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Cells Apr 2024Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including... (Review)
Review
Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome. Despite viral suppression with combination antiretroviral therapy (ART), people living with HIV (PLWH) are prone to many comorbidities, including neurological and neuropsychiatric complications, cardiovascular and metabolic diseases, premature aging, and malignancies. HIV and viral proteins can directly contribute to the development of these comorbidities. However, with the continued high prevalence of these comorbidities despite viral suppression, it is likely that ART or some antiretroviral (ARVs) drugs contribute to the development and persistence of comorbid diseases in PLWH. These comorbid diseases often involve vascular activation, injury, and dysfunction. The purpose of this manuscript is to review the current literature on ARVs and the vascular endothelium in PLWH, animal models, and in vitro studies. I also summarize evidence of an association or lack thereof between ARV drugs or drug classes and the protection or injury/dysfunction of the vascular endothelium and vascular diseases.
Topics: Animals; Humans; Anti-HIV Agents; Anti-Retroviral Agents; Endothelium, Vascular; HIV Infections
PubMed: 38667287
DOI: 10.3390/cells13080672 -
Journal of Cancer Research and Clinical... Dec 2023The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma...
PURPOSE
The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist.
METHODS
A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed.
RESULTS
The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis.
CONCLUSIONS
The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.
Topics: Humans; Animals; Mice; Maraviroc; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Retrospective Studies; Cell Line, Tumor; Mouth Neoplasms; RNA, Small Interfering; Head and Neck Neoplasms; Tumor Microenvironment; Chemokine CCL5
PubMed: 37831273
DOI: 10.1007/s00432-023-05443-1 -
Drug Metabolism and Disposition: the... Sep 2019Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several...
Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several autoimmune, cancer, and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ATP-binding cassette (ABC) efflux transporters that have a recognized role in the protection of a developing fetus: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance protein 2 (ABCC2). We found that maraviroc does not inhibit any of the three studied ABC transporters and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine P-glycoprotein (Abcb1) expressed in Madin-Darby canine kidney II (MDCKII) cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the fetal-to-maternal direction, which suggests that ABCB1/Abcb1 facilitates in situ maraviroc transport. This transplacental transport was saturable and significantly diminished after the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood. SIGNIFICANCE STATEMENT: Antiretroviral drug maraviroc shows low toxicity and is thus a good candidate for prevention of mother-to-child transmission of human immunodeficiency virus when failure of recommended therapy occurs. Using in vitro cell-based experiments and in situ dually perfused rat term placenta, we examined maraviroc interaction with the placental ABC drug transporters ABCB1, ABCG2, and ABCC2. We demonstrate for the first time that placental ABCB1 significantly reduces mother-to-fetus transport of maraviroc, which suggests that ABCB1 may be responsible for the low cord-blood/maternal-blood ratio observed in humans.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; CCR5 Receptor Antagonists; Dogs; Female; Fetus; HIV Infections; Humans; Madin Darby Canine Kidney Cells; Maraviroc; Maternal-Fetal Exchange; Models, Animal; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Permeability; Placenta; Placental Circulation; Pregnancy; Pregnancy Complications, Infectious; Rats
PubMed: 31266750
DOI: 10.1124/dmd.119.087684 -
Radiology and Oncology Nov 2019Background Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to... (Review)
Review
Background Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to therapy resistant glioblastoma stem cells in addition to intertumour heterogeneity that is due to infiltration of a plethora of host cells. Besides endothelial cells, mesenchymal stem cells and their differentiated progenies, immune cells of various differentiation states, including monocytes, comprise resident, brain tumour microenvironment. There are compelling evidence for CCL5/CCR5 in the invasive and metastatic behaviour of many cancer types. CCR5, a G-protein coupled receptor, known to function as an essential co-receptor for HIV entry, is now known to participate in driving tumour heterogeneity, the formation of cancer stem cells and the promotion of cancer invasion and metastasis. Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple negative breast cancer (TNBC) or a small molecule inhibitor (maraviroc) for metastatic colon cancer. There are important CCL5 and CCR5 structure and signalling mechanisms in glioblastoma. In addition, the CCL5/CCR5 axis directs infiltration and interactions with monocytes/macrophages and mesenchymal stem cells, comprising glioblastoma stem cell niches. Conclusions CCR5 is highly expressed in glioblastoma and is associated with poor prognosis of patients. CCL5/CCR5 is suggested to be an excellent new target for glioblastoma therapy. The molecular mechanisms, by which chemoattractant and receptor respond within the complex tissue microenvironment to promote cancer stem cells and tumour heterogeneity, should be considered in forthcoming studies.
