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DNA Repair Jan 2020Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5'-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes...
Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5'-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA-Binding Proteins; Drug Screening Assays, Antitumor; Drug Synergism; Etoposide; Flavins; Humans; Mitoxantrone; Molecular Docking Simulation; Molecular Structure; Mutation; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases
PubMed: 31775111
DOI: 10.1016/j.dnarep.2019.102747 -
Biomedicine & Pharmacotherapy =... Dec 2023Non-unions represent a major complication in trauma and orthopedic surgery. Many factors contribute to bone regeneration, out of which an adequate vascularization has...
Non-unions represent a major complication in trauma and orthopedic surgery. Many factors contribute to bone regeneration, out of which an adequate vascularization has been recognized as crucial. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in a variety of preclinical studies. Hence, we herein investigated the effects of cilostazol on bone regeneration in an atrophic non-union model in mice. For this purpose, a 1.8 mm femoral segmental defect was stabilized by pin-clip fixation and the animals were treated daily with 30 mg/kg body weight cilostazol or saline (control) per os. At 2, 5 and 10 weeks after surgery the healing of femora was analyzed by X-ray, biomechanics, photoacoustic imaging, and micro-computed tomography (µCT). To investigate the cellular composition and the growth factor expression of the callus tissue additional histological, immunohistochemical and Western blot analyses were performed. Cilostazol-treated animals showed increased bone formation within the callus, resulting in an enhanced bending stiffness when compared to controls. This was associated with a more pronounced expression of vascular endothelial growth factor (VEGF), a higher number of CD31-positive microvessels and an increased oxygen saturation within the callus tissue. Furthermore, cilostazol induced higher numbers of tartrate-resistant acidic phosphate (TRAP)-positive osteoclasts and CD68-positive macrophages. Taken together, these findings demonstrate that cilostazol is a promising drug candidate for the adjuvant treatment of atrophic non-unions in clinical practice.
Topics: Mice; Animals; Cilostazol; Fracture Healing; Vascular Endothelial Growth Factor A; X-Ray Microtomography; Bone Regeneration; Phosphodiesterase Inhibitors
PubMed: 37864892
DOI: 10.1016/j.biopha.2023.115697 -
Clinical Interventions in Aging 2008Symptomatic and asymptomatic peripheral arterial disease (PAD) is a common problem in the elderly. The management of PAD includes the prevention of cardiovascular events... (Review)
Review
Symptomatic and asymptomatic peripheral arterial disease (PAD) is a common problem in the elderly. The management of PAD includes the prevention of cardiovascular events and relief of symptoms--most commonly intermittent claudication (IC). Both require treatment of the causes and consequences of atherothrombosis, but some strategies are more effective for prevention of cardiovascular events and others are more effective for the relief of symptoms. Priorities for the prevention of cardiovascular events include smoking cessation, exercise, antiplatelet therapy, and the treatment of dyslipidemia, hypertension, and diabetes. Walking time and ability are improved by exercise. The benefit of numerous drugs in the treatment of IC has been assessed. The results have generally been disappointing, but there is some evidence that statins and cilostazol (an inhibitor of phosphodiesterase 3) are of benefit. Meta-analyses suggest that cilostazol increases maximum walking distance by 40%-50% and improves other objective measures of walking. The safety profile of cilostazol in patients with PAD appears to be acceptable although the mechanism for its effect on IC is unclear. In addition to risk factor management, treatment with cilostazol should be considered in patients with disabling IC.
Topics: Aged; Cilostazol; Diabetic Angiopathies; Dose-Response Relationship, Drug; Dyslipidemias; Humans; Hypertension; Intermittent Claudication; Peripheral Vascular Diseases; Phosphodiesterase Inhibitors; Smoking; Smoking Cessation; Tetrazoles
PubMed: 18488875
DOI: 10.2147/cia.s1735 -
Frontiers in Cellular and Infection... 2022The persistence of erythrocytes infected with gametocytes in the bloodstream is closely related to the modulation of their mechanical properties. New drugs that...
