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1.
PLoS One ; 17(1): e0261578, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35061724

RESUMO

We propose a model of cancer initiation and progression where tumor growth is modulated by an evolutionary coordination game. Evolutionary games of cancer are widely used to model frequency-dependent cell interactions with the most studied games being the Prisoner's Dilemma and public goods games. Coordination games, by their more obscure and less evocative nature, are left understudied, despite the fact that, as we argue, they offer great potential in understanding and treating cancer. In this paper we present the conditions under which coordination games between cancer cells evolve, we propose aspects of cancer that can be modeled as results of coordination games, and explore the ways through which coordination games of cancer can be exploited for therapy.


Assuntos
Dilema do Prisioneiro
2.
Cell Death Differ ; 27(4): 1200-1213, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31506606

RESUMO

Cellular DNA is constantly under threat from internal and external insults, consequently multiple pathways have evolved to maintain chromosomal fidelity. Our previous studies revealed that chronic stress, mediated by continuous stimulation of the ß2-adrenergic-ßarrestin-1 signaling axis suppresses activity of the tumor suppressor p53 and impairs genomic integrity. In this pathway, ßarrestin-1 (ßarr1) acts as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, MDM2. We sought to determine whether ßarr1 plays additional roles in the repair of DNA damage. Here we demonstrate that in mice ßarr1 interacts with p53-binding protein 1 (53BP1) with major consequences for the repair of DNA double-strand breaks. 53BP1 is a principle component of the DNA damage response, and when recruited to the site of double-strand breaks in DNA, 53BP1 plays an important role coordinating repair of these toxic lesions. Here, we report that ßarr1 directs 53BP1 degradation by acting as a scaffold for the E3-ubiquitin ligase Rad18. Consequently, knockdown of ßarr1 stabilizes 53BP1 augmenting the number of 53BP1 DNA damage repair foci following exposure to ionizing radiation. Accordingly, ßarr1 loss leads to a marked increase in irradiation resistance both in cells and in vivo. Thus, ßarr1 is an important regulator of double strand break repair, and disruption of the ßarr1/53BP1 interaction offers an attractive strategy to protect cells against high levels of exposure to ionizing radiation.


Assuntos
Reparo do DNA , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , beta-Arrestina 1/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Intestinos/patologia , Camundongos Endogâmicos C57BL , Ligação Proteica/efeitos da radiação , Processamento de Proteína Pós-Traducional/efeitos da radiação , Tolerância a Radiação/efeitos da radiação , Radiação Ionizante
3.
Assay Drug Dev Technol ; 17(6): 275-284, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31532712

RESUMO

Solute carrier proteins (SLCs) are a superfamily of transmembrane transporters that control essential physiological functions such as nutrient uptake, ion transport, and cellular waste elimination. Although many SLCs are associated with various disease states and are considered "druggable," they remain underexplored as a drug target class. One subfamily of SLCs that has gained attention for its therapeutic potential is the monocarboxylate solute transporter family. The monocarboxylate transporter protein 1 (MCT1) is a passive transporter of lactate and has gained significant attention for its role(s) in cancer progression; moreover, upregulation of MCT1 connotes poor patient outcome and survival. Consequently, small molecule inhibitors of MCT1 activity are being pursued as anticancer therapies. However, typical for members of this SLC subfamily, there is a paucity of potent and selective modulators of MCT1. This is in part due to methods used for their identification, typically relying on the use of radiolabeled substrate tracing. In addition to the safety concerns associated with radioactivity, this methodology is also expensive and time consuming. In this study, we describe the use of an MCT1 cytotoxic substrate as a tool to enable the development of a nonradioactive cell-based homogeneous assay that facilitates industry-scale high-throughput screening (HTS) of large compound libraries to identify novel MCT1 inhibitors to interrogate the therapeutic potential of MCT1. Our assay is robust, reproducible, HTS amenable, and establishes a conceptually novel way to identify chemical probes to investigate the therapeutic potential of SLC proteins.


