ginsenoside-rg3 and Melanoma

Advanced metastatic melanoma is a malignant tumor for which there is currently no effective treatment due to resistance development. Ginsenoside Rg3, a saponin component extracted from ginseng roots, has been shown to reduce melanoma cell proliferation by decreasing histone deacetylase 3 and increasing p53 acetylation. The availability of data on the role of Rg3 in melanoma is currently extremely limited. The aim of the present study was to further investigate the effects of Rg3 on B16 melanoma cells and the underlying molecular events. The findings demonstrated that Rg3 suppressed the proliferation and DNA synthesis of B16 cells. Rg3 exposure induced tumor cell cycle arrest at the S phase and reduced the expression of proliferating cell nuclear antigen (PCNA). Rg3 treatment also decreased metastasis of B16 cells in vitro and in vivo. The results indicated that this reduction was due to downregulation of matrix metalloproteinase (MMP)‑2 and MMP‑9. Moreover, Rg3 inhibited melanoma‑induced angiogenesis, most likely by downregulating vascular endothelial growth factor (VEGF) in B16 cells. Rg3 exposure decreased the expression of VEGF in B16 cells and the VEGF downregulation further suppressed angiogenesis by attenuating the proliferation and migration of vascular endothelial cells. Finally, the western blotting data demonstrated that Rg3 reduced the expression of extracellular signal‑regulated kinase (ERK) and protein kinase B (Akt) in vitro and in vivo. This result indicated that the antimelanoma effects of Rg3 may be mediated through suppression of ERK and Akt signaling. Further research is required to assess the value of Rg3 as a novel therapeutic strategy for melanoma in the clinical setting.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Male; MAP Kinase Signaling System; Melanoma; Mice; Proto-Oncogene Proteins c-akt; Xenograft Model Antitumor Assays

Malignant melanoma is a destructive and lethal form of skin cancer with poor prognosis. An effective treatment for melanoma is greatly needed. Ginsenoside Rg3 is a herbal medicine with high antitumor activity. It is reported that abnormal glycosylation is correlated with the tumor cell growth. However, the antitumor effect of Rg3 on melanoma and its mechanism on regulating glycosylation are unknown. We found that Rg3 did not only inhibit A375 melanoma cell proliferation in a dose-dependent manner, but also decreased the expression of fucosyltransferase IV (FUT4) and its synthetic product Lewis Y (LeY), a tumor-associated carbohydrate antigen (TACA). Knocking down FUT4 expression by siRNA dramatically reduced FUT4/LeY level and inhibited cell proliferation through preventing the activation of EGFR/MAPK pathway. Consistently, the inhibitory effect of the Rg3 and FUT4 knockdown on melanoma growth was also seen in a xenograft melanoma mouse model. In conclusion, Rg3 effectively inhibited melanoma cell growth by downregulating FUT4 both in vitro and in vivo. Targeting FUT4/LeY mediated fucosylation by Rg3 inhibited the activation of EGFR/MAPK pathway and prevented melanoma growth. Results from this study suggest Rg3 is a potential novel therapy agent for melanoma treatment.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Fucosyltransferases; Ginsenosides; Humans; Lewis Blood Group Antigens; Lewis X Antigen; Male; MAP Kinase Signaling System; Melanoma; Mice; Mice, Nude; Skin Neoplasms; Xenograft Model Antitumor Assays

Abnormal glycosylation is catalyzed by the specific glycosyltransferases and correlates with tumor cell apoptosis. Increased fucosyltransferase IV (FUT4) is seen in many types of cancer, and manipulating FUT4 expression through specific signaling pathway inhibits cell growth and induces apoptosis. NF-κB is known playing a vital role to control cell growth and apoptosis. Ginsenoside Rg3 is an herbal medicine with strong antitumor activity through inhibiting tumor growth and promoting tumor cell death. However, whether Rg3-induced inhibition on tumor development involves reduced NF-κB signaling and FUT4 expression remains unknown. In the present study, we found that Rg3 suppressed FUT4 expression by abrogating the binding of NF-κB to FUT4 promoter through inhibiting the expression of signaling molecules of NF-κB pathway, reducing NF-κB DNA binding activity and NF-κB transcription activity. NF-κB inhibitor (Bay 11-7082) or knocking down p65 expression by p65 siRNA also led to a significant decreased FUT4 expression. In addition, Rg3 induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways. Moreover, in a xenograft mouse model, Rg3 downregulated FUT4 and NF-κB/p65 expression and suppressed melanoma cell growth and induced apoptosis without any noticeable toxicity. In conclusion, Rg3 induces tumor cell apoptosis correlated with its inhibitory effect on NF-κB signaling pathway-mediated FUT4 expression. Results suggest Rg3 might be a novel therapy agent for melanoma treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Binding Sites; Cell Line, Tumor; Cell Survival; Fucosyltransferases; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Lewis X Antigen; Male; Melanoma; Mice; NF-kappa B; Promoter Regions, Genetic; Signal Transduction; Skin Neoplasms; Xenograft Model Antitumor Assays

Ginsenoside Rg3 is a bioactive ginseng constituent that has been reported to have diverse pathological and physiological effects, including anti-inflammatory and anti-metastatic activities. Metastasis is one of the most important factors involved in patients with melanoma. However, the molecular mechanism underlying the anti-metastatic activities of Rg3 in malignant melanoma cancer has not been fully elucidated. In this study, we have evaluated that Rg3 effectively inhibits metastasis of B16F10 melanoma cancer cells. We found that Rg3 significantly suppresses the migration, invasion, wound healing, and colony-forming abilities of B16F10 cells in a dose-dependent manner. Mechanistically, we demonstrate that Rg3 suppresses B16F10 cell metastasis by inhibiting MMP-13 expression. These results indicate that Rg3 suppresses the metastasis of B16F10 mouse melanoma cancer cells via MMP-13 regulation. Importantly, MMP-13 downregulation may influence the migration and invasion capabilities of melanoma cells and has been correlated with melanoma progression. Therefore, Rg3 is a potential therapeutic candidate that could be used to treat patients with metastatic melanoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Drug; Ginsenosides; Matrix Metalloproteinase 13; Melanoma; Mice; Neoplasm Metastasis

Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma.

Topics: Acetylation; Aged; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Ginsenosides; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Male; Melanoma; Middle Aged; Tumor Suppressor Protein p53