ABSTRACT
Cerebral edema is one of the deadliest complications of ischemic stroke for which there is currently no pharmaceutical treatment. Aquaporin-4 (AQP4), a water-channel polarized at the astrocyte endfoot, is known to be highly implicated in cerebral edema. We previously showed in randomized studies that (S)-roscovitine, a cyclin-dependent kinase inhibitor, reduced cerebral edema 48 h after induction of focal transient ischemia, but its mechanisms of action were unclear. In our recent blind randomized study, we confirmed that (S)-roscovitine was able to reduce cerebral edema by 65% at 24 h post-stroke (t test, p = .006). Immunofluorescence analysis of AQP4 distribution in astrocytes revealed that (S)-roscovitine decreased the non-perivascular pool of AQP4 by 53% and drastically increased AQP4 clusters in astrocyte perivascular end-feet (671%, t test p = .005) compared to vehicle. Non-perivascular and clustered AQP4 compartments were negatively correlated (R = -0.78; p < .0001), suggesting a communicating vessels effect between the two compartments. α1-syntrophin, AQP4 anchoring protein, was colocalized with AQP4 in astrocyte endfeet, and this colocalization was maintained in ischemic area as observed on confocal microscopy. Moreover, (S)-roscovitine increased AQP4/α1-syntrophin interaction (40%, MW p = .0083) as quantified by proximity ligation assay. The quantified interaction was negatively correlated with brain edema in both treated and placebo groups (R = -.57; p = .0074). We showed for the first time, that a kinase inhibitor modulated AQP4/α1-syntrophin interaction, and was implicated in the reduction of cerebral edema. These findings suggest that (S)-roscovitine may hold promise as a potential treatment for cerebral edema in ischemic stroke and as modulator of AQP4 function in other neurological diseases.
Subject(s)
Brain Edema , Ischemic Stroke , Humans , Brain Edema/drug therapy , Brain Edema/etiology , Brain Edema/metabolism , Ischemic Stroke/complications , Ischemic Stroke/metabolism , Roscovitine/therapeutic use , Roscovitine/metabolism , Aquaporin 4/metabolism , Astrocytes/metabolismABSTRACT
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death. Certain signaling pathways are implicated in colorectal carcinogenesis. Cyclin-dependent kinases (CDKs) are commonly hyperactivated in CRC and hence multitarget CDK inhibitors serve as promising therapeutic drugs against CRC. OBJECTIVE: Off-target effects of multitarget CDK inhibitors with differential CDK inhibitory spectrum viz. P276-00 (also known as riviciclib), roscovitine and UCN-01 on CRC cell lines of varied genetic background were delineated. METHOD: Protein expression was analyzed for key signaling proteins by western blotting. ß-catenin localization was assessed using immunofluorescence. HIF-1 transcriptional activity and target gene expression were studied by reporter gene assay and RT-PCR respectively. Anti-migratory and anti-angiogenic potential was evaluated by wound healing assay and endothelial tube formation assay. RESULTS: CDK inhibitors modulated various signaling pathways in CRC and for certain proteins showed a highly cell line-dependent response. Riviciclib and roscovitine inhibited HIF-1 transcriptional activity and HIF-1α accumulation in hypoxic HCT116 cells. Both of these drugs also abrogated migration of HCT116 and in vitro angiogenesis in HUVECs. CONCLUSION: Anticancer activity of multitarget CDK inhibitors can be certainly attributed to their off-target effects and should be analyzed while assessing their therapeutic utility against CRC.
Subject(s)
Colorectal Neoplasms , Cyclin-Dependent Kinases , Humans , Cell Line, Tumor , Roscovitine/pharmacology , Roscovitine/therapeutic use , Cyclin-Dependent Kinases/metabolism , Cyclin-Dependent Kinases/pharmacology , Signal Transduction , Protein Kinase Inhibitors/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathologyABSTRACT
CONTEXT: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. OBJECTIVE: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). METHODS: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end. RESULTS: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. CONCLUSION: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.
