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1.
Prostate ; 80(14): 1223-1232, 2020 10.
Article in English | MEDLINE | ID: mdl-33258507

ABSTRACT

BACKGROUND: Antiandrogens are effective therapies that block androgen receptor (AR) transactivation and signaling in over 50% of castration-resistant prostate cancer (CRPC) patients. However, an estimated 30% of responders will develop resistance to these therapies within 2 years. JNJ-pan-AR is a broad-spectrum AR antagonist that inhibits wild-type AR as well as several mutated versions of AR that have emerged in patients on chronic antiandrogen treatment. In this work, we aimed to identify the potential underlying mechanisms of resistance that may result from chronic JNJ-pan-AR treatment. METHODS: The LNCaP JNJR prostate cancer subline was developed by chronically exposing LNCaP parental cells to JNJ-pan-AR. Transcriptomic and proteomic profiling was performed to identify potential drivers and/or biomarkers of the resistant phenotype. RESULTS: Several enzymes critical to intratumoral androgen biosynthesis, Aldo-keto reductase family 1 member C3 (AKR1C3), UGT2B15, and UGT2B17 were identified as potential upstream regulators of the JNJ-pan-AR resistant cells. While we confirmed the overexpression of all three enzymes in the resistant cells only AKR1C3 expression played a functional role in driving JNJ-pan-AR resistance. We also discovered that AKR1C3 regulates UGT2B15 and UGT2B17 expression in JNJ-pan-AR resistant cells. CONCLUSIONS: This study supports the rationale to further investigate the benefits of AKR1C3 inhibition in combination with antiandrogens to prevent CRPC disease progression.


Subject(s)
Aldo-Keto Reductase Family 1 Member C3/metabolism , Androgen Receptor Antagonists/pharmacology , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Aldo-Keto Reductase Family 1 Member C3/biosynthesis , Aldo-Keto Reductase Family 1 Member C3/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm , Genomics , Glucuronosyltransferase/biosynthesis , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Humans , Male , Minor Histocompatibility Antigens/biosynthesis , Minor Histocompatibility Antigens/genetics , Minor Histocompatibility Antigens/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Proteomics , Receptors, Androgen/metabolism , Transcription, Genetic
2.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26288682

ABSTRACT

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

3.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Article in English | MEDLINE | ID: mdl-26288683

ABSTRACT

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

4.
J Biol Chem ; 287(44): 37406-19, 2012 Oct 26.
Article in English | MEDLINE | ID: mdl-22948158

ABSTRACT

The innate immune system protects the host from bacterial and viral invasion. Surfactant protein A (SPA), a lung-specific collectin, stimulates macrophage chemotaxis. However, the mechanisms regulating this function are unknown. Hyaluronan (HA) and its receptors RHAMM (receptor for HA-mediated motility, CD168) and CD44 also regulate cell migration and inflammation. We therefore examined the role of HA, RHAMM, and CD44 in SPA-stimulated macrophage chemotaxis. Using antibody blockade and murine macrophages, SPA-stimulated macrophage chemotaxis was dependent on TLR2 but not the other SPA receptors examined. Anti-TLR2 blocked SPA-induced production of TGFß. In turn, TGFß1-stimulated chemotaxis was inhibited by HA-binding peptide and anti-RHAMM antibody but not anti-TLR2 antibody. Macrophages from TLR2(-/-) mice failed to migrate in response to SPA but responded normally to TGFß1 and HA, effects that were blocked by anti-RHAMM antibody. Macrophages from WT and CD44(-/-) mice had similar responses to SPA, whereas those from RHAMM(-/-) mice had decreased chemotaxis to SPA, TGFß1, and HA. In primary macrophages, SPA-stimulated TGFß production was dependent on TLR2, JNK, and ERK but not p38. Pam3Cys, a specific TLR2 agonist, stimulated phosphorylation of JNK, ERK, and p38, but only JNK and ERK inhibition blocked Pam3Cys-stimulated chemotaxis. We have uncovered a novel pathway for SPA-stimulated macrophage chemotaxis where SPA stimulation via TLR2 drives JNK- and ERK-dependent TGFß production. TGFß1, in turn, stimulates macrophage chemotaxis in a RHAMM and HA-dependent manner. These findings are highly relevant to the regulation of innate immune responses by SPA with key roles for specific components of the extracellular matrix.


Subject(s)
Chemotaxis , Extracellular Matrix Proteins/metabolism , Hyaluronan Receptors/metabolism , Hyaluronic Acid/physiology , Macrophages/physiology , Pulmonary Surfactant-Associated Protein A/physiology , Toll-Like Receptor 2/metabolism , Transforming Growth Factor beta1/physiology , Animals , Cell Line , Cytoskeleton/metabolism , Extracellular Matrix Proteins/genetics , Gene Knockout Techniques , Hyaluronan Receptors/genetics , Hyaluronic Acid/metabolism , Lipoproteins/pharmacology , MAP Kinase Signaling System , Macrophages/metabolism , Mice , Mink , Mitogen-Activated Protein Kinases/metabolism , Pseudopodia/metabolism , Pseudopodia/physiology , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/genetics , Transforming Growth Factor beta1/metabolism
5.
Pediatrics ; 120(2): 346-53, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17671061

ABSTRACT

OBJECTIVES: We hypothesized that inhaled nitric oxide treatment of premature infants at risk for bronchopulmonary dysplasia would not adversely affect endogenous surfactant function or composition. METHODS: As part of the Nitric Oxide Chronic Lung Disease Trial of inhaled nitric oxide, we examined surfactant in a subpopulation of enrolled infants. Tracheal aspirate fluid was collected at specified intervals from 99 infants with birth weights <1250 g who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Large-aggregate surfactant was analyzed for surface activity with a pulsating bubble surfactometer and for surfactant protein contents with an immunoassay. RESULTS: At baseline, before administration of study gas, surfactant function and composition were comparable in the 2 groups, and there was a positive correlation between minimum surface tension and severity of lung disease for all infants. Over the first 4 days of treatment, minimum surface tension increased in placebo-treated infants and decreased in inhaled nitric oxide-treated infants. There were no significant differences between groups in recovery of large-aggregate surfactant or contents of surfactant protein A, surfactant protein B, surfactant protein C, or total protein, normalized to phospholipid. CONCLUSIONS: We conclude that inhaled nitric oxide treatment for premature infants at risk of bronchopulmonary dysplasia does not alter surfactant recovery or protein composition and may improve surfactant function transiently.


