. In summary, the results illustrated the involvement of multiple signaling pathways targeted by DBDFT in mediating G2/M cell cycle arrest and apoptosis in SGC-7901 cells, which suggested that DBDFT might have therapeutic potential against gastric carcinoma as an effective compound.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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CDC2 Protein Kinase
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Checkpoint Kinase 2 / genetics
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Checkpoint Kinase 2 / metabolism
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Cyclin B1 / genetics
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Cyclin B1 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Dose-Response Relationship, Drug
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G2 Phase Cell Cycle Checkpoints / drug effects*
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Gene Expression Regulation, Neoplastic*
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Humans
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology*
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mice
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Mice, Inbred ICR
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Neoplasm Transplantation
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Organotin Compounds / chemistry
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Organotin Compounds / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction
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Time Factors
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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cdc25 Phosphatases / genetics
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cdc25 Phosphatases / metabolism
Substances
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Antineoplastic Agents
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CCNB1 protein, human
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CDKN1A protein, human
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Cyclin B1
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Cyclin-Dependent Kinase Inhibitor p21
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Hydroxamic Acids
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Organotin Compounds
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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di-n-butyl-(2,6-difluorobenzohydroxamato)tin(IV)
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Checkpoint Kinase 2
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CHEK2 protein, human
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CDC2 Protein Kinase
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CDK1 protein, human
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Cyclin-Dependent Kinases
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CDC25C protein, human
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cdc25 Phosphatases
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Caspase 3
Grants and funding
This research was supported by the National Natural Science Foundation of China (No. 30973603), the “Innovative Drug Development” State Key Science and Technology of China (No. 2009ZX09103-104), the Shanxi Foundation for overseas returned (No. 2010-54) and preferred project supported by the science and technology activities (No. 201368), the Program for the Top Young and Middle-aged Innovative Talents of Higher Learning Institutions of Shanxi Province and by Shanxi Province Foundation Science for Youths, the Foundation for the Younth Doctor from Shanxi Medical University in 2008 and Program for the Top Science and Technology Innovation Teams of Higher Learning Institutions of Shanxi province(2011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.