Subject(s)
Pituitary ACTH Hypersecretion , Adult , Humans , Pituitary ACTH Hypersecretion/drug therapy , Roscovitine/therapeutic use , Prospective Studies , Hydrocortisone , Adrenocorticotropic HormoneABSTRACT
Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and, eventually, death in individuals with cystic fibrosis (CF), a genetic disease caused by biallelic mutations in the CF transmembrane conductance regulator (CFTR) gene. Therefore, we examined whether roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defense, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immunopathophysiology, combined with murine and human approaches, we sought to determine the effects of roscovitine on innate immune responses to tissue injury and pathogens in the CF condition. We show that roscovitine exerts antiinflammatory and proresolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial reactive oxygen species (ROS)-mediated neutrophil trafficking by reducing DUOX2/NADPH-oxidase activity and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. It is important to note that, although roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo, we found that treatment with roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/NADPH oxidase-dependent ROS production, roscovitine reduces the number of neutrophils at infection sites and, consequently, compromises granuloma formation and maintenance, favoring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of roscovitine and have significant therapeutic implications for safely targeting inflammation in CF.
Subject(s)
Mycobacterium Infections, Nontuberculous , Neutrophils , Animals , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Dual Oxidases , Mice , Mycobacterium Infections, Nontuberculous/microbiology , Roscovitine/pharmacology , Roscovitine/therapeutic use , ZebrafishABSTRACT
BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.
Subject(s)
Cystic Fibrosis , Roscovitine , Animals , Cystic Fibrosis/diagnosis , Cystic Fibrosis/drug therapy , Cystic Fibrosis/metabolism , Cystic Fibrosis/microbiology , Double-Blind Method , Humans , Protein Kinase Inhibitors/therapeutic use , Pseudomonas Infections/drug therapy , Pseudomonas Infections/metabolism , Pseudomonas aeruginosa , Quality of Life , Roscovitine/therapeutic useABSTRACT
Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cystic Fibrosis/drug therapy , Inflammation/drug therapy , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Azithromycin/pharmacology , Azithromycin/therapeutic use , COVID-19/complications , COVID-19/metabolism , Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Cystic Fibrosis/complications , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Eicosanoids/metabolism , Humans , Inflammation/complications , Inflammation/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Roscovitine/pharmacology , Roscovitine/therapeutic use , Signal Transduction/drug effects , Thymalfasin/pharmacology , Thymalfasin/therapeutic use , COVID-19 Drug TreatmentABSTRACT
Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia.
Subject(s)
Brain Ischemia/drug therapy , Brain Ischemia/immunology , Brain/blood supply , Brain/pathology , Cyclin-Dependent Kinases/antagonists & inhibitors , Leukocytes/pathology , Roscovitine/therapeutic use , Animals , Cyclin-Dependent Kinases/metabolism , Humans , Leukocytes/drug effects , Models, Biological , Roscovitine/chemistry , Roscovitine/pharmacologyABSTRACT
Cystic fibrosis (CF) is characterized by chronic bacterial infections and heightened inflammation. Widespread ineffective antibiotic use has led to increased isolation of drug resistant bacterial strains from respiratory samples. (R)-roscovitine (Seliciclib) is a unique drug that has many benefits in CF studies. We sought to determine roscovitine's impact on macrophage function and killing of multi-drug resistant bacteria. Human blood monocytes were isolated from CF (F508del/F508del) and non-CF persons and derived into macrophages (MDMs). MDMs were infected with CF clinical isolates of B. cenocepacia and P. aeruginosa. MDMs were treated with (R)-roscovitine or its main hepatic metabolite (M3). Macrophage responses to infection and subsequent treatment were determined. (R)-roscovitine and M3 significantly increased killing of B. cenocepacia and P. aeruginosa in CF MDMs in a dose-dependent manner. (R)-roscovitine-mediated effects were partially dependent on CFTR and the TRPC6 channel. (R)-roscovitine-mediated killing of B. cenocepacia was enhanced by combination with the CFTR modulator tezacaftor/ivacaftor and/or the alternative CFTR modulator cysteamine. (R)-roscovitine also increased MDM CFTR function compared to tezacaftor/ivacaftor treatment alone. (R)-roscovitine increases CF macrophage-mediated killing of antibiotic-resistant bacteria. (R)-roscovitine also enhances other macrophage functions including CFTR-mediated ion efflux. Effects of (R)-roscovitine are greatest when combined with CFTR modulators or cysteamine, justifying further clinical testing of (R)-roscovitine or optimized derivatives.
