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Marine Drugs Apr 2020Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor...
α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors.
Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8-3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.
Topics: Animals; Arachidonic Acid; Carcinoma; Carcinoma, Ehrlich Tumor; Cell Survival; Cobra Neurotoxin Proteins; Conotoxins; Cyclooxygenase Inhibitors; Drug Synergism; Flavanones; Indomethacin; Lipoxygenase Inhibitors; Masoprocol; Mice; Nicotinic Antagonists; Receptors, Nicotinic
PubMed: 32272633
DOI: 10.3390/md18040193 -
Journal of Korean Medical Science Jan 2009The selective cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX) inhibitors might inhibit prostaglandin synthesis and reduce proteinuria. The present study was designed...
The selective cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX) inhibitors might inhibit prostaglandin synthesis and reduce proteinuria. The present study was designed to investigate the anti-proteinuric effects of nordihydroguaiaretic acid (NDGA) as compared with celecoxib in puromycin aminonucleoside (PAN) nephrosis rats. Fifty five male Sprague-Dawley rats were divided into 4 groups; A, normal control; B, PAN group; C, PAN+COX-2 inhibitor (celecoxib) group; and D, PAN+5-LOX inhibitor (NDGA) group. After induction of PAN nephrosis through repeated injections of PAN (7.5 and 15 mg/100 g body weight), rats were treated with celecoxib, NDGA, or vehicle for 2 weeks. Twenty four hour urine protein excretions were significantly lower in PAN+celecoxib and PAN+NDGA groups than in PAN group. Serum creatinine (SCr) concentrations and 24 hr urine creatinine clearances (CCr) were not significantly different in the four groups. Electron microscopy showed that podocyte morphology was changed after the induction of PAN nephrosis and was recovered after celecoxib or NDGA administration. Celecoxib significantly recovered the expressions of nephrin, CD2AP, COX-2, and TGF-beta. NDGA also recovered TGF-beta expression, but did not alter the expressions of nephrin, CD2AP and COX-2. The present study suggested that celecoxib and NDGA might effectively reduce proteinuria in nephrotic syndrome without impairing renal function.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Celecoxib; Creatinine; Cyclooxygenase Inhibitors; Male; Masoprocol; Microscopy, Electron; Nephrosis; Podocytes; Puromycin Aminonucleoside; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors
PubMed: 19194550
DOI: 10.3346/jkms.2009.24.S1.S183 -
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 -
The Journals of Gerontology. Series A,... Dec 2010We used a heterogeneous stock of mice-UM-HET3, the first generation offspring of CByB6F1/J and C3D2F1/J parents-to test effects of six antiaging treatments on life span....
We used a heterogeneous stock of mice-UM-HET3, the first generation offspring of CByB6F1/J and C3D2F1/J parents-to test effects of six antiaging treatments on life span. In the first report of diet restriction in a structured, segregating heterogeneous population, we observed essentially the same increases in mean and maximum life span as found in CByB6F1/J hybrid positive controls. We also report results of treatment with N-acetyl-L-cysteine started at 7 months, and aspirin, nitroflurbiprofen, 4-hydroxy phenyl N-tert-butyl nitrone, and nordihydroguaiaretic acid, all started at 16-18 months. Only male UM-HET3 mice receiving N-acetyl-L-cysteine had significantly increased life span, and this may have been due to treatment-related inadvertent diet restriction. The other agents had no significant effects on life span. The use of UM-HET3 mice helps assure that these results are not the result of unresponsiveness of a single genotype but that they more broadly represent laboratory mice.
Topics: Acetylcysteine; Animals; Aspirin; Crosses, Genetic; Diet; Female; Flurbiprofen; Imines; Life Expectancy; Longevity; Male; Masoprocol; Mice; Mice, Inbred Strains; Phenols; Sex Factors
PubMed: 20819793
DOI: 10.1093/gerona/glq155 -
Kidney International Sep 1987Germ free rats provide a unique model in which to assess biological response to environment. In 48 germ-free male, Sprague-Dawley rats we examined the consequences of...
