Zerumbone Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors in Human Colon Cancer Cells: Evidence for an Essential Role of Reactive Oxygen Species

Abstract

Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this correlated with the up-regulation of TRAIL death receptor (DR) 4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell-type specific, as its expression was also up-regulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species. Inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase but not of Jun NH 2 -terminal kinase abolished the effect of zerumbone on DR induction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DR induction or for enhancement of TRAIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results show that zerumbone can potentiate TRAIL-induced apoptosis through the reactive oxygen species-mediated activation of extracellular signal-regulated kinase 1/2 and p38 mitogenactivated protein kinase leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL. [Cancer Res 2009;69(16):6581-9]

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

“…Moreover, we noticed that the knockdown of DR5 and DR4 by their respective siRNAs effectively inhibited the cell death induced by the combination of emodin and TRAIL, demonstrating the pivotal role of death receptors in the apoptotic process (data not shown). These results are consistent to a previous reported in which another chemopreventive agent, zerumbone was found to enhance TRAIL-induced apoptosis through induction of death receptors in colorectal cancer cells [41]. Our results are also partially in agreement with another study by Kim and coworkers who have previously reported that the inhibition of casein kinase 2 by emodin can sensitize HCC cells to both Fas ligand-and TRAIL-induced apoptosis and also increased the NK cell-mediated tumor cell killing [42].…”

Acrolein sensitizes human renal cancer Caki cells to TRAIL-induced apoptosis via ROS-mediated up-regulation of death receptor-5 (DR5) and down-regulation of Bcl-2

“…Zerumbone has been reported to enhance TRAILinduced apoptosis through ROS-mediated induction of DR5 [43]. Our findings also demonstrated that combined treatment with acrolein and TRAIL increased ROS levels in Caki cells and antioxidant (NAC) pretreatment prevented ROS generation and this apoptosis induced by acrolein plus TRAIL (Fig.…”

Gelam Honey and Ginger Potentiate the Anti Cancer Effect of 5-FU against HCT 116 Colorectal Cancer Cells

“…However, shogaols have gained more interest because of recent discoveries revealing their higher anti-cancer potencies over gingerols (Sang et al, 2009). Another component in ginger extract, zerumbone, a sesquiterpene in ginger, has been suggested to induce apoptosis in HCT 116 cell line as indicated by upregulation of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) death receptor (DR) 4 and DR5 (Yodkeeree et al, 2009) while 6-shogaol has been suggested to induce apoptosis in colon adenocarcinoma cell line COLO 205 (Pan et al, 2008). Nevertheless in this study crude ginger extract was used instead of either individual gingerol or shogaol as there is recent evidence suggesting combination of active compounds present in ginger could synergistically enhance the anti-cancer effect of ginger (Brahmbhatt et al, 2013).…”