beta-elemene and Stomach-Neoplasms

β-Elemene is a natural agent extracted from the traditional Chinese herbal medicine Curcuma wenyujin that is a promising novel plant-derived drug with broad-spectrum anticancer activity. Our previous study identified an enhanced capacity for metastasis in multidrug resistant (MDR) gastric cancer and breast cancer cells. However, the anti-metastatic effects of β-Elemene on MDR cancer cells remain unknown.. In this study, we posit the hypothesis that β-elemene possesses antimetastatic effects on MDR cancer cells.. Cell viability assay was used to assess the resistance of SGC7901/ADR cells and the cytotoxic effects of β-Elemene. Wound healing, transwell assay and lung metastatic mice model were used to the anti-metastasis effects of β-Elemene. MicroRNA microarray analysis was used to explore potential regulated miRNAs. Luciferase reporter assay was used to identify the direct target. Human MMP antibody array, western blot, immunoprecipitation, qRT-PCR analyses and immunohistochemistry were conducted to investigate the underlying anti-metastasis mechanism of β-Elemene.. In this study, we found that β-Elemene significantly inhibited the metastatic capacity of MDR gastric cells in vivo and in vitro. Mechanistically, we found that β-Elemene regulated MMP-2/9 expression and reversed epithelial-mesenchymal transition. Further studies showed that β-Elemene upregulated Cbl-b expression, resulting in inhibition of the EGFR-ERK/AKT pathways, which regulate MMP-2/9. Additionally, we confirmed that β-Elemene upregulated Cbl-b by inhibiting miR-1323 expression. Finally, we found that numbers of metastatic tumor nodules were significantly decreased in the lungs of nude mice after β-Elemene treatment.. Our results suggested that β-Elemene inhibits the metastasis of MDR gastric cancer cells by modulating the miR-1323/Cbl-b/EGFR signaling axis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; ErbB Receptors; Humans; Lung Neoplasms; Male; Matrix Metalloproteinases; Mice, Nude; MicroRNAs; Proto-Oncogene Proteins c-cbl; Sesquiterpenes; Signal Transduction; Stomach Neoplasms

Peritoneal metastasis is common in advanced gastric cancer patients and is typically associated with a worse prognosis. β-Elemene is a natural compound that can be isolated from the Curcuma wenyujin plant and has been widely used in China to treat a variety of cancers. However, the anti-metastatic impacts of β-elemene on gastric cancer remain unknown. In our study, we found that β-elemene significantly inhibited the migration and invasive capacity of gastric cells in vitro and inhibited the capacity of gastric cancer cells to peritoneally diffuse and metastasize in vivo. Mechanistically, we demonstrated that the anti-metastatic effects of β-elemene were exerted by downregulating the expression of Claudin-1. Furthermore, β-elemene was found to inhibit the metastatic capacity of cells by downregulating FAK phosphorylation, which regulated Claudin-1. Overall, our result revealed that β-elemene inhibited peritoneal metastases from gastric cancer by modulating the FAK/Claudin-1 pathway.

Topics: Animals; Cell Line, Tumor; Claudin-1; Female; Humans; Mice; Mice, Nude; Neoplasm Metastasis; Peritoneal Neoplasms; Phosphorylation; Sesquiterpenes; Signal Transduction; Stomach Neoplasms

β-Elemene, an anti-cancer drug extracted from traditional Chinese medicinal herb, showed anti-tumor effects on gastric cancer cells. Our previous studies reported gastric cancer cells are insensitive to TRAIL. However, whether β-elemene could enhance anti-cancer effects of TRAIL on gastric cancer cells is unknown. In our present study, β-elemene prevented gastric cancer cell viability in dose-dependent manner, and when combined with TRAIL, obviously inhibited proliferation and promoted apoptosis in gastric cancer cells. Compared to β-elemene or TRAIL alone, treatment with β-elemene and TRAIL obviously promoted DR5 clustering as well as translocation of Caspase-8, DR5 and FADD into lipid rafts. This led to cleavage of Caspase-8 and the formation of death-inducing signaling complex (DISC) in lipid rafts. The cholesterol-sequestering agent nystatin partially reversed DR5 clustering and DISC formation, preventing apoptosis triggered by the combination of β-elemene and TRAIL. Our results suggest that β-elemene increases the sensitivity of gastric cancer cells to TRAIL partially by promoting the formation of DISC in lipid rafts.

