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Oncotarget Dec 2016Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show...
Tumor metastasis is a major cause leading to the deaths of cancer patients. Nordihydroguaiaretic acid (NDGA) is a natural product that has been demonstrated to show therapeutic values in multiple diseases. In this study, we report that NDGA can inhibit cell migration and tumor metastasis via a novel mechanism. NDGA suppresses NRP1 function by downregulating its expression, which leads to attenuated cell motility, cell adhesion to ECM and FAK signaling in cancer cells. Moreover, due to its cross-cell type activity on NRP1 suppression, NDGA also impairs angiogenesis function of endothelial cells and fibronectin assembly by fibroblasts, both of which are critical to promote metastasis. Based on these comprehensive effects, NDGA effectively suppresses tumor metastasis in nude mice model. Our findings reveal a novel mechanism underlying the anti-metastasis function of NDGA and indicate the potential value of NDGA in NRP1 targeting therapy for selected subtypes of cancer.
Topics: Animals; Cell Adhesion; Cell Line, Tumor; Cell Movement; Endothelial Cells; Fibroblasts; Focal Adhesion Protein-Tyrosine Kinases; Humans; Male; Masoprocol; Mice; Neoplasm Metastasis; Neuropilin-1; Prostatic Neoplasms
PubMed: 27863391
DOI: 10.18632/oncotarget.13368 -
Journal of Pharmacological Sciences Sep 2016The prevalence rate of cardiovascular disease is higher for males than females, and estradiol (E2) induces AMP-activated protein kinase (AMPK) activation, which is known...
The prevalence rate of cardiovascular disease is higher for males than females, and estradiol (E2) induces AMP-activated protein kinase (AMPK) activation, which is known to regulate proliferation of VSMC. We identified the estrogenic properties of nordihydroguaiaretic acid (NDGA, a lignan phytoestrogen) that inhibit VSMC proliferation and explored the underlying mechanisms. Both the phosphorylation and expression of LKB1 were increased by NDGA. In addition, NDGA significantly attenuated angiotensin II (Ang II)-induced VSMC proliferation. To elucidate the estrogenic effects, we confirmed that NDGA increased estrogen receptor α (ERα) expression, similar to treatment with E2 and estriol (E3). Furthermore, tamoxifen and ERα siRNA obstructed the effects of NDGA including ERα expression, AMPK phosphorylation and both LKB1 phosphorylation and expression. VSMC proliferation was restored by tamoxifen and ERα siRNA. LKB1 siRNA also reversed the NDGA-mediated inhibition of VSMC proliferation. The estrogenic activity of NDGA induced LKB1 translocation from nucleus to cytosol, and tamoxifen obstructed LKB1 translocation. The absence of LKB1 completely abolished the increase of ERα expression induced by NDGA. Taken together, the beneficial effects of estrogenic compound (E2 and NDGA) on inhibition of VSMC proliferation are mediated by interaction between LKB1 and ERα, suggesting a potential mechanism for females having less cardiovascular disease.
Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Angiotensin II; Animals; Aorta, Thoracic; Cell Cycle; Cell Proliferation; Cells, Cultured; Dihydrotestosterone; Estradiol; Estriol; Estrogen Receptor alpha; Estrogens; Masoprocol; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Protein Serine-Threonine Kinases; RNA, Small Interfering; Rats, Sprague-Dawley
PubMed: 27665370
DOI: 10.1016/j.jphs.2016.09.001 -
PloS One 2016Exogenous drugs that are used as antidote against chemotheray, inflammation or viral infection, gets absorbed and interacts reversibly to the major serum transport...
Exogenous drugs that are used as antidote against chemotheray, inflammation or viral infection, gets absorbed and interacts reversibly to the major serum transport protein i.e. albumins, upon entering the circulatory system. To have a structural guideline in the rational drug designing and in the synthesis of drugs with greater efficacy, the binding mechanism of an antineoplastic and anti-inflammatory drug Nordihydroguaiaretic acid (NDGA) with human and bovine serum albumins (HSA & BSA) were examined by spectroscopic and computational methods. NDGA binds to site II of HSA with binding constant (Kb) ~105 M-1 and free energy (ΔG) ~ -7.5 kcal.mol-1. It also binds at site II of BSA but with lesser binding affinity (Kb) ~105 M-1 and ΔG ~ -6.5 kcal.mol-1. The negative value of ΔG, ΔH and ΔS for both the albumins at three different temperatures confirmed that the complex formation process between albumins and NDGA is spontaneous and exothermic. Furthermore, hydrogen bonds and hydrophobic interactions are the main forces involved in complex formation of NDGA with both the albumins as evaluated from fluorescence and molecular docking results. Binding of NDGA to both the albumins alter the conformation and causes minor change in the secondary structure of proteins as indicated by the CD spectra.
Topics: Animals; Antineoplastic Agents; Cattle; Computer Simulation; Humans; Masoprocol; Models, Chemical; Protein Binding; Serum Albumin, Bovine; Spectrophotometry, Ultraviolet
PubMed: 27391941
DOI: 10.1371/journal.pone.0158833 -
Aging Cell Oct 2016The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each...
The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin - the latter with and without rapamycin, and two drugs previously examined: 17-α-estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17-α-estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male-specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α-glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.
