ginsenoside-rg3 and Skin-Neoplasms

The metastatic rate of human cutaneous squamous cell carcinoma (CSCC) has increased in recent years. Despite the current advances in therapies, effective treatments remain lacking. Ginsenoside 20(R)-Rg3 is an effective antitumor monomer extracted from ginseng, but the role of Rg3 in CSCC remains unknown. It has been reported that aberrantly elevated histone deacetylase 3 (HDAC3) is involved in tumor malignancy in multiple malignant tumors. However, the effects of HDAC3 on the regulation of c-Jun acetylation in tumor epithelial-mesenchymal transition (EMT) and migration have not been clearly illuminated. In our research, the immunohistochemistry staining results of skin tissue microarrays showed that HDAC3 staining was increased in CSCC compared with the normal dermal tissue. Then, we found that Rg3 treatment (25 and 50 μg/ml) inhibited CSCC cell (A431 and SCC12 cells) EMT through increasing E-cadherin and decreasing N-cadherin, vimentin, and Snail expression. Wound-healing and transwell assays showed that Rg3 could inhibit migration. Meanwhile, Rg3 significantly downregulated the expression of HDAC3 in CSCC cells as detected by real-time quantitative PCR, western blot, and immunofluorescence. Importantly, c-Jun acetylation was increased by the downregulation of HDAC3 with HDAC3 shRNA, and the downregulation was associated with CSCC cell EMT inhibition. Collectively, our results showed that downregulation of HDAC3 by Rg3 or shHDAC3 treatment resulted in c-Jun acetylation, which in turn inhibited CSCC cell EMT. These results indicate that HDAC3 could potentially serve as a therapeutic target therapeutic target for CSCC. Rg3 is an attractive and efficient agent that has oncotherapeutic effects and requires further investigation.

Topics: Acetylation; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Dermis; Down-Regulation; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Ginsenosides; Histone Deacetylases; Humans; Proto-Oncogene Proteins c-jun; Skin Neoplasms; Up-Regulation

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 an effective chemical component extracted from the red Panix. The experiment demonstrated that it might effectively inhibit proliferation and metastasis of tumor cells. The exact molecular mechanism of Rg3 remains unclear so far. To further explore the antitumor function of Rg3, we investigated the in-vitro and in-vivo activity of Rg3 in the treatment of B16 melanoma cells, derived from C57BL/6 mouse, capable of forming tumor colonies in the lungs following intravenous injection. Cell proliferation was measured by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay. Morphological changes of cells were observed by staining with Giesma and Hoechst 33258. Cell cycle and apoptosis rate were analyzed by flow cytometry. The expression of caspase-3 and bcl-2 in cells was detected by immunocytochemistry and western blot analysis. We found that Rg3 could inhibit cell proliferation, regulate cell cycle, and induce cell apoptosis in vitro. B16 melanoma-bearing mice were used to evaluate in vivo the antitumor activity of Rg3. Mice that were injected with Rg3 showed significant inhibition of the tumor metastasis with lighter lung weight, lower density of microvessels, fewer metastasis nodules, and longer survival time than those in the control group (P<0.001). In conclusion, the results reveal that antitumor metastasis of Rg3 is also associated with inducing apoptosis, regulating cell cycle, and blocking angiogenesis in addition to inhibiting proliferation. This research might supply valuable data for chemotherapy with Rg3 in melanoma. Rg3 would turn out to be an anticancer drug with promising prospects.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Ginsenosides; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms

In the present investigation the chemopreventive action and antimutagenic effects of a standardized Panax Ginseng extract (EFLA400, processed Panax ginseng extract containing a high titre of ginsenoside Rg3 (>3.0% w/w) known as Phoenix ginseng) in Swiss albino mice have been evaluated. The oral administration of EFLA400 at 1, 3 and 10 mg/kg body weight at pre, peri and post-initiational phases, showed significant reductions in the number, size and weight of the papillomas. A significant reduction in tumour incidence (71.41 +/- 6.73%, 72.19 +/- 4.54% and 70.46 +/- 0.38% at 1, 3 and 10 mg/kg body weight, respectively) was observed in animals in the EFLA400 treated group compared with 100% tumour incidence in the control group. The cumulative number of papillomas during an observation period of 16 weeks was significantly reduced in the EFLA400 treated group (24 +/- 0.94, 16 +/- 1.41 and 11 +/- 1.41 at 1, 3 and 10 mg/kg body weight, respectively). However, the average latent period was significantly increased from 10.81 +/- 0.1 weeks in the control group to 12.39 +/- 0.28 weeks in the treated group (10 mg/kg body weight). The average tumour weight was recorded as 128.55 +/- 8.48, 116.00 +/- 8.48 and 57.5 +/- 3.29 mg in 1, 3 and 10 mg/kg body weight EFLA400 treated groups respectively. Chromosomal aberrations and micronuclei induction was also evaluated in bone marrow cells. These genotoxicity end-points were compared with papilloma occurrence at the same dose levels of carcinogen and ginseng. In the EFLA400 treated groups significantly reduced frequencies of chromosomal aberrations and micronuclei induced by DMBA and croton oil were observed. However, the maximum decrease in the frequencies of chromosomal aberrations and micronuclei were recorded in the 10 mg/kg body weight EFLA400 treated group than that of the 1 and 3 mg/kg body weight EFLA400 treated animals. The results from the present study suggest the dose dependent effectiveness of EFLA400 in chemoprevention and antimutagenicity in Swiss albino mice.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Animals; Antimutagenic Agents; Antineoplastic Agents, Phytogenic; Bone Marrow Cells; Chromosome Aberrations; Croton Oil; Ginsenosides; Male; Mice; Micronuclei, Chromosome-Defective; Panax; Papilloma; Phytotherapy; Skin Neoplasms