Topics: Brain Neoplasms; CCR5 Receptor Antagonists; Chemokine CCL5; Disease Progression; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Receptors, CCR5; Tumor Microenvironment
PubMed: 31747383
DOI: 10.2478/raon-2019-0057 -
Journal of Biomolecular Structure &... Aug 2021Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2....
Non-Structural Protein 16 (nsp-16), a viral RNA methyltransferase (MTase), is one of the highly viable targets for drug discovery of coronaviruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been performed by a virtual drug repurposing approach. First, drug shape-based screening (among FDA approved drugs) with a known template of MTase inhibitor, sinefungin was done and best compounds with high similarity scores were selected. In addition to the selected compounds, 4 nucleoside analogs of anti-viral (Raltgravir, Maraviroc and Favipiravir) and anti-inflammatory (Prednisolone) drugs were selected for further investigations. Then, binding energies and interaction modes were found by molecular docking approaches and compouds with lower energy were selected for further investigation. After that, Molecular dynamics (MD) simulation was carried to test the potential selected compounds in a realistic environment. The results showed that Raltegravir and Maraviroc among other compounds can bind strongly to the active site of the protein compared to sinefungin, and can be potential candidates to inhibit NSP-16. Also, the MD simulation results suggested that the Maraviroc and Raltegravir are more effective drug candidates than Sinefungin for inhibiting the enzyme. It is concluded that Raltegravir and Maraviroc which may be used in the treatment of COVID-19 after Invitro and invivo studies and clinical trial for final confirmation of drug effectiveness. Communicated by Ramaswamy H. Sarma.
Topics: Antiviral Agents; COVID-19; Drug Repositioning; Humans; Molecular Docking Simulation; SARS-CoV-2
PubMed: 32573355
DOI: 10.1080/07391102.2020.1779133 -
Expert Opinion on Therapeutic Targets Nov 2014Chemokines play a crucial role in breast cancer tumorigenesis and progression. Recently, the chemokine (C-C motif) ligand 5 (CCL5), which can be secreted either by tumor... (Review)
Review
INTRODUCTION
Chemokines play a crucial role in breast cancer tumorigenesis and progression. Recently, the chemokine (C-C motif) ligand 5 (CCL5), which can be secreted either by tumor cells or by mesenchymal stromal cells recruited to the tumor, has been identified as a key node in the bidirectional communication between breast cancer and normal cells.
AREAS COVERED
In this review, the authors discuss the role of CCL5/chemokine receptor 5 (CCR5) axis in promoting breast cancer onset and progression. Interrogation of large clinical databases has demonstrated increased expression of the CCL5/CCR5 axis in specific subtypes of breast cancer. The activation of the receptor CCR5 in breast cancer cells controls their invasiveness serving as a driver for metastasis. Furthermore, the CCL5/CCR5 axis participates in the recruitment of specific immune cells into tumors, inducing local immunosuppression and favoring tumor progression.
EXPERT OPINION
The role of CCR5 in HIV infection led to the development of specific and potent CCR5 antagonists. The data reviewed here includes basic and translational studies that support the use of such CCR5 antagonists in breast cancer patients as adjuvant therapy to block the metastasis.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; CCR5 Receptor Antagonists; Chemokine CCL5; Disease Progression; Drug Design; Female; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Receptors, CCR5
PubMed: 25256399
DOI: 10.1517/14728222.2014.949238 -
Biochemical Society Transactions Jun 2021The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine... (Review)
Review
The chemokine system plays a fundamental role in a diverse range of physiological processes, such as homeostasis and immune responses. Dysregulation in the chemokine system has been linked to inflammatory diseases and cancer, which renders chemokine receptors to be considered as therapeutic targets. In the past two decades, around 45 drugs targeting chemokine receptors have been developed, yet only three are clinically approved. The challenging factors include the limited understanding of aberrant chemokine signalling in malignant diseases, high redundancy of the chemokine system, differences between cell types and non-specific binding of the chemokine receptor antagonists due to the broad ligand-binding pockets. In recent years, emerging studies attempt to characterise the chemokine ligand-receptor interactions and the downstream signalling protein-protein interactions, aiming to fine tuning to the promiscuous interplay of the chemokine system for the development of precision medicine. This review will outline the updates on the mechanistic insights in the chemokine system and propose some potential strategies in the future development of targeted therapy.
Topics: Animals; Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines; Cyclams; Humans; Inflammation; Maraviroc; Molecular Targeted Therapy; Neoplasms; Protein Binding; Receptors, Chemokine; Signal Transduction
PubMed: 34060588
DOI: 10.1042/BST20201114 -
Aging Apr 2020As age increases, the risk of developing fragility also increases. Improving the knowledge of frailty could contribute to maintaining the functional ability of elderly...