Subject(s)
Burkholderia cenocepacia/immunology , Burkholderia cenocepacia/pathogenicity , Cystic Fibrosis Transmembrane Conductance Regulator/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis/microbiology , Macrophages/immunology , Phagocytosis/drug effects , Roscovitine/pharmacology , Roscovitine/therapeutic use , Adolescent , Adult , Cysteamine/pharmacology , Cysteamine/therapeutic use , Cystic Fibrosis/immunology , Drug Therapy, Combination , Female , Humans , Male , Pseudomonas aeruginosa/immunology , Pseudomonas aeruginosa/pathogenicity , Young AdultABSTRACT
Under physiological conditions, microglia are unique immune cells resident in the brain that is isolated from the systemic immune system by brain-blood barrier. Following status epilepticus (SE, a prolonged seizure activity), microglia are rapidly activated and blood-derived monocytes that infiltrate the brain; therefore, the regulations of microglia activation and monocyte infiltration are one of the primary therapeutic strategies for inhibition of undesirable consequences from SE. Roscovitine, a potent (but not selective) cyclin-dependent kinase 5 (CDK5) inhibitor, has been found to exert anti-inflammatory and microglia-inhibiting actions in several in vivo models, although the underlying mechanisms have not been clarified. In the present study, roscovitine attenuated SE-induces monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC), accompanied by reducing expressions of monocyte chemotactic protein-1 (MCP-1) and lysosome-associated membrane protein 1 (LAMP1) in resident microglia, while it did not affect microglia transformation to amoeboid form. Furthermore, roscovitine ameliorated the up-regulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, but not nuclear factor-κB-S276 phosphorylation. Similar to roscovitine, SB202190, a p38 MAPK inhibitor, mitigated monocyte infiltration and microglial expressions of MCP-1 and LAMP1 in the FPC following SE. Therefore, these findings suggest for the first time that roscovitine may inhibit SE-induced neuroinflammation via regulating p38 MAPK-mediated microglial responses.
Subject(s)
Microglia/drug effects , Monocytes/drug effects , Roscovitine , Status Epilepticus/drug therapy , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Blood-Brain Barrier , Chemokine CCL2/metabolism , Frontal Lobe/drug effects , Lysosomal Membrane Proteins/metabolism , Male , Microglia/metabolism , Monocytes/cytology , Monocytes/metabolism , Rats , Rats, Sprague-Dawley , Roscovitine/pharmacokinetics , Roscovitine/pharmacology , Roscovitine/therapeutic useABSTRACT
The specific mechanisms underlying cyclin-dependent kinase 5 (Cdk5)-mediated neuropathic pain at the spinal cord level remain elusive. The aim of the present study was to explore the role of crosstalk between Cdk5/p35 and extracellular signal-regulated kinase 1/2 (ERK1/2) signalling in mediating spinal astrocyte activity via the PPARγ pathway in a rat model of chronic constriction injury (CCI). Here, we quantified pain behaviour after CCI; detected the localization of p35, Cdk5, phosphorylated ERK1/2 (pERK1/2), phosphorylated peroxisome proliferator-activated receptor γ (pPPARγ), neuronal nuclei (a neuronal marker), glial fibrillary acidic protein (GFAP, an activated astrocyte marker) and ionized calcium binding adaptor molecule 1 (a microglial marker) in the dorsal horn using immunofluorescence; measured the protein levels of Cdk5, p35, pERK1/2, pPPARγ and GFAP using western blot analysis; and gauged the enzyme activity of Cdk5/p35 kinase using a Cdk5/p35 kinase activity assay kit. Tumour necrosis factor-α, interleukin (IL)-1ß and IL-6 levels were measured using enzyme-linked immunosorbent assay (ELISA). Ligation of the right sciatic nerve induced mechanical allodynia; thermal hyperalgesia; and the time-dependent upregulation of p35, pERK1/2 and GFAP and downregulation of pPPARγ. p35 colocalized with Cdk5, pERK1/2, pPPARγ, neurons and astrocytes but not microglia. Meanwhile, intrathecal injection of the Cdk5 inhibitor roscovitine, the mitogen-activated ERK kinase (MEK) inhibitor U0126 and the PPARγ agonist pioglitazone prevented or reversed behavioural allodynia, increased pPPARγ expression, inhibited astrocyte activation and alleviated proinflammatory cytokine (tumour necrosis factor-α, IL-1ß, and IL-6) release from activated astrocytes. Furthermore, crosstalk between the Cdk5/p35 and ERK1/2 pathways was observed with CCI. Blockade of either Cdk5/p35 or ERK1/2 inhibited Cdk5 activity. These findings indicate that spinal crosstalk between the Cdk5/p35 and ERK1/2 pathways mediates astrocyte activity via the PPARγ pathway in CCI rats and that targeting this crosstalk could be an effective strategy to attenuate CCI and astrocyte-derived neuroinflammation.