The persistence of erythrocytes infected with gametocytes in the bloodstream is closely related to the modulation of their mechanical properties. New drugs that increase the stiffness of infected erythrocytes may thus represent a novel approach to block malaria parasite transmission. The phosphodiesterase inhibitor tadalafil has been shown to impair the ability of infected erythrocytes to circulate in an model for splenic retention. Here, we used a humanized mouse model to address the effect of tadalafil on the circulation kinetics of mature gametocyte-infected erythrocytes. We show that stiff immature gametocyte-infected erythrocytes are retained in the spleen of humanized mice at rates comparable to that of the model. Accordingly, tadalafil-induced stiffening of mature gametocyte-infected erythrocytes impairs their circulation in the bloodstream and triggers their retention by the spleen. These results validate that tadalafil is a novel drug lead potentially capable of blocking malaria parasite transmission by targeting GIE mechanical properties.
Topics: Animals; Malaria, Falciparum; Mice; Phosphodiesterase Inhibitors; Plasmodium falciparum; Spleen; Tadalafil
PubMed: 35694548
DOI: 10.3389/fcimb.2022.883759 -
The Journal of Pharmacology and... May 2022Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE)...
Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment of autoimmune disorders. This study develops a pharmacokinetic/pharmacodynamic (PK/PD) model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH. The pharmacokinetics of the PDE inhibitors (PDEi) were assessed in male BALB/c mice after intraperitoneal administration. In pharmacodynamic studies, mice received PDEi and AIH was induced in these animals by intravenous injection of concanavalin A (ConA). Serum drug concentrations, tumor necrosis factor (TNF), interleukin 17 (IL-17), and aminotransferase activities were quantified. The PK/PD analysis was performed using ADAPT5 software. The PK/PD model assumes inhibition of cAMP hydrolysis in T cells by PDEi, ConA-triggered formation of TNF and IL-17, suppression of TNF and IL-17 production by cAMP, and stimulatory effects of TNF and IL-17 on the hepatic release of aminotransferases. Selective blockage of PDE4 leads to the highest inhibition of cAMP degradation in T cells and amelioration of disease outcomes. However, inhibition of both PDE3 and PDE7 also contribute to this effect. The proposed PK/PD model may be used to assess and predict the activities of novel PDEi and their combinations in ConA-induced hepatitis. A balanced suppression of different types of PDE appears to be a promising treatment option for AIH; however, this hypothesis warrants testing in humans based on translation of the PK/PD model into clinical settings. SIGNIFICANCE STATEMENT: A novel PK/PD model of PDE inhibitor effects in mice with ConA-induced autoimmune hepatitis was developed involving a mechanistic component describing changes in cAMP concentrations in mouse T cells. According to model predictions, inhibition of PDE4 in T cells causes the highest cAMP elevation in T cells, but suppression of PDE3 and PDE7 also contribute to this effect. A balanced inhibition of PDE3, PDE4, and PDE7 appears to be a promising treatment strategy for AIH.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Hepatitis, Autoimmune; Interleukin-17; Male; Mice; Mice, Inbred BALB C; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 35221290
DOI: 10.1124/jpet.121.001004 -
Circulation Aug 2014Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right...
BACKGROUND
Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH.
METHODS AND RESULTS
The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil.
CONCLUSIONS
PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.
Topics: Animals; Cells, Cultured; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Humans; Hypertension, Pulmonary; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction; Triazines
PubMed: 24899690
DOI: 10.1161/CIRCULATIONAHA.114.009751 -
Journal of Medicinal Chemistry Jun 2021As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can...
Synthesis of Methoxy-, Methylenedioxy-, Hydroxy-, and Halo-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1) Inhibitors and Their Biological Activity for Drug-Resistant Cancer.
As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (, , , , , , and ) showed a robust TOP1 inhibitory activity (+++ or ++++), and four compounds (, , , and ) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 μM). We also show that the dual TOP1 and TDP1 inhibitor induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.
Topics: Antineoplastic Agents; Apoptosis; Benzophenanthridines; Binding Sites; Cell Line, Tumor; Cell Survival; DNA Damage; DNA Topoisomerases, Type I; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Molecular Dynamics Simulation; Neoplasms; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Structure-Activity Relationship; Topoisomerase I Inhibitors
PubMed: 34008967
DOI: 10.1021/acs.jmedchem.1c00318 -
Molecular Oncology Oct 2020Dipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell-specific apoptosis. However, given the polypharmacology of...
