Mechanisms by which the antitumor compound di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) induces apoptosis and the mitochondrial-mediated signaling pathway in human cancer SGC-7901 cells

Yunlan Li, Jinjie Liu, Qingshan Li
Molecular Carcinogenesis 2010, 49 (6): 566-81
The mechanisms by which the strong antitumor diorganotin(IV) compound di-n-butyl-di-(4-chlorobenzohydroxamato)tin(IV) (DBDCT) induces apoptosis of SGC-7901 cells were first investigated. Inhibition of proliferation of four cancer cell lines compared with normal human hepatic L-O2 cells, cancer cell apoptosis, and expression of related mRNA and protein were detected using the methyl thiazolyl tetrazolium (MTT), flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), Western blot, and DNA ladder assays, and electron microscopy and immunocytochemistry. DBDCT decreased cancer cell proliferation rates in a dose- and time-dependent manner and changed the cycle distribution of SGC-7901 cells; the proportion of cells in G(0)-G(1) phase was increased, whereas the numbers in S and G(2)-M phases were decreased. Blockade of the cell cycle was perhaps associated with increased levels of p21, p27, p53 and the decreased level of proliferating cell nuclear antigen (PCNA). Apoptosis was characterized by DNA fragmentation, chromosomal condensation, apoptotic bodies, sub-G(1) peaks, and an increased apoptotic rate, as shown using the annexin V-FITC method. Pretreatment of cells with N-acetylcysteine and caspase-9 inhibitor could reduce growth inhibition and DBDCT-induced apoptosis. The results showed that DBDCT-mediated cell-cycle arrest might occur through the induction of p21 in a p53-dependent manner and that DBDCT induction of the mitochondrial apoptotic signaling pathway is perhaps mediated by increasing Bax/Bcl-2 ratios, which result in the loss of DeltaPsi(m), release of cytochrome c into the cytoplasm, activation of caspase-3 and -9, and increased reactive oxygen species (ROS) generation.

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