Subject(s)
Astrocytes/metabolism , MAP Kinase Signaling System/physiology , PPAR gamma/biosynthesis , Phosphotransferases/biosynthesis , Sciatic Neuropathy/metabolism , Spinal Cord/metabolism , Animals , Astrocytes/drug effects , Butadienes/pharmacology , Butadienes/therapeutic use , Constriction, Pathologic/drug therapy , Constriction, Pathologic/metabolism , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Cyclin-Dependent Kinase 5/biosynthesis , Cyclin-Dependent Kinase 5/genetics , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , MAP Kinase Signaling System/drug effects , Male , Nitriles/pharmacology , Nitriles/therapeutic use , PPAR gamma/genetics , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Sprague-Dawley , Roscovitine/pharmacology , Roscovitine/therapeutic use , Sciatic Neuropathy/drug therapy , Spinal Cord/drug effectsABSTRACT
Tubulointerstitial fibrosis is the hallmark of diabetic nephropathy, which is the leading cause of end-stage renal disease worldwide. Roscovitine, an inhibitor of Cdks, exhibits anti-fibrosis effects. The present study was aimed to explore the protected role of roscovitine from renal fibrosis of diabetic nephropathy. In vivo study showed that roscovitine treatment significantly ameliorated renal functional and histological injuries in diabetic mice. It was also showed that roscovitine coordinately inhibited the expression of collagen, α-SMA, TGF-ß1, and retaining E-cadherin expression. At the cellular level, roscovitine treated HK2 cells cultured with high glucose. It was revealed that roscovitine successfully reduced α-SMA expression and ameliorated the decrease expression of E-cadherin, the two markers of tubular cell EMT. At the molecular level, roscovitine was found to exert this effect through inhibiting the up-regulation of TGF-ß1/p38MAPK pathway in high glucose cultured HK2 cells. These study demonstrated a novel mechanism that roscovitine has the anti-fibrosis effects by inhibiting the TGF-ß1/p38MAPK pathway in diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/parasitology , Kidney/pathology , Roscovitine/therapeutic use , Transforming Growth Factor beta/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Dose-Response Relationship, Drug , Epithelial-Mesenchymal Transition/drug effects , Fibrosis , Humans , Kidney/drug effects , Kidney/metabolism , Kidney Function Tests , Male , Mice, Inbred Strains , Signal Transduction/drug effects , StreptozocinABSTRACT
KHC-4 is a 2-phenyl-4-quinolone analogue that exhibits anticancer activity. Aberrant activation of ß-catenin signaling contributes to prostate cancer development and progression. Therefore, targeting ß-catenin expression could be a useful approach to treating prostate cancer. We found that KHC-4 can inhibit ß-catenin expression and its signaling pathway in DU145 prostate cancer cells. Treatment with KHC-4 decreased total ß-catenin expression and concomitantly decreased ß-catenin levels in both the cytoplasm and nucleus of cells. KHC-4 treatment also inhibited ß-catenin expression and that of its target proteins, PI3K, AKT, GSK3ß and TBX3. We monitored the stability of ß-catenin with the proteasomal inhibitor, MG132, in DU145 cells and found that MG132 reversed KHC-4-induced proteasomal ß-catenin degradation. We verified CDK1/ß-catenin expression in KHC-4 treated DU145 cells. We found that roscovitine treatment reversed cell proliferation by arresting the cell cycle at the G2/M phase and ß-catenin expression caused by KHC-4 treatment. We suggest that KHC-4 inhibits ß-catenin signaling in DU145 prostate cancer cells.
