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20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway.

Zhang F, Li M, Wu X, Hu Y, Cao Y, Wang X, Xiang S, Li H, Jiang L, Tan Z, Lu W, Weng H, Shu Y, Gong W, Wang X, Zhang Y, Shi W, Dong P, Gu J, Liu Y - Drug Des Devel Ther (2015)

Bottom Line: However, the anticancer effect of 20(S)-Rg3 in human GBC has not yet been determined.In this study, we primarily found that 20(S)-Rg3 exposure suppressed the survival of both NOZ and GBC-SD cell lines in a concentration-dependent manner.Our results demonstrated that 20(S)-Rg3 potently inhibited growth and survival of GBC cells both in vitro and in vivo. 20(S)-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

ABSTRACT
Gallbladder cancer (GBC), the most frequent malignancy of the biliary tract, is associated with high mortality and extremely poor prognosis. 20(S)-ginsenoside Rg3 (20(S)-Rg3) is a steroidal saponin with high pharmacological activity. However, the anticancer effect of 20(S)-Rg3 in human GBC has not yet been determined. In this study, we primarily found that 20(S)-Rg3 exposure suppressed the survival of both NOZ and GBC-SD cell lines in a concentration-dependent manner. Moreover, induction of cellular senescence and G0/G1 arrest by 20(S)-Rg3 were accompanied by a large accumulation of p53 and p21 as a result of murine double minute 2 (MDM2) inhibition. 20(S)-Rg3 also caused a remarkable increase in apoptosis via the activation of the mitochondrial-mediated intrinsic caspase pathway. Furthermore, intraperitoneal injection of 20(S)-Rg3 (20 or 40 mg/kg) for 3 weeks markedly inhibited the growth of xenografts in nude mice. Our results demonstrated that 20(S)-Rg3 potently inhibited growth and survival of GBC cells both in vitro and in vivo. 20(S)-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis. Therefore, 20(S)-Rg3 may be a potential chemotherapeutic agent for GBC therapy.

No MeSH data available.


Related in: MedlinePlus

A working model for the action of 20(S)-Rg3 on gallbladder cancer cells.Notes: 20(S)-Rg3 activates the p53 pathway, which induces both senescence and apoptosis in gallbladder cancer cells.
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f7-dddt-9-3969: A working model for the action of 20(S)-Rg3 on gallbladder cancer cells.Notes: 20(S)-Rg3 activates the p53 pathway, which induces both senescence and apoptosis in gallbladder cancer cells.

Mentions: The related ginseng-derived 20(S)-ginsenoside Rh2 has been shown to induce apoptosis in leukemia Reh cells through mitochondrial signaling pathways.37 As expected, 20(S)-Rg3 induced mitochondrial-related apoptosis through activation of caspase-3, upregulation of Bad and Bax expression, and downregulation of Bcl-2 and Bcl-XL expression in NOZ and GBC-SC cells. MDM2, a product of a p53-inducible gene, binds directly with the transactivation domain of p53 and assists in ubiquitin-proteasomal degradation of p53, thereby acting as a negative regulator.38 20(S)-Rg3 neutralized the ability of MDM2 to promote p53 degradation, leading to the stabilization and accumulation of p53. Previous studies have shown that 20(S)-Rg3 induces apoptosis in several human cancers. For instance, 20(S)-Rg3 promotes apoptosis in colon cancer cells through AMPK pathway.19 20(S)-Rg3-induced apoptosis in ovarian cancer cells is associated with PI3K/Akt and XIAP pathways.21 Our data provide a novel mechanism for 20(S)-Rg3-induced apoptosis in GBC cells that involves the activation of p53 pathway through a mitochondria-dependent apoptotic cascade. Therefore, a model depicting our findings is presented in Figure 7. 20(S)-Rg3 down-regulates MDM2 expression in GBC cells, leading to the accumulation of p53. On one hand, p53-mediated p21 expression accelerates cellular senescence accompanied by a cell cycle arrest. On the other hand, the activation of p53 leads to induction of the mitochondria-dependent apoptotic cascade.


20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway.

