ginsenoside-rg3 and Gallbladder-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Gallbladder Neoplasms; Ginsenosides; Humans; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Time Factors; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

In the current study, we examined the potential effect of Ginsenoside Rg3 against gallbladder cancer cells, the underlying signaling mechanisms were also studied. We demonstrated that Rg3 exerted potent cytotoxic and pro-apoptotic activity against established and primary human gallbladder cancer cells. Yet it was safe to non-cancerous gallbladder epithelial cells. At the molecular level, we showed that Rg3 induced endoplasmic reticulum (ER) stress activation, the latter was evidenced by C/EBP homologous protein (CHOP) upregulation, inositol-requiring enzyme 1 (IRE1)/PKR-like endoplasmic reticulum kinase (PERK) phosphorylations, and caspase-12 activation in gallbladder cancer cells. Reversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP shRNA knockdown significantly attenuated Rg3-induced cytotoxicity against gallbladder cancer cells. In vivo, we showed that Rg3 oral administration significantly inhibited GBC-SD gallbladder cancer xenograft growth in nude mice, its activity was, however, compromised with co-administration of the ER stress inhibitor salubrinal. Thus, we suggest that ER stress activation mediates Ginseng Rg3-induced anti-gallbladder cancer cell activity in vitro and in vivo.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 12; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Epithelial Cells; Gallbladder Neoplasms; Gene Expression Profiling; Ginsenosides; Humans; Male; Mice; Mice, Nude; Middle Aged; Panax; Transcription Factor CHOP; Xenograft Model Antitumor Assays