Subject(s)
Antineoplastic Agents/therapeutic use , Morpholines/therapeutic use , Prostatic Neoplasms/metabolism , Quinolones/therapeutic use , beta Catenin/biosynthesis , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Morpholines/metabolism , Prostatic Neoplasms/drug therapy , Quinolones/metabolism , Roscovitine/metabolism , Roscovitine/therapeutic use , Signal Transduction/drug effectsABSTRACT
Context: The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited. Design: Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease." Results: At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined. Conclusions: For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.
Subject(s)
ACTH-Secreting Pituitary Adenoma/drug therapy , Adenoma/drug therapy , Antineoplastic Agents/therapeutic use , Corticotrophs/drug effects , Pituitary ACTH Hypersecretion/drug therapy , ACTH-Secreting Pituitary Adenoma/complications , ACTH-Secreting Pituitary Adenoma/pathology , Adenoma/complications , Adenoma/pathology , Antineoplastic Agents/pharmacology , Cabergoline/pharmacology , Cabergoline/therapeutic use , Clinical Trials as Topic , Corticotrophs/pathology , Humans , Pituitary ACTH Hypersecretion/etiology , Pituitary ACTH Hypersecretion/pathology , Roscovitine/pharmacology , Roscovitine/therapeutic use , Silybin/pharmacology , Silybin/therapeutic use , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Somatostatin/therapeutic use , Treatment Outcome , Tretinoin/pharmacology , Tretinoin/therapeutic useABSTRACT
OBJECTIVES: Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis. METHODS: C57BL/6 mice were infected by injection of pneumococci into the cisterna magna. Treatment was begun 21 h after infection, and consisted of ceftriaxone plus (a) dexamethasone, (b) dexamethasone plus daptomycin, (c) daptomycin, (d) daptomycin plus an anti-IL1 antibody, (e) daptomycin plus roscovitine, or (f) daptomycin plus an anti-C5 antibody. Animals were followed until 45 h after infection. Furthermore, adjunctive daptomycin plus anti-C5 antibodies were assessed in a long-term follow-up. RESULTS: Adjunctive treatment with daptomycin and an anti-C5 antibody was superior to adjunctive dexamethasone and reduced disease symptoms (clinical score 1.1 ± 1.1 versus 5.0 ± 2.7, p < 0.0083), improved explorative activity (open field test 17.8 ± 8.2 versus 7.4 ± 4.3 crossed fields/2 minutes, p < 0.0083), and reduced hearing impairment (thresholds for click stimulus 96.1 ± 14.7 versus 114.8 ± 9.3 dB SPL, p < 0.0083) in the acute stage. Furthermore, explorative activity (14.4 ± 7.3 crossed fields/2 minutes versus 6.3 ± 7.2, p < 0.05) and cognitive function (t-maze test, exploration time previously unknown alley 72.4 ± 14.3 versus 48.7 ± 25.6%, p < 0.05) was improved at 2 weeks after infection. Treatment with daptomycin plus an anti-IL-1ß antibody or roscovitine was not of significant benefit in comparison to adjunctive therapy with dexamethasone. CONCLUSIONS: An adjunctive combination of the non-lytic antibiotic daptomycin plus an anti-C5 antibody was superior to standard therapy with adjunctive dexamethasone in the treatment of pneumococcal meningitis.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Meningitis, Pneumococcal/drug therapy , Animals , Antibodies/therapeutic use , Brain/drug effects , Brain/microbiology , Chemotherapy, Adjuvant , Combined Modality Therapy , Daptomycin/therapeutic use , Dexamethasone/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Interleukin-1beta/therapeutic use , Male , Mice , Mice, Inbred C57BL , Roscovitine/therapeutic use , Streptococcus pneumoniae/drug effectsABSTRACT
Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.