Journal
MOLECULES
Volume 19, Issue 8, Pages 10877-10897Publisher
MDPI
DOI: 10.3390/molecules190810877
Keywords
indole phytoalexins; homobrassinin; antiproliferative; apoptosis; ROS
Funding
- project Medicinsky univerzitny park v Kosiciach (MediPark, Kosice) [ITMS: 26220220185]
- Slovak Grant Agency for Science [1/0322/14]
- Operational Programme Research and Development [OP VaV-2012/2.2/08-RO, OPVaV/12/2013]
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This study was designed to examine the in vitro antiproliferative effect of brassinin and its derivatives on human cancer cell lines. Among seven tested compounds, homobrassinin (K1; N-[2-(indol-3-yl) ethyl]-S-methyldithiocarbamate) exhibited the most potent activity with IC50 = 8.0 mu M in human colorectal Caco2 cells and was selected for further studies. The flow cytometric analysis revealed a K1-induced increase in the G(2)/M phase associated with dysregulation of alpha-tubulin, alpha(1)-tubulin and beta(5)-tubulin expression. These findings suggest that the inhibitory effect of K1 can be mediated via inhibition of microtubule formation. Furthermore, simultaneously with G(2)/M arrest, K1 also increased population of cells with sub-G(1) DNA content which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by annexin V/PI double staining, DNA fragmentation assay and chromatin condensation assay. The apoptosis was associated with the loss of mitochondrial membrane potential (MMP), caspase-3 activation as well as intracellular reactive oxygen species (ROS) production. Moreover, the antioxidant Trolox blocked ROS production, changes in MMP and decreased K1 cytotoxicity, which confirmed the important role of ROS in cell apoptosis. Taken together, our data demonstrate that K1 induces ROS-dependent apoptosis in Caco2 cells and provide the rationale for further in vivo anticancer investigation.
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