Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis.
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.
Central Research Laboratory, Jilin University Bethune Second Hospital, Changchun 130041, People's Republic of China.
Azhar
A
Rasul
Chuan
C
Ding
Xiaomeng
X
Li
Muhammad
M
Khan
Fei
F
Yi
Muhammad
M
Ali
Tonghui
T
Ma
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D001578:Benzopyrans; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C060327:dracorhodin; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin