beta-elemene and Neoplasm-Metastasis

Entry of β-elemene into various phases of clinical trials advocates its significance as a premium candidate likely to gain access to mainstream medicine. Based on the insights gleaned from decades of research, it seems increasingly transparent that β-elemene has shown significant ability to modulate multiple cell signaling pathways in different cancers. We partition this multicomponent review into how β-elemene strategically modulates various signal transduction cascades. We have individually summarized regulation of tumor necrosis factor related apoptosis-inducing ligand, signal transducers and activators of transcription, transforming growth factor/SMAD, NOTCH, and mammalian target of rapamycin pathways by β-elemene. Last, we will discuss the results of clinical trials of β-elemene and how effectively we can use these findings to stratify patients who can benefit most from β-elemene.

Topics: Animals; Apoptosis; Clinical Trials as Topic; Disease Progression; Humans; Neoplasm Metastasis; Neoplasms; Sesquiterpenes; Signal Transduction

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

Pyruvate kinase M2 (PKM2), playing a central role in regulating aerobic glycolysis, was considered as a promising target for cancer therapy. However, its role in cancer metastasis is rarely known. Here, we found a tight relationship between PKM2 and breast cancer metastasis, demonstrated by the findings that beta-elemene (β-elemene), an approved drug for complementary cancer therapy, exerted distinct anti-metastatic activity dependent on PKM2. The results indicated that β-elemene inhibited breast cancer cell migration, invasion in vitro as well as metastases in vivo. β-Elemene further inhibited the process of aerobic glycolysis and decreased the utilization of glucose and the production of pyruvate and lactate through suppressing pyruvate kinase activity by modulating the transformation of dimeric and tetrameric forms of PKM2. Further analysis revealed that β-elemene suppressed aerobic glycolysis by blocking PKM2 nuclear translocation and the expression of EGFR, GLUT1 and LDHA by influencing the expression of importin α5. Furthermore, the effect of β-elemene on migration, invasion, PKM2 transformation, and nuclear translocation could be reversed in part by fructose-1,6-bisphosphate (FBP) and L-cysteine. Taken together, tetrameric transformation and nuclear translocation of PKM2 are essential for cancer metastasis, and β-elemene inhibited breast cancer metastasis via blocking aerobic glycolysis mediated by dimeric PKM2 transformation and nuclear translocation, being a promising anti-metastatic agent from natural compounds.

Topics: Aerobiosis; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cysteine; ErbB Receptors; Female; Fructosediphosphates; Gene Expression Regulation, Neoplastic; Glucose Transporter Type 1; Glycolysis; Humans; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Neoplasm Invasiveness; Neoplasm Metastasis; Protein Multimerization; Protein Transport; Pyruvate Kinase; Sesquiterpenes; Signal Transduction

This paper explores the underlying mechanism through which β-elemene inhibits the growth of intraocular melanoma in a mouse model. C57BL/6J mice were administered a subretinal injection of B16F10 melanoma cells and divided into two groups: treatment and control. The treatment group was administered β-elemene through an intravitreal injection and the control group was injected with a blank emulsion. After 21 days of continuous treatment, tumor masses were removed and weighed. The mRNA expression levels of the urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), matrix metalloproteinase (MMP)-2, and MMP-9 were assayed by real-time PCR, and the protein expression levels of uPA, uPAR, MMP-2, and MMP-9 were assayed by immunocytochemistry and western blotting. Tumor size was inhibited by β-elemene in the treatment group, and the expressions of uPA, uPAR, MMP-2, and MMP-9 were all downregulated at both the mRNA and the protein level compared with the control group. In a mouse model of intraocular melanoma, β-elemene inhibits tumor growth by downregulating the expression of uPA, uPAR, MMP-2, and MMP-9.

Topics: Animals; Disease Models, Animal; Eye Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Medicine, Chinese Traditional; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Receptors, Urokinase Plasminogen Activator; Sesquiterpenes; Urokinase-Type Plasminogen Activator

β-Elemene has been reported to be effective for the treatment of leukemia and certain solid tumors in basic and clinical studies. However, the mechanism of action of this phytochemical remains unknown. This study aimed to investigate the effect and mechanism of β-elemene in the mouse melanoma cell line B16F10. Cell viability was measured using the MTT assay. β-Elemene inhibited B16F10 melanoma cell metastasis, examined using scratch and Transwell migration/invasion assays. The mRNA and protein expression of urokinase-type plasminogen activator (uPA), the uPA receptor (uPAR), matrix metalloproteinase (MMP)-2, and MMP-9 were assayed using real-time PCR, immunocytochemistry, and western blotting methods. The results indicated that β-elemene inhibited the viability of B16F10 melanoma cells in a dose-dependent and time-dependent manner. The migratory and invasive capacities of B16F10 cells were also inhibited by β-elemene. The expression of uPA, uPAR, MMP-2, and MMP-9 was reduced by β-elemene at both the mRNA and protein level. β-Elemene inhibits the metastasis of B16F10 melanoma cells through downregulation of the expression of uPA, uPAR, MMP-2, and MMP-9. Thus, β-elemene is a natural potential anticancer drug.

Topics: Animals; Cell Line, Tumor; Cell Movement; Down-Regulation; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma, Experimental; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Receptors, Urokinase Plasminogen Activator; RNA, Messenger; Sesquiterpenes; Skin Neoplasms; Urokinase-Type Plasminogen Activator

It was to assess antiangiogenic effect of β-elemene in vitro and in vivo, and it was involved in inhibiting melanoma growth and metastasis, as well as to elucidate its intrinsic mechanism.. Inhibitive effect of β-elemene on B16F10 cells was performed by cell proliferation assay. Angiogenesis assays in vitro including rat aortic ring and chick embryo chorioallantoic membrane were used, as well as melanoma growth and metastasis assay in C57BL/6 mice. Vascular endothelial growth factor (VEGF) expression in vitro and in vivo was measured respectively by western blot analysis and enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry analysis of CD34 and VEGF expression in primary melanoma was also presented.. β-Elemene inhibited B16BF10 cell proliferation starting from 200 μM, but VEGF from 20 μM. Both 20 and 50 μM β-elemene in vitro inhibited VEGF-induced sprouting vessel of rat aortic ring and microvessel formation of chick embryo chorioallantoic membrane. In vivo, tumor size of primary melanoma in mice intraperitoneally treated with β-elemene was significantly smaller than that of the control; CD34 expression of primary melanoma was also suppressed; and the metastatic melanoma colonies and content of melanin in lung were detected obviously decreased in mice of β-elemene-treated groups. Furthermore, results of VEGF expressing in primary melanoma, serum and lung of mice also disclosed that VEGF was inhibited in vivo.. β-Elemene inhibited melanoma growth and metastasis through suppressing VEGF-mediated angiogenesis. It is a natural potential antiangiogenic agent.

Topics: Angiogenesis Inhibitors; Animals; Antigens, CD34; Aorta, Thoracic; Blotting, Western; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Vascular Endothelial Growth Factor A