Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis

Abstract

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.

Dracorhodin perchlorate induces apoptosis in bladder cancer cells through Bcl-2, Bcl-XL, survivin down-regulation and caspase-3 activation

“…The results of flow cytometric analysis showed that the rates of apoptosis were 15.5 ± 2.2%, 24.4 ± 2.1% and 45.5 ± 1.8% in the cells treated with 100 µM of dracorhodin perchlorate for 12, 24, and 48 h respectively as compared to the 5.3 ± 1.0% in control cells (Figure 3). Dracorhodin perchlorate-induced apoptosis in T24 cells were compatible with previously reported studies (He et al, 2011;Rasul et al, 2012a;Xia et al, 2005;Xia et al, 2006).…”

“…Morphological changes were observed under phase contrast microscopy after treating cells with dracorhodin perchlorate resulting in the decreased number of cells as compared to control group and cells become rounded and shrinked, which were polygonal in untreated cells (data not shown). These results reveal that dracorhodin perchlorate can act as growth inhibitor of human bladder cancer T24 cells in a similar fashion as described in previous studies dealing with various other types of cancer cells including melanoma cells (Xia et al, 2005), leukemic cancer cells (Xia et al, 2006), prostate cancer cells (He et al, 2011) and gastric cancer cells (Rasul et al, 2012a).…”

“…More than 50% of neoplasms undergo aberrations in the apoptotic machinery which leads to abnormal cells proliferation (Mashima and (Fulda, 2010;Lawen, 2003;Reed, 2002). Accumulated evidences indicated that most of chemotherapeutic agents halt tumor cells proliferation via induction of apoptosis (Rasul et al, 2013;Rasul et al, 2012a;Rasul et al, 2011a;Rasul et al, 2012b;Rasul et al, 2011d;Rasul et al, 2012b). We examined whether dracorhodin perchlorate inhibited cell growth T24 cells through the induction of apoptosis.…”

“…Other studies have shown that dracorhodin perchlorate inhibited cell growth and triggered apoptosis in melanoma and leukemic cancer cells (Xia et al, 2005;Xia et al, 2006). Previously, we demonstrated that dracorhodin perchlorate altered cell cycle distribution and induced apoptosis in the human gastric adenocarcinoma T24 cell line (Rasul et al, 2012a). However, the effects of dracorhodin perchlorate on human bladder cancer SGC-7901 cells were still unknown.…”

Antiproliferative and apoptotic effects of pinocembrin in human prostate cancer cells

“…Prevailing treatment options have limited therapeutic success in human prostate cancer, therefore, there is considerable emphasis on identifying novel natural products that selectively induce apoptosis and growth arrest in prostate cancer cells without cytotoxic effects in normal cells (Tsao et al, 2004). In the last few decades, several natural compounds have shown a great promise in treatment of cancer and prevention of metastasis; most of the researchers are interested in and are focusing on finding a cure for cancer and several published reports have identified numerous dietary and botanical natural compounds that have chemopreventive potential (Rasul et al, 2013;Rasul et al, 2012a;Rasul et al, 2012c). Therefore, novel therapeutic agents and treatment approaches are desired to improve the clinical outcome.…”