Topics: Antineoplastic Agents; Apoptosis; Caspase 8; Cell Line, Tumor; Cell Survival; China; Death Domain Receptor Signaling Adaptor Proteins; Gene Expression Regulation, Neoplastic; Humans; Membrane Microdomains; Sesquiterpenes; Signal Transduction; Stomach Neoplasms; TNF-Related Apoptosis-Inducing Ligand

To explore the potential of β-elemene as a radiosensitizer for gastric cancer cells and the underlying mechanisms.. SGC7901, MKN45, MKN28, N87, and AGS human gastric cancer cell lines were used to screen for radioresistant gastric cancer cell lines. A 3-(4,5-dimeth-ylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay was used to determine the effects of β-elemene and IPA-3 on cell viability in MKN45 and SGC7901 gastric cancer cell lines. A clonogenic survival assay and annexin V-FITC/PI apoptosis detection assay were used to evaluate cellular radiosensitivity and radiation-induced cell death, respectively. A proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), was employed to screen the proteins regulated by β-elemene pretreatment prior to ionizing radiation (IR) in SGC7901 gastric cancer cell line. IPA-3 was used as a specific small molecule inhibitor of p21-activated protein kinase 1 (Pak1) to target Pak1 signaling. Protein levels of PAK1IP1 (p21-activated protein kinase-interacting protein 1), total Pak1 (t-Pak1), phospho-Pak1 (T423), phospho-ERK1/2 (Thr202/Tyr204), and cleaved caspase-3 (17 kDa) were assessed by western blotting.. MKN45 and SGC7901 gastric cancer cell lines were relatively more resistant to IR. β-elemene pretreatment decreased clonogenic survival following IR in MKN45 and SGC7901 gastric cancer cell lines. Additionally, β-elemene pretreatment prior to IR increased radiation-induced cell death compared with IR alone in MKN45 (10.4% ± 0.9% vs 34.8% ± 2.8%, P < 0.05) and SGC7901 (11.6% ± 0.9% vs 46.7% ± 5.2%, P < 0.05) human gastric cancer cell lines, respectively, consistent with the level of cleaved caspase-3 (17 kDa). Through iTRAQ analysis and western blot validation, we found that β-elemene upregulated PAK1IP1 and downregulated phospho-Pak1 (T423) and phospho-ERK1/2 in SGC7901 gastric cancer cells. IR increased the level of phospho-Pak1 (T423). Pretreatment with β-elemene decreased radiation-induced Pak1 and ERK1/2 phosphorylation. Inhibition of Pak1 using IPA-3 decreased clonogenic survival following IR. In addition, IPA-3 increased radiation-induced cell death in MKN45 (13.4% ± 0.3% vs 26.6% ± 1.0%, P < 0.05) and SGC7901 (16.0% ± 0.6% vs 37.3% ± 1.7%, P < 0.05) gastric cancer cell lines, respectively, consistent with the level of cleaved caspase-3 (17 kDa). Western blotting showed that IPA-3 decreased radiation-induced Pak1 and ERK1/2 phosphorylation.. This is the first demonstration that β-elemene enhances radiosensitivity of gastric cancer cells, and that the mechanism involves inhibition of Pak1 signaling.

