Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in
cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric
tumor cells. In this study, effects of
Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC-7901 cells. The results showed that
Dracorhodin perchlorate induced cellular and
DNA morphological changes and decreased the viability of SGC-7901 cells.
Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in
protein levels of phosphorylated
retinoblastoma and E2F1.
Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K/Akt, and NF-κB, thereby decreasing the expression of the
anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that
Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-κB transcriptional activity in the NF-κBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-κB may provide a molecular basis for the ability of
Dracorhodin perchlorate to induce apoptosis.
Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of
caspase-3 and its substrate, PARP. Moreover,
Dracorhodin perchlorate dramatically enhanced the
wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/Akt, p53 and NF-κB pathways that are frequently deregulated in
cancer and suggest that their simultaneous targeting by
Dracorhodin perchlorate could result in efficacious and selective killing of
cancer cells.