BACKGROUND
As age increases, the risk of developing fragility also increases. Improving the knowledge of frailty could contribute to maintaining the functional ability of elderly people. Interleukin (IL)-10 homozygous knockout mice (IL-10 [IL10KO]) constitute an excellent tool for the study of frailty. Because patients with frailty demonstrate an overexpression of CCR5, rapamycin (RAPA) and/or maraviroc (MVC), two molecules able to decrease CCR5 expression, were evaluated.
RESULTS
Muscle myostatin was reduced in all the therapeutic groups but the MVC group (p <0.001 for RAPA and MVC-RAPA) and in serum samples (p <0.01 for all the groups). Serum CK levels were also significantly lower in MVC and RAPA groups (p <0.01 in both cases). Lower AST levels were observed in all the therapeutic groups (p <0.05 for all of them). The apoptotic effector caspase-3 was significantly lower in MVC and RAPA groups (p<0.05 in both cases). Combined treatment with MVC-RAPA showed a synergistic increase in p-AKT, p-mTOR and SIRT1 levels.
CONCLUSIONS
MVC and RAPA show a protective role in some factors involved in frailty. More studies are needed to prove their clinical applications.
MATERIAL AND METHODS
Eighty male homozygous IL10KOs were randomly assigned to one of 4 groups (n= 20): i) IL10KO group (IL10KO); ii) IL10KO receiving MVC in drinking water (MVC group), iii) IL10KO receiving RAPA in drinking water (RAPA group), and finally, iv) MVC-RAPA group that received MVC and RAPA in drinking water. Blood and muscle samples were analysed. Survival analysis, frailty index calculation, and functional assessment were also performed.
Topics: Aging; Animals; Cytokines; Disease Models, Animal; Frailty; Interleukin-10; Male; Maraviroc; Mice; Mice, Knockout; Muscle, Skeletal; Random Allocation; Receptors, Chemokine; Sirolimus; Survival Rate
PubMed: 32353830
DOI: 10.18632/aging.103167 -
Drug Design, Development and Therapy 2015The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine... (Review)
Review
The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug-drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Interactions; Drug Resistance, Viral; Genotype; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Maraviroc; Mutation; Phenotype; Polypharmacy; Treatment Outcome; Triazoles
PubMed: 26491256
DOI: 10.2147/DDDT.S90580 -
Biochemical Pharmacology Jan 2022Chemokine (C- Cmotif) ligand 5 (CCL5) and its receptor C-C motif chemokine receptor 5 (CCR5), have been broadly studied in conjunction with infectious pathogens,...
BACKGROUND
Chemokine (C- Cmotif) ligand 5 (CCL5) and its receptor C-C motif chemokine receptor 5 (CCR5), have been broadly studied in conjunction with infectious pathogens, however, their involvement in cardiovascular disease is not completely understood. NADPH oxidases (Noxs) are the major source of reactive oxygen species (ROS) in the vasculature. Whether the activation of Noxs is CCL5/CCR5 sensitive and whether such interaction initiates vascular injury is unknown. We investigated whether CCL5/CCR5 leads to vascular damage by activating Noxs.
MATERIAL AND METHODS
We used rat aortic smooth muscle cells (RASMC) to investigate the molecular mechanisms by which CCL5 leads to vascular damage and carotid ligation (CL) to analyze the effects of blocking CCR5 on vascular injury.
RESULTS
CCL5 induced Nox1 expression in concentration and time-dependent manners, with no changes in Nox2 or Nox4. Maraviroc pre-treatment (CCR5 antagonist, 40uM) blunted CCL5-induced Nox1 expression. Furthermore, CCL5 incubation led to ROS production and activation of Erk1/2 and NFkB, followed by increased vascular cell migration, proliferation, and inflammatory markers. Notably, Nox1 inhibition (GKT771, 10uM) blocked CCL5-dependent effects. In vivo, CL induced pathological vascular remodeling and inflammatory genes and increased Nox1 and CCR5 expression. Maraviroc treatment (25 mg/Kg/day) reduced pathological vascular growth and Nox1 expression.
CONCLUSIONS
Our findings suggest that CCL5 activates Nox1 in the vasculature, leading to vascular injury likely via NFkB and Erk1/2. Herein, we place CCR5 antagonists and/or Nox1 inhibitors might be preeminent antiproliferative compounds to reduce the cardiovascular risk associated with medical procedures (e.g. angioplasty) and vascular diseases associated with vascular hyperproliferation.
Topics: Animals; CCR5 Receptor Antagonists; Cell Movement; Cells, Cultured; Chemokine CCL5; Gene Expression Regulation; Male; Maraviroc; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NADPH Oxidase 1; Rats; Receptors, CCR5; Recombinant Proteins; Vascular System Injuries; Mice
PubMed: 34843718
DOI: 10.1016/j.bcp.2021.114859