Topics: Apoptosis; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Intracellular Signaling Peptides and Proteins; p21-Activated Kinases; Phosphorylation; Protein Kinase Inhibitors; Proteomics; Radiation Tolerance; Radiation-Sensitizing Agents; Sesquiterpenes; Signal Transduction; Stomach Neoplasms; Time Factors

To investigate the effects of β-elemene in suppressing the proliferation and apoptosis of SGC7901 gastric cancer cells in vitro and explore the underlying mechanisms.. Using MTT assay, flow cytometry, and clonogenic survival assay, we assessed the effects of β-elemene on the viability, apoptosis, cell cycle distribution, and clonogenic survival of gastric cancer SGC7901 cells and gastric mucosal epithelial GES-1 cells. Western blotting was employed to determine the changes in the protein expression profiles in SGC7901 cells in response to β-elemene treatment.. β-elemene significantly suppressed the cell viability and increased the apoptosis of SGC7901 cells, and these effects were less obvious in GES-1 cells. β-elemene decreased clonogenic survival of SGC7901 cells, increased the proportion of G2/M phase cells, decreased the expression of Bcl-2, and increased the expression of Bax and cleaved caspase-3. β-elemene did not obviously affect the expression of total p21-activated protein kinase 1 (Pak1) but decreased the level of phospho-Pak1 (Thr423) and phospho-ERK1/2 (Thr202/Tyr204) in SGC7901 cells.. β-elemene inhibits the proliferation and induces apoptosis of gastric cancer cells possibly by inhibiting Pak1/ERK signaling and regulating apoptosis-associated proteins such as Bcl-2 and Bax.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Sesquiterpenes; Signal Transduction; Stomach Neoplasms

To study radiation-enhancing effects on human gastric cancer MKN28 cell line and underlying mechanisms of β-elemene.. Inhibition of MKN28 cell proliferation at different concentrations of β-elemene was assessed using the methyl thiazolyl blue colorimetric method (MTT method), with calculation of IC50 value and choice of 20% of the IC50 as the experimental drug concentration. Irradiation group and β-elemene+irradiation group were established, and the cell survival fraction (SF) was calculated from flat panel colony forming analysis, and fitted by the 'multitarget click mathematical model'. Draw the survival curve and get the radiobiological parameters D0, Dq, SF2, N and SER. Flow cytometry (FCM) was used to detect changes in the cell cycle and cell apoptosis rates was detected by Annexin-V/PI assay.. β-elemene exerted inhibitory effects on proliferation of gastric cancer MKN28 cells, with an IC50 of 45.6 mg/L and we chose 8 mg/L as the experimental concentration. The cell survival fraction of MKN28 cells with irradiation decreased significantly after treated with β-elemene; D0, Dq decreased, SER = 1.3. After combined treatment of β-elemene+irradiation, the results of FCM showed that cells could be arrested in the G2/M phase and the cell apoptosis increased significantly.. β-elemene can enhance the radiosensitivity of gastric cancer MKN28 cell line. Mechanistically, β-elemene mainly influences the cell cycle distribution of MKN28 cells by inducing G2/M phase arrest, inhibits the repair of sublethal damage and induces cell apoptosis to enhance the killing effects of radioactive rays.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Radiation Tolerance; Sesquiterpenes; Stomach Neoplasms

Gastric cancer is a common malignancy with a poor prognosis. β-elemene is a broad-spectrum anticancer drug extracted from the traditional Chinese medicinal herb Curcuma wenyujin. In the present study, we investigated the anticancer effects of β-elemene in gastric cancer cells and the potential proteins involved. Human SGC7901 and MKN45 gastric cancer cells were treated with different concentrations of β-elemene. Cell viability, clonogenic survival and apoptotic cell death were assessed. β-elemene inhibited viability and decreased clonogenic survival of gastric cancer cells in a dose-dependent manner. Apoptosis induction contributed to the anticancer effects. We then employed a proteomic method, isobaric tags for relative and absolute quantitation (iTRAQ), to detect the proteins altered by β-elemene. In total, 147 upregulated proteins and 86 downregulated proteins were identified in response to β-elemene treatment in SGC7901 gastric cancer cells. Among them, expression of p21-activated protein kinase‑interacting protein 1 (PAK1IP1), Bcl-2-associated transcription factor 1 (BTF) and topoisomerase 2-α (TOPIIα) were validated by western blot analyses and the trends were consistent with iTRAQ results. Top pathways involved in β-elemene treatment in SGC7901 gastric cancer cells included ribosome signaling, peroxisome proliferator-activated receptors (PPARs) signaling pathway, regulation of actin cytoskeleton, phagosome, biosynthesis and metabolism of some amino acids. Collectively, our results suggest a promising therapeutic role of β-elemene in gastric cancer. The differentially expressed proteins provide further insight into the potential mechanisms involved in gastric cancer treatment using β-elemene.

