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.
Highlights
During the last few decades, significant attention has been paid to the bioactive diorganotin(IV) compounds with similar antitumor activity to cisplatin against several human tumors such as gastric carcinoma, immature granulocyte leukemia, henrietta carcinoma, and urinary bladder [1,2,3,19]
The representative compound di-n-butyl-di-(4-chlorobenzohydroxamato) tin(IV) (DBDCT) was previously investigated and the results indicated that DBDCT induced the G0–G1 phase cell-cycle arrest associated with increased levels of p21, p27, p53 and induction of the mitochondrial apoptotic signaling pathway is perhaps mediated by increasing Bax/Bcl-2 ratios, which resulted in the release of cytochrome c into the cytoplasm, activation of caspase-3 and -9, and increased reactive oxygen species (ROS) generation [19]
The results indicated that DBDFT exhibited a significantly higher inhibition against human cancer cells than that of the normal human HL-7702 cells (p,0.05) as shown in Figure 2 (b), indicating that DBDFT may have a limited but significant selectivity to human cancer cells versus normal cells in vitro
Summary
During the last few decades, significant attention has been paid to the bioactive diorganotin(IV) compounds with similar antitumor activity to cisplatin against several human tumors such as gastric carcinoma, immature granulocyte leukemia, henrietta carcinoma, and urinary bladder [1,2,3,19]. These diorganotin(IV) compounds are active against cancer cells via different molecular mechanisms [4,5,6,7]. Sequential activation of cyclin-dependent kinases is involved in cell cycle regulation and deregulated expression of these proteins is commonly observed in cancer cells [9]
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