Germ free rats provide a unique model in which to assess biological response to environment. In 48 germ-free male, Sprague-Dawley rats we examined the consequences of oral exposure to nordihydroguaiaretic acid (NDGA), a nephrotoxin; to Staphylococcus epidermidis and bacillus species, non-endotoxin-containing bacteria; to Escherichia coli and Proteus mirabilis, endotoxin-containing bacteria; and injected E. coli endotoxin on peripheral leukocyte counts and renal morphology. Morphological changes were evaluated by light microscopy and scored blindly on a 0 to 4+ scale for 15 parameters of renal structure. Means of these renal "pathology scores" correlated with counts of polymorphonuclear leukocytes and lymphocytes in the peripheral blood. The highest counts and scores were found in rats given NDGA and exposed to endotoxin, either by injection or by oral feeding of endotoxin-containing bacteria. Counts and scores were lower in the absence of endotoxin and with non-endotoxin-containing bacteria, given alone or in combination with either NDGA or endotoxin. Results exclude bacterial colonization and intrarenal accumulation of NDGA as causes of nephropathy. They indicate that endotoxin and NDGA act synergistically to provoke renal damage in the germ free NDGA-fed rat and suggest that leukocytes are involved in the process.
Topics: Animals; Disease Models, Animal; Endotoxins; Escherichia coli; Kidney; Kidney Diseases, Cystic; Leukocyte Count; Lymphocytes; Male; Masoprocol; Neutrophils; Proteus mirabilis; Rats; Rats, Inbred Strains; Staphylococcus epidermidis
PubMed: 3312760
DOI: 10.1038/ki.1987.213 -
Yakugaku Zasshi : Journal of the... Apr 2010
[Elucidation of mechanism underlying amyloid-beta peptide aggregation and its neurotoxicity expression and inhibition of these molecular processes by beneficial synthetic and natural compounds with low-molecular weights-new approaches to fundamental treatment and prevention of Alzheimer's disease].
Topics: Agglutination; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Enzyme Inhibitors; Humans; Masoprocol; Molecular Weight
PubMed: 20371991
DOI: 10.1248/yakushi.130.493 -
Experimental Cell Research Jun 1994The signal transduction pathways through which growth factors regulate vascular cell growth are not fully understood. Recent studies suggest that metabolites of the...
The signal transduction pathways through which growth factors regulate vascular cell growth are not fully understood. Recent studies suggest that metabolites of the lipoxygenase pathway may be involved in vascular cell growth. We have measured the effect of the lipoxygenase pathway inhibitors nordihydroguiaretic acid (NDGA), 5,6-dehydroarachidonic acid, and baicalein on bovine capillary endothelial cell (EC) and aortic smooth muscle cell (SMC) growth in the presence or the absence of growth factors. NDGA totally suppressed serum-stimulated EC and SMC growth as well as growth factor-stimulated proliferation over a 9-day time course. Removal of the inhibitor revealed that the inhibitory effect of NDGA was reversible and not due to cytotoxicity. The morphology of NDGA-treated EC was changed in a reversible manner from the characteristic polygonal to spindle shape. The 5-lipoxygenase inhibitor 5,6-dehydroarachidonic acid had no effect on vascular cell proliferation, but inhibition of 12-lipoxygenase with baicalein blocked both EC and SMC cell growth in a dose-dependent manner, in the presence and the absence of growth factors. Indomethacin, an inhibitor of the cyclooxygenase pathway, had no effect on EC and SMC proliferation. Quinacrine and oleyloxyethylphosphorycholine inhibition of the phospholipase A2-catalyzed release of arachidonic acid from membrane phospholipids blocked growth factor- and serum-stimulated proliferation of EC and SMC. These results suggested that arachidonic acid metabolites are critical intermediaries in the regulation of vascular cell growth.
Topics: Animals; Arachidonic Acid; Cattle; Cell Division; Cells, Cultured; Cyclooxygenase Inhibitors; Endothelium, Vascular; Fibroblast Growth Factor 2; Flavanones; Flavonoids; In Vitro Techniques; Lipoxygenase Inhibitors; Masoprocol; Muscle, Smooth, Vascular; Phospholipase D; Phospholipases A; Phospholipases A2; Platelet-Derived Growth Factor; Propranolol; Quinacrine; Signal Transduction
PubMed: 8187818
DOI: 10.1006/excr.1994.1142 -
Biochemistry Feb 2017Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP)...
Fibrillar aggregates of the protein α-synuclein (αS) are one of the hallmarks of Parkinson's disease. Here, we show that measuring the fluorescence polarization (FP) of labels at several sites on αS allows one to monitor changes in the local dynamics of the protein after binding to micelles or vesicles, and during fibril formation. Most significantly, these site-specific FP measurements provide insight into structural remodeling of αS fibrils by small molecules and have the potential for use in moderate-throughput screens to identify small molecules that could be used to treat Parkinson's disease.