Topics: Apoptosis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Neoplasm Proteins; Proteomics; Sesquiterpenes; Stomach Neoplasms

Recent studies indicate that β-elemene, a compound isolated from the Chinese herbal medicine Curcuma wenyujin, is capable of reversing tumor MDR, although the mechanism remains elusive. In this study, β-Elemene treatment markedly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 in both K562/DNR and SGC7901/ADR cells and significantly inhibited the expression of P-gp. Treatment of SGC7901/ADR cells with β-elemene led to downregulation of Akt phosphorylation and significant upregulation of the E3 ubiquitin ligases, c-Cbl and Cbl-b. Importantly, β-elemene significantly enhanced the anti-tumor activity of DOX in nude mice bearing SGC7901/ADR xenografts. Taken together, our results suggest that β-elemene may target P-gp-overexpressing leukemia and gastric cancer cells to enhance the efficacy of DOX treatment.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Curcuma; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gastric Mucosa; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-cbl; Sesquiterpenes; Signal Transduction; Stomach; Stomach Neoplasms

β-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which β-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of β-elemene on human gastric cancer cells and the molecular mechanism involved.. β-Elemene inhibited the viability of human gastric cancer MGC803 and SGC7901 cells in a dose-dependent manner. The suppression of cell viability was due to the induction of apoptosis. A robust autophagy was observed in the cells treated with β-elemene; it was characterized by the increase of punctate LC3 dots, the cellular morphology, and the increased levels of LC3-II protein. Further study showed that β-elemene treatment up-regulated Atg5-Atg12 conjugated protein but had little effect on other autophagy-related proteins. PI3K/Akt/mTOR/p70S6K1 activity was inhibited by β-elemene. Knockdown of Beclin 1 with small interfering RNA, or co-treatment with the autophagy inhibitor, 3-methyladenine or chlorochine enhanced significantly the antitumor effects of β-elemene.. Our data provides the first evidence that β-elemene induces protective autophagy and prevents human gastric cancer cells from undergoing apoptosis. A combination of β-elemene with autophagy inhibitor might thus be a useful therapeutic option for advanced gastric cancer.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Humans; Phosphoinositide-3 Kinase Inhibitors; Plant Extracts; Proto-Oncogene Proteins c-akt; Sesquiterpenes; Signal Transduction; Stomach Neoplasms; TOR Serine-Threonine Kinases

To investigate the effect of traditional Chinese medicine (TCM) on quality of life (QOF) and survival period in patients with progressive gastric cancer, and thus exploring its clinical efficacy.. TCM therapy applied in the 34 patients assigned in the TCM group (Group I ) included intravenous injection of Cinobufotalin, beta-elemene, or orally taking of anti-cancer Chinese herbs. The same TCM was also applied in the 36 of the combined treatment group (Group II), but in combined use of FOLFOX chemotherapeutic protocol. Twenty-one days was taken as one cycle and all the patients received 2 cycles of treatment.. The median survival period in group II was 31 months, while it was 30 months in group I; the 1-, 2-, 3-year survival rates in group II were 88.89%, 84.38% and 59.26%, and those in the group I were 82.35%, 71.43% and 65.00%, respectively with insignificant difference between the two groups (chi2 = 0.298, P > 0.05); QOF in group I was significantly superior to that in group II (P < 0.05), and the adverse reaction occurrence was significantly less in Group I than that in group II.. Chinese medicine treatment can improve the QOF and prolong the survival period of patients with progressive gastric cancer with few side effects.

Topics: Adenocarcinoma; Adult; Aged; Bufanolides; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Humans; Male; Medicine, Chinese Traditional; Middle Aged; Phytotherapy; Quality of Life; Retrospective Studies; Sesquiterpenes; Stomach Neoplasms; Survival Analysis; Survival Rate