Dipyridamole, an antiplatelet drug, has been shown to synergize with statins to induce cancer cell-specific apoptosis. However, given the polypharmacology of dipyridamole, the mechanism by which it potentiates statin-induced apoptosis remains unclear. Here, we applied a pharmacological approach to identify the activity of dipyridamole specific to its synergistic anticancer interaction with statins. We evaluated compounds that phenocopy the individual activities of dipyridamole and assessed whether they could potentiate statin-induced cell death. Notably, we identified that a phosphodiesterase (PDE) inhibitor, cilostazol, and other compounds that increase intracellular cyclic adenosine monophosphate (cAMP) levels potentiate statin-induced apoptosis in acute myeloid leukemia and multiple myeloma cells. Additionally, we demonstrated that both dipyridamole and cilostazol further inhibit statin-induced activation of sterol regulatory element-binding protein 2, a known modulator of statin sensitivity, in a cAMP-independent manner. Taken together, our data support that PDE inhibitors such as dipyridamole and cilostazol can potentiate statin-induced apoptosis via a dual mechanism. Given that several PDE inhibitors are clinically approved for various indications, they are immediately available for testing in combination with statins for the treatment of hematological malignancies.
Topics: Cell Death; Cell Line, Tumor; Cilostazol; Cyclic AMP; Dipyridamole; Drug Synergism; Humans; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Biological; Neoplasms; Phosphodiesterase Inhibitors; Sterols
PubMed: 32749766
DOI: 10.1002/1878-0261.12775 -
Journal of the Chinese Medical... Mar 2005Current interventions with proven efficacy, such as glycemic and blood pressure control, dietary protein restriction, and angiotensin II blockade, slow the progression... (Review)
Review
Current interventions with proven efficacy, such as glycemic and blood pressure control, dietary protein restriction, and angiotensin II blockade, slow the progression of chronic kidney disease (CKD); however, whether long-term cessation of CKD progression is possible remains unclear. Because of the pathogenetic complexity of this condition, multidrug interventions with the least adverse effects should be investigated as the next step in attempts to stop CKD progression. Pentoxifylline, a non-selective phosphodiesterase inhibitor with indiscernible toxicity, exerts potent inhibitory effects against cell proliferation, inflammation, and extracellular matrix accumulation, all of which play important roles in CKD progression. Pentoxifylline monotherapy markedly reduces proteinuria in patients with membranous nephropathy. Moreover, limited human studies have proven pentoxifylline efficacy in reducing proteinuria in patients with diabetes receiving angiotensin-converting enzyme inhibitors, and in patients with nephrotic syndrome secondary to lupus nephritis despite immunosuppressive therapy. Further clinical trials are necessary to examine whether pentoxifylline can improve renal outcomes in patients receiving interventions of proven efficacy.
Topics: Cell Proliferation; Diabetic Nephropathies; Humans; Kidney Failure, Chronic; Pentoxifylline; Phosphodiesterase Inhibitors; Proteinuria
PubMed: 15813241
DOI: 10.1016/S1726-4901(09)70228-X -
Vascular Health and Risk Management May 2010Pulmonary hypertension (PH) is found in a vast array of diseases, with a minority representing pulmonary arterial hypertension (PAH). Idiopathic PAH or PAH in... (Review)
Review
Pulmonary hypertension (PH) is found in a vast array of diseases, with a minority representing pulmonary arterial hypertension (PAH). Idiopathic PAH or PAH in association with other disorders has been associated with poor survival, poor exercise tolerance, progressive symptoms of dyspnea, and decreased quality of life. Left untreated, patients with PAH typically have a progressive decline in function with high morbidity ultimately leading to death. Advances in medical therapy for PAH over the past decade have made significant inroads into improved function, quality of life, and even survival in this patient population. Three classes of pulmonary artery-specific vasodilators are currently available in the United States. They include prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 (PDE5) inhibitors. In May 2009, the FDA approved tadalafil, the first once-daily PDE5 inhibitor for PAH. This review will outline the currently available data on tadalafil and its effects in patients with PAH.
Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Administration Schedule; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Tadalafil; Treatment Outcome; Vasodilator Agents
PubMed: 20479949
DOI: 10.2147/vhrm.s6392