Topics: Amino Acid Sequence; Catechin; Dopamine; Fluorescence Polarization; Fluorescent Dyes; Humans; Masoprocol; Phosphatidylcholines; Protein Aggregates; Recombinant Proteins; Small Molecule Libraries; Sodium Dodecyl Sulfate; Unilamellar Liposomes; Xanthenes; alpha-Synuclein
PubMed: 28045494
DOI: 10.1021/acs.biochem.6b01060 -
Journal of Thoracic Oncology : Official... Jan 2011Survivin, an inhibitor of apoptosis protein and key regulator of mitosis, is up-regulated in a variety of cancers and is often associated with a worse prognosis....
INTRODUCTION
Survivin, an inhibitor of apoptosis protein and key regulator of mitosis, is up-regulated in a variety of cancers and is often associated with a worse prognosis. Terameprocol down-regulates the Sp1-mediated transcription of survivin and Cdk1, which is important for cell cycle progression and many other proteins. Survivin inhibition has previously been shown to result in the induction of apoptosis and radiosensitization.
METHODS
This study examined the effects of terameprocol administration on survivin transcription and expression in HCC2429 and H460 lung cancer cells. We also examined the combined effects of radiation and terameprocol on apoptosis and radiosensitivity.
RESULTS
Using immunoblot analysis and luciferase assays, we confirmed that terameprocol decreases survivin transcription and protein expression. Ultimately, however, decreases in survivin expression failed to correlate with an increase in apoptosis. Nonetheless, clonogenic assay revealed that terameprocol induces increased radiosensitization in HCC2429 (dose enhancement ratio = 1.26, p = 0.019) and H460 (dose enhancement ratio = 1.18, p = 0.001) cells. Additionally, the data show no effect of terameprocol on cell cycle in either HCC2429 or H460 cells.
CONCLUSIONS
Terameprocol significantly enhances the sensitivity of non-small cell lung carcinoma cell lines to radiation therapy, although the mechanism of action remains unclear. Further study is warranted to assess the potential of terameprocol as an agent that may enhance the therapeutic ratio of radiotherapy in lung cancer.
Topics: Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Masoprocol; Radiation-Sensitizing Agents; Sp1 Transcription Factor; Survivin; Tumor Cells, Cultured; Tumor Stem Cell Assay
PubMed: 21107289
DOI: 10.1097/JTO.0b013e3181fa646a -
British Journal of Pharmacology May 19961. In NIH3T3 fibroblasts, the chloride channel involved in regulatory volume decrease (RVD) was identified as ICln, a protein isolated from a cDNA library derived from...
1. In NIH3T3 fibroblasts, the chloride channel involved in regulatory volume decrease (RVD) was identified as ICln, a protein isolated from a cDNA library derived from Madin Darby canine Kidney (MDCK) cells. ICln expressed in Xenopus laevis oocytes gives rise to an outwardly rectifying chloride current, sensitive to the extracellular addition of nucleotides and the known chloride channel blockers, DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid) and NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid). We set out to study whether substances structurally similar to NPPB are able to interfere with RVD. 2. RVD in NIH3T3 fibroblasts and MDCK cells is temperature-dependent. 3. RVD, the swelling-dependent chloride current and the depolarization seen after reducing extracellular osmolarity can be blocked by gossypol and NDGA (nordihydroguaiaretic acid), both structurally related to NPPB. 4. The cyclic AMP-dependent chloride current elicited in CaCo cells is less sensitive to the two substances tested while the calcium-activated chloride current in fibroblasts is insensitive. 5. The binding site for the two phenol derivatives onto ICln seems to be distinct but closely related to the nucleotide binding site identified as G x G x G, a glycine repeat located at the predicted outer mouth of the ICln channel protein.
Topics: 3T3 Cells; Animals; Binding Sites; Caco-2 Cells; Calcium; Cell Size; Chloride Channels; Chlorides; Cyclic AMP; Dogs; Gossypol; Humans; Kidney; Masoprocol; Membrane Potentials; Mice; Phenols; Thymine Nucleotides; Xenopus laevis
PubMed: 8733574
DOI: 10.1111/j.1476-5381.1996.tb15364.x