Zhang F, Li M, Wu X, Hu Y, Cao Y, Wang X, Xiang S, Li H, Jiang L, Tan Z, Lu W, Weng H, Shu Y, Gong W, Wang X, Zhang Y, Shi W, Dong P, Gu J, Liu Y - Drug Des Devel Ther (2015)

A working model for the action of 20(S)-Rg3 on gallbladder cancer cells.Notes: 20(S)-Rg3 activates the p53 pathway, which induces both senescence and apoptosis in gallbladder cancer cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539091&req=5

f7-dddt-9-3969: A working model for the action of 20(S)-Rg3 on gallbladder cancer cells.Notes: 20(S)-Rg3 activates the p53 pathway, which induces both senescence and apoptosis in gallbladder cancer cells.
Mentions: The related ginseng-derived 20(S)-ginsenoside Rh2 has been shown to induce apoptosis in leukemia Reh cells through mitochondrial signaling pathways.37 As expected, 20(S)-Rg3 induced mitochondrial-related apoptosis through activation of caspase-3, upregulation of Bad and Bax expression, and downregulation of Bcl-2 and Bcl-XL expression in NOZ and GBC-SC cells. MDM2, a product of a p53-inducible gene, binds directly with the transactivation domain of p53 and assists in ubiquitin-proteasomal degradation of p53, thereby acting as a negative regulator.38 20(S)-Rg3 neutralized the ability of MDM2 to promote p53 degradation, leading to the stabilization and accumulation of p53. Previous studies have shown that 20(S)-Rg3 induces apoptosis in several human cancers. For instance, 20(S)-Rg3 promotes apoptosis in colon cancer cells through AMPK pathway.19 20(S)-Rg3-induced apoptosis in ovarian cancer cells is associated with PI3K/Akt and XIAP pathways.21 Our data provide a novel mechanism for 20(S)-Rg3-induced apoptosis in GBC cells that involves the activation of p53 pathway through a mitochondria-dependent apoptotic cascade. Therefore, a model depicting our findings is presented in Figure 7. 20(S)-Rg3 down-regulates MDM2 expression in GBC cells, leading to the accumulation of p53. On one hand, p53-mediated p21 expression accelerates cellular senescence accompanied by a cell cycle arrest. On the other hand, the activation of p53 leads to induction of the mitochondria-dependent apoptotic cascade.

Bottom Line: However, the anticancer effect of 20(S)-Rg3 in human GBC has not yet been determined.In this study, we primarily found that 20(S)-Rg3 exposure suppressed the survival of both NOZ and GBC-SD cell lines in a concentration-dependent manner.Our results demonstrated that 20(S)-Rg3 potently inhibited growth and survival of GBC cells both in vitro and in vivo. 20(S)-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.

ABSTRACT
Gallbladder cancer (GBC), the most frequent malignancy of the biliary tract, is associated with high mortality and extremely poor prognosis. 20(S)-ginsenoside Rg3 (20(S)-Rg3) is a steroidal saponin with high pharmacological activity. However, the anticancer effect of 20(S)-Rg3 in human GBC has not yet been determined. In this study, we primarily found that 20(S)-Rg3 exposure suppressed the survival of both NOZ and GBC-SD cell lines in a concentration-dependent manner. Moreover, induction of cellular senescence and G0/G1 arrest by 20(S)-Rg3 were accompanied by a large accumulation of p53 and p21 as a result of murine double minute 2 (MDM2) inhibition. 20(S)-Rg3 also caused a remarkable increase in apoptosis via the activation of the mitochondrial-mediated intrinsic caspase pathway. Furthermore, intraperitoneal injection of 20(S)-Rg3 (20 or 40 mg/kg) for 3 weeks markedly inhibited the growth of xenografts in nude mice. Our results demonstrated that 20(S)-Rg3 potently inhibited growth and survival of GBC cells both in vitro and in vivo. 20(S)-Rg3 attenuated GBC growth probably via activation of the p53 pathway, and subsequent induction of cellular senescence and mitochondrial-dependent apoptosis. Therefore, 20(S)-Rg3 may be a potential chemotherapeutic agent for GBC therapy.

No MeSH data available.


Related in: MedlinePlus