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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

20(S)-Rg3 inhibits MDM2-mediated ubiquitination and degradation of p53.Notes: (A, B) NOZ and GBC-SD cells were treated with CHX for 4 hours. Western blot analysis was carried out using an antibody specific for p53. β-actin was used as a loading control. (C, D) NOZ and GBC-SD cells showed a dose- and time-dependent decrease in MDM2 expression following 20(S)-Rg3 treatment. Data represent the mean ± SD of three independent experiments.Abbreviations: CHX, cycloheximide; SD, standard deviation; DMSO, dimethyl sulfoxide.
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f5-dddt-9-3969: 20(S)-Rg3 inhibits MDM2-mediated ubiquitination and degradation of p53.Notes: (A, B) NOZ and GBC-SD cells were treated with CHX for 4 hours. Western blot analysis was carried out using an antibody specific for p53. β-actin was used as a loading control. (C, D) NOZ and GBC-SD cells showed a dose- and time-dependent decrease in MDM2 expression following 20(S)-Rg3 treatment. Data represent the mean ± SD of three independent experiments.Abbreviations: CHX, cycloheximide; SD, standard deviation; DMSO, dimethyl sulfoxide.

Mentions: p53 is a key player in tumor suppression, as it regulates cellular senescence, cell cycle arrest, and apoptosis. Thus, understanding the mechanism of p53 regulation is very important for cancer therapy.31 Real-time PCR analysis revealed that 20(S)-Rg3 had no influence on the transcription level of p53 (Figure S3). We next investigated the involvement of the transcription-independent function of p53 using a protein synthesis inhibitor, (CHX), and found the suppressive effect of CHX on p53 protein accumulation was neutralized by 20(S)-Rg3 (Figure 5A and B). Western blot further showed that MDM2 protein levels were decreased by 20(S)-Rg3 treatment, in a dose- and time-dependent manner (Figure 5C and D). These results suggest that p53 protein levels were elevated as a result of MDM2 inhibition in GBC cells.


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)

20(S)-Rg3 inhibits MDM2-mediated ubiquitination and degradation of p53.Notes: (A, B) NOZ and GBC-SD cells were treated with CHX for 4 hours. Western blot analysis was carried out using an antibody specific for p53. β-actin was used as a loading control. (C, D) NOZ and GBC-SD cells showed a dose- and time-dependent decrease in MDM2 expression following 20(S)-Rg3 treatment. Data represent the mean ± SD of three independent experiments.Abbreviations: CHX, cycloheximide; SD, standard deviation; DMSO, dimethyl sulfoxide.
© Copyright Policy
Related In: Results  -  Collection

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

f5-dddt-9-3969: 20(S)-Rg3 inhibits MDM2-mediated ubiquitination and degradation of p53.Notes: (A, B) NOZ and GBC-SD cells were treated with CHX for 4 hours. Western blot analysis was carried out using an antibody specific for p53. β-actin was used as a loading control. (C, D) NOZ and GBC-SD cells showed a dose- and time-dependent decrease in MDM2 expression following 20(S)-Rg3 treatment. Data represent the mean ± SD of three independent experiments.Abbreviations: CHX, cycloheximide; SD, standard deviation; DMSO, dimethyl sulfoxide.
Mentions: p53 is a key player in tumor suppression, as it regulates cellular senescence, cell cycle arrest, and apoptosis. Thus, understanding the mechanism of p53 regulation is very important for cancer therapy.31 Real-time PCR analysis revealed that 20(S)-Rg3 had no influence on the transcription level of p53 (Figure S3). We next investigated the involvement of the transcription-independent function of p53 using a protein synthesis inhibitor, (CHX), and found the suppressive effect of CHX on p53 protein accumulation was neutralized by 20(S)-Rg3 (Figure 5A and B). Western blot further showed that MDM2 protein levels were decreased by 20(S)-Rg3 treatment, in a dose- and time-dependent manner (Figure 5C and D). These results suggest that p53 protein levels were elevated as a result of MDM2 inhibition in GBC cells.

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