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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 accelerates the senescence of GBC cells.Notes: (A, B) Morphological changes of NOZ and GBC-SD cells were examined under a microscope. (C, D) Positive green-colored staining of senescent cells increased in both cell lines after 20(S)-Rg3 treatment. (E) Western blot analysis of senescence-related p53–p21 and p16–pRB pathways in both cell lines. β-actin was used as a loading control. Data represent the mean ± SD of three independent experiments. *P<0.05, **P<0.01, ***P<0.001 vs control.Abbreviations: GBC, gallbladder cancer; SD, standard deviation; vs, versus.
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f2-dddt-9-3969: 20(S)-Rg3 accelerates the senescence of GBC cells.Notes: (A, B) Morphological changes of NOZ and GBC-SD cells were examined under a microscope. (C, D) Positive green-colored staining of senescent cells increased in both cell lines after 20(S)-Rg3 treatment. (E) Western blot analysis of senescence-related p53–p21 and p16–pRB pathways in both cell lines. β-actin was used as a loading control. Data represent the mean ± SD of three independent experiments. *P<0.05, **P<0.01, ***P<0.001 vs control.Abbreviations: GBC, gallbladder cancer; SD, standard deviation; vs, versus.

Mentions: Morphological changes of NOZ and GBC-SD cells could be seen in Figure 2A and B. Both cell lines became enlarged and flattened, had more cytoplasmic vacuoles in a concentration-dependent manner, representing a senescence-like state. SA-β-gal is of lysosomal origin and appears as the result of their increased biogenesis,28 paralleled by increased expression of the GLB1 gene encoding acidic lysosomal β-galactosidase,29 making it a widely used marker of senescent cells in vitro and in vivo. As shown in Figure 2C and D, the higher the concentration of 20(S)-Rg3, the more SA-β-gal positive cells in both cell lines was observed. Moreover, the protein amounts of p53 and p21Cip1 increased in senescent cells but not the p16 and pRB protein (Figure 2E). These results suggest that the growth arrest in GBC cells results from an increase in p53-mediated p21 expression as cells enter senescence.


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 accelerates the senescence of GBC cells.Notes: (A, B) Morphological changes of NOZ and GBC-SD cells were examined under a microscope. (C, D) Positive green-colored staining of senescent cells increased in both cell lines after 20(S)-Rg3 treatment. (E) Western blot analysis of senescence-related p53–p21 and p16–pRB pathways in both cell lines. β-actin was used as a loading control. Data represent the mean ± SD of three independent experiments. *P<0.05, **P<0.01, ***P<0.001 vs control.Abbreviations: GBC, gallbladder cancer; SD, standard deviation; vs, versus.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-9-3969: 20(S)-Rg3 accelerates the senescence of GBC cells.Notes: (A, B) Morphological changes of NOZ and GBC-SD cells were examined under a microscope. (C, D) Positive green-colored staining of senescent cells increased in both cell lines after 20(S)-Rg3 treatment. (E) Western blot analysis of senescence-related p53–p21 and p16–pRB pathways in both cell lines. β-actin was used as a loading control. Data represent the mean ± SD of three independent experiments. *P<0.05, **P<0.01, ***P<0.001 vs control.Abbreviations: GBC, gallbladder cancer; SD, standard deviation; vs, versus.
Mentions: Morphological changes of NOZ and GBC-SD cells could be seen in Figure 2A and B. Both cell lines became enlarged and flattened, had more cytoplasmic vacuoles in a concentration-dependent manner, representing a senescence-like state. SA-β-gal is of lysosomal origin and appears as the result of their increased biogenesis,28 paralleled by increased expression of the GLB1 gene encoding acidic lysosomal β-galactosidase,29 making it a widely used marker of senescent cells in vitro and in vivo. As shown in Figure 2C and D, the higher the concentration of 20(S)-Rg3, the more SA-β-gal positive cells in both cell lines was observed. Moreover, the protein amounts of p53 and p21Cip1 increased in senescent cells but not the p16 and pRB protein (Figure 2E). These results suggest that the growth arrest in GBC cells results from an increase in p53-mediated p21 expression as cells enter senescence.

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