Topics: Acarbose; Animals; Antioxidants; Drugs, Chinese Herbal; Estradiol; Fish Oils; Glycoside Hydrolase Inhibitors; Hand Strength; Longevity; Male; Masoprocol; Metformin; Mice; NF-E2-Related Factor 2; Rotarod Performance Test; Sirolimus; Survival Analysis; Ursodeoxycholic Acid; alpha-Glucosidases
PubMed: 27312235
DOI: 10.1111/acel.12496 -
Scientific Reports Feb 2016Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees...
Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees are wounded by external stimuli do they form agarwood sesquiterpene defensive compounds. Therefore, understanding the signaling pathway of wound-induced agarwood formation is important. Jasmonic acid (JA) is a well-characterized molecule that mediates a plant's defense response and secondary metabolism. However, little is known about the function of endogenous JA in agarwood sesquiterpene biosynthesis. Here, we report that heat shock can up-regulate the expression of genes in JA signaling pathway, induce JA production and the accumulation of agarwood sesquiterpene in A. sinensis cell suspension cultures. A specific inhibitor of JA, nordihydroguaiaretic acid (NDGA), could block the JA signaling pathway and reduce the accumulation of sesquiterpene compounds. Additionally, compared to SA and H2O2, exogenously supplied methyl jasmonate has the strongest stimulation effect on the production of sesquiterpene compounds. These results clearly demonstrate the central induction role of JA in heat-shock-induced sesquiterpene production in A. sinensis.
Topics: Acetates; Cell Culture Techniques; Cyclopentanes; Gene Expression Regulation, Plant; Heat-Shock Proteins; Heat-Shock Response; Hot Temperature; Masoprocol; Oxylipins; Plant Cells; Plant Proteins; Secondary Metabolism; Sesquiterpenes; Signal Transduction; Thymelaeaceae
PubMed: 26902148
DOI: 10.1038/srep21843 -
PloS One 2016The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells,...
Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01.
The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments.
Topics: Antineoplastic Agents; Autophagy; Carbohydrate Metabolism; Caspase 7; Cell Line, Tumor; Down-Regulation; Drug Synergism; Energy Metabolism; Etoposide; Glutathione; Humans; Lipid Metabolism; Male; Masoprocol; Metabolic Networks and Pathways; Metabolome; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Sirolimus; Staurosporine
PubMed: 26886430
DOI: 10.1371/journal.pone.0148685 -
International Immunopharmacology Feb 2016Tuberculosis (TB) remains as a global health problem. The prevalence of this infection is related to the association with other diseases, such as HIV, neglect treatment...
Tuberculosis (TB) remains as a global health problem. The prevalence of this infection is related to the association with other diseases, such as HIV, neglect treatment and misuse of antibiotics. Hence, the identification of new drugs is required to eradicate TB. Possible alternatives to existing antibiotics include pure compounds extracted from medicinal plants, which are an important source of antimicrobial agents. The aim of this study was to evaluate the effect of nordihydroguaiaretic acid (NDGA) and α-mangostin on Mycobacterium tuberculosis growth and bacterial survival in infected macrophages derived from the human THP-1 cell line and monocytes. Our results show that both compounds directly inhibit M. tuberculosis growth in liquid medium with Minimal Inhibitory Concentrations (MIC) of 250 and 62 μg/mL respectively, likely through preventing bacterial replication. In addition, NDGA and α-mangostin were able to induce autophagy in human cells at lower concentrations (7 and 6 μg/mL, respectively) and contributed to the elimination of intracellular bacteria. NDGA and α-mangostin could be candidates for coadjuvant therapy in cases of drug-resistant TB, and their ability to enhance the immune response by promoting autophagy might contribute to TB treatment.
Topics: Autophagy; Cell Line; Humans; Macrophages; Masoprocol; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Xanthones
PubMed: 26735610
DOI: 10.1016/j.intimp.2015.12.027 -
Cell Cycle (Georgetown, Tex.) 2015p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle...
p21(WAF1) is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21(WAF1) in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21(WAF1) was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21(WAF1) in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21(WAF1) silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21(WAF1) expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21(WAF1) regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; B-Lymphocytes; Caspase 3; Caspase 7; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Etoposide; Gene Expression Regulation, Leukemic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Masoprocol; Phosphatidylserines; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; RNA, Small Interfering; Signal Transduction; Sp1 Transcription Factor; T-Lymphocytes; Transcription, Genetic; Tumor Suppressor Protein p53; Vorinostat
PubMed: 26506264
DOI: 10.1080/15384101.2015.1100774 -
PloS One 2015Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS),...
Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.
Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.
Topics: AMP-Activated Protein Kinases; Acetyl-CoA Carboxylase; Animals; Blotting, Western; Fatty Acid-Binding Proteins; Fatty Liver; Fructose; Gene Expression Regulation; Hypertriglyceridemia; Larrea; Lipid Metabolism; Lipogenesis; Liver; Male; Masoprocol; PPAR alpha; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 1
PubMed: 26394137
DOI: 10.1371/journal.pone.0138203 -
American Journal of Physiology. Lung... Sep 2015Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular...
Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.
Topics: Animals; Arachidonate 15-Lipoxygenase; Blood Platelets; Cells, Cultured; Chemokine CCL2; Cytokines; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Hypoxia; Indazoles; Lipoxygenase Inhibitors; Male; Masoprocol; Platelet Activation; Propionates; Pulmonary Artery; RNA Interference; RNA, Small Interfering; Random Allocation; Rats; Rats, Wistar; Signal Transduction; Thrombosis; Vascular Resistance
PubMed: 26092993
DOI: 10.1152/ajplung.00004.2015