Cyclooxygenase-2 Inhibits Novel Ginseng Metabolite-Mediated Apoptosis

Abstract

Recently, a novel intestinal bacterial metabolite of ginseng protopanaxadiol saponins, i.e., 20-O-(B-D-glucopyranosyl)-20(S)-protopanaxadiol (IH-901), has been reported to induce apoptosis in a variety of cancer cells. Here we show a differential effect of IH-901 on several cell types. Exposure to IH-901 for 48 hours at a supposedly subapoptotic concentration of 40 A Amol/L led to both apoptotic cell death and G 1 arrest in Hep3B cells, but only resulted in G 1 arrest in MDA-MB-231, Hs578T, and MKN28 cells. Additionally, the treatment of MDA-MB-231, but not of Hep3B, with IH-901 up-regulated cyclooxygenase-2 (COX-2) mRNA (2 hours) and protein (6 hours), and enhanced the production of prostaglandin E 2 . In MDA-MB-231 cells, IH-901 induced the sustained activation of extracellular signal-regulated kinase (ERK), whereas inhibition of mitogen-activated protein/ERK kinase blocked IH-901-mediated COX-2 induction and resulted in apoptosis, suggesting the involvement of an ERK-COX-2 pathway. Combined treatment with IH-901 and nonsteroidal anti-inflammatory drugs inhibited COX-2 enzyme and induced apoptosis in MDA-MB-231 and Hs578T cells. Adenovirus-mediated COX-2 small interfering RNAs also effectively inhibited COX-2 protein expression and enhanced IH-901-mediated apoptosis without inhibiting ERK 1/2 phosphorylation, thus providing direct evidence that COX-2 is an antiapoptotic molecule. Moreover, IH-901-mediated G 1 arrest resulted from an increase in p27Kip1 mRNA and protein expression followed by a decrease in CDK2 kinase activity that was concurrent with the hypophosphorylation of Rb and p130. In conclusion, IH-901 induced both G 1 arrest and apoptosis, and this apoptosis could be inhibited by COX-2 induction. (Cancer Res 2005; 65(5): 1952-60)

Therapeutic Effects of Korean Red Ginseng Extract in Egyptian Patients with Chronic Liver Diseases

“…Along the same lines, Ming et al [55] suggested that IH-901 induced apoptotic cell death concurrently with cell cycle arrest in SMMC7721 cells. Similar effects of IH-901 in inhibiting the cell growth have been reported previously in other cancer cell lines [54].…”

“…It is the integration of multiple survival and death signals that determine whether a cell survives or undergoes apoptosis. Moreover, IH-901 was shown to induce apoptosis in several different cancer cell lines [12,52], and several apoptosis-related molecules play important regulatory roles in IH-901-induced tumor cell death [53,54]. Along the same lines, Ming et al [55] suggested that IH-901 induced apoptotic cell death concurrently with cell cycle arrest in SMMC7721 cells.…”

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

“…165 There are a number of reports that cox-2 activity is associated with a suppression of spontaneous apoptosis in various types of cancer cells; conversely, cox-2 inhibitors have been reported to boost the responsiveness of certain cancer cell lines to cytotoxic drugs or radiotherapy. [166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184] (Some of these results need to be viewed circumspectly, however, as some cox-2-specific inhibitors such as celecoxib can exert proapoptotic effects that are independent of cox-2 inhibition. 185 ) Although the impact of cox-2 on apoptosis is likely mediated by PGE2 or other prostanoids, the mechanisms involved are less well understood than those that mediate the impact of NF-κB; increased expression of Bad and/or decreased expression of Bcl-2 appear to play a role in some cell lines.…”

Herbal extract “Songyou Yin” inhibits tumor growth and prolongs survival in nude mice bearing human hepatocellular carcinoma xenograft with high metastatic potential

“…Regarding liver cancer, Sho-Saiko-To (a mixture of seven herbs) was reported to inhibit proliferation of KIM-1 human hepatoma cells and KMC-1 cholangiocarcinoma cells (Yano et al 1994), and aqueous extracts of Paeoniae lactiXora and Bu-Zhong-Yi-Qi Tang (a mixture of ten herbs) have also been shown to suppress the growth of hepatoma cells (Kao et al 2001;Lee et al 2002). Recent studies revealed that the anticancer eYcacy of herbal agents has been linked to the modulation of apoptotic signaling, cell cycle regulation, angiogenic factors, matrix metalloproteinase (MMPs), invasion, and metastatic events in cancer cells Yim et al 2005;Lee et al 2006;Singh and Agarwal 2006), including liver cancer (Yuan et al 1998;Lee et al 2002;Yuan et al 2004).…”