Subject(s)
Infant, Premature/physiology , Nitric Oxide/administration & dosage , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/physiology , Pulmonary Surfactant-Associated Proteins/chemistry , Pulmonary Surfactant-Associated Proteins/physiology , Administration, Inhalation , Bronchopulmonary Dysplasia/drug therapy , Bronchopulmonary Dysplasia/physiopathology , Bronchopulmonary Dysplasia/prevention & control , Female , Humans , Infant, Newborn , Male , Pulmonary Alveoli/chemistry , Surface Tension/drug effects
6.
Am J Physiol Lung Cell Mol Physiol ; 292(1): L249-57, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16997883

ABSTRACT

In the fetal lung, endogenous transforming growth factor (TGF)-beta inhibits early morphogenesis and blocks hormone-induced type II cell differentiation. We hypothesized that endogenous TGF-beta inhibits type II cell differentiation and that the stimulatory effects of glucocorticoids result in part from suppression of TGF-beta. Epithelial cells were isolated from human fetal lung and cultured under defined conditions with and without dexamethasone plus cAMP to promote type II cell differentiation. Control cells produced TGF-beta, which was activated in part by alpha(V)beta(6)-integrin. Treatment with dexamethasone, but not cAMP, reduced TGF-beta1 and -beta2 transcripts and TGF-beta bioactivity in culture medium. To examine the effects of decreased TGF-beta in the absence of glucocorticoid, cells were treated with antibodies to TGF-beta and its receptors. By real-time RT-PCR, antibody blockade of TGF-beta reduced serpine1, a TGF-beta-inducible gene, and increased gene expression for sftpa, sftpb, sftpc, and titf1, mimicking the response to hormone treatment. By microarray analysis, 29 additional genes were induced by both TGF-beta antibody and hormone treatment, and 20 other genes were repressed by both treatments. For some genes, the fold response was comparable for antibody and hormone treatment. We conclude that endogenous TGF-beta suppresses expression of surfactant proteins and selected other type II cell genes in fetal lung, in part secondary to increased expression of titf1, and we propose that the mechanism of glucocorticoid-induced type II cell differentiation includes antagonism of TGF-beta gene suppression. Surfactant production during fetal development is likely influenced by relative levels of TGF-beta and glucocorticoids.


Subject(s)
Glucocorticoids/pharmacology , Lung/cytology , Lung/drug effects , Transforming Growth Factor beta/metabolism , Animals , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line , Cells, Cultured , DNA-Binding Proteins/metabolism , Dexamethasone/pharmacology , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Fetus/cytology , Fetus/metabolism , Gene Expression Profiling , Humans , Lung/metabolism , Mink , Pulmonary Surfactant-Associated Proteins/genetics , Pulmonary Surfactant-Associated Proteins/metabolism , Signal Transduction , Transcription Factors , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/genetics
7.
J Nutr ; 135(2): 160-4, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15671207

ABSTRACT

Carotenoids, plant pigments with potent antioxidant activity, are implicated in chronic disease protection. They are absorbed from the diet and transported by plasma lipoproteins. Monocytes, as circulating blood cells, are exposed to carotenoid-rich lipoproteins. Such exposure may lead to enrichment with carotenoids and may affect the functions of monocyte-derived macrophages. This study explored the effect of cellular enrichment in vitro with beta-carotene, lycopene, or lutein on monocyte/macrophage function, using U937 cells as a model. Cell proliferation, production of reactive oxygen species, and cell-substrate adhesion were examined. Maximal carotenoid levels in medium supplemented with preenriched human serum were 2-8 mumol/L; incubation for 1-6 d resulted in 0.2-1.1 nmol carotenoid/mg cell protein (0.25-1 nmol/10(6) cells), approximately 10-fold more than that reported in normal tissue in vivo but within the range that might be anticipated with dietary supplementation. beta-Carotene, lycopene, and lutein markedly inhibited the proliferation of U937 cells, to an extent similar to or greater than that due to phorbol myristic acetate, a known differentiation/activation agent. Lycopene, but not beta-carotene or lutein, caused a significant increase in reactive oxygen species, indicating the induction of cell differentiation. Adhesion and LDL oxidation were unaffected. Thus, cellular carotenoids inhibit proliferation, and for lycopene at least, this may involve cell differentiation. The effectiveness of lycopene, a nonprovitamin A carotenoid, is consistent with a vitamin A-independent pathway modulating cell function.


Subject(s)
Carotenoids/blood , Carotenoids/pharmacology , Cell Differentiation/drug effects , Cell Division/drug effects , Macrophages/cytology , Monocytes/cytology , Cell Line , Humans , Kinetics , Lutein/pharmacology , Lycopene , Macrophages/drug effects , Monocytes/drug effects , Tetradecanoylphorbol Acetate , U937 Cells , beta Carotene/pharmacology
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