Assuntos
Ensaios de Triagem em Larga Escala , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Pirimidinonas/farmacologia , Piruvatos/farmacologia , Simportadores/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo
4.
Assay Drug Dev Technol ; 16(5): 278-288, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30019946

RESUMO

GPR119 drug discovery efforts in the pharmaceutical industry for the treatment of type 2 diabetes mellitus (T2DM) and obesity, were initiated based on its restricted distribution in pancreas and GI tract, and its possible role in glucose homeostasis. While a number of lead series have emerged, the pharmacological endpoints they provide have not been clear. In particular, many lead series have demonstrated loss of efficacy and significant toxic side effects. Thus, we sought to identify novel, potent, positive modulators of GPR119. In this study, we have successfully developed and optimized a high-throughput screening strategy to identify GPR119 modulators using a live cell assay format that utilizes a cyclic nucleotide-gated channel as a biosensor for cAMP production. Our high-throughput screening (HTS) approach is unique to that of previous HTS approaches targeting this receptor, as changes in cAMP were measured both in the presence and absence of an EC10 of the endogenous ligand, oleoylethanolamide, enabling detection of both agonists and potential allosteric modulators in a single assay. From these efforts, we have identified positive modulators of GPR119 with similar as well as unique scaffolds compared to existing compounds and similar as well as unique signaling properties. Our compounds will not only serve as novel molecular probes to better understand GPR119 pleiotropic signaling and the underlying physiological consequences of receptor activation, but are also well-suited for translation as potential therapeutic agents.


Assuntos
Endocanabinoides/farmacologia , Hipoglicemiantes/farmacologia , Ácidos Oleicos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Células Cultivadas , Endocanabinoides/química , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/química , Estrutura Molecular , Ácidos Oleicos/química , Receptores Acoplados a Proteínas G/metabolismo
5.
Cell Signal ; 41: 65-74, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28931490

RESUMO

G protein-coupled receptors (GPCRs) constitute the largest and most diverse protein family in the human genome with over 800 members identified to date. They play critical roles in numerous cellular and physiological processes, including cell proliferation, differentiation, neurotransmission, development and apoptosis. Consequently, aberrant receptor activity has been demonstrated in numerous disorders/diseases, and as a result GPCRs have become the most successful drug target class in pharmaceuticals treating a wide variety of indications such as pain, inflammation, neurobiological and metabolic disorders. Many independent studies have also demonstrated a key role for GPCRs in tumourigenesis, establishing their involvement in cancer initiation, progression, and metastasis. Given the growing appreciation of the role(s) that GPCRs play in cancer pathogenesis, it is surprising to note that very few GPCRs have been effectively exploited in pursuit of anti-cancer therapies. The present review provides a broad overview of the roles that various GPCRs play in cancer growth and development, highlighting the potential of pharmacologically modulating these receptors for the development of novel anti-cancer therapeutics.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Receptores Acoplados a Proteínas G/metabolismo , Animais , Progressão da Doença , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética
6.
Nat Commun ; 6: 8918, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26621478

RESUMO

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein ß-arrestin; preferential signalling of ligands through one or the other of these branches is known as 'ligand bias'. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced ß-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Hipoglicemiantes/administração & dosagem , Peptídeos/administração & dosagem , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Avaliação Pré-Clínica de Medicamentos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Cell Signal ; 27(7): 1449-56, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25857454

RESUMO

The orexin 1 receptor (OX1R) and the kappa opioid receptor (KOR) are two G protein-coupled receptors (GPCRs) previously demonstrated to play important roles in modulating the rewarding effects of drugs of abuse such as cocaine. Using cells heterologously expressing both receptors, we investigated whether OX1R can regulate the function of KOR and vice versa. Activation of OX1R was found to attenuate agonist-activated KOR-mediated inhibition of cAMP production. In contrast, agonist-activated KOR-mediated ß-arrestin recruitment and p38 activation were enhanced in the presence of activated OX1R. These effects are independent of OX1R internalization but are blocked in the presence of the JNK inhibitor SP-600125. OX1R signaling does not affect ligand binding by KOR. Taken together, these data suggest that OX1R signaling can modulate KOR function in a JNK-dependent manner, promoting preferential signaling of KOR via ß-arrestin/p38 rather than Gαi. Conversely, Gαq coupling of OX1R is unaffected by activation of KOR, suggesting that this crosstalk is unidirectional. Given that KOR Gαi-mediated signaling events and ß-arrestin-mediated signaling events are thought to promote distinct cellular responses and physiological outcomes downstream of KOR activation, this mechanism may have important implications on the behavioral effects of KOR activity.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Receptores de Orexina/metabolismo , Receptores Opioides kappa/metabolismo , Animais , Antracenos/toxicidade , Arrestinas/metabolismo , Células CHO , Colforsina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores Opioides kappa/química , Transdução de Sinais/efeitos dos fármacos , beta-Arrestinas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Bioorg Med Chem Lett ; 24(16): 3974-8, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24997685

RESUMO

Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, such as schizophrenia, Parkinson's disease and drug addiction. The discovery of small-molecule non-peptide neurotensin receptor (NTSR) modulators would represent an important breakthrough as such compounds could be used as pharmacological tools, to further decipher the cellular functions of neurotensin, and potentially as therapeutic agents to treat human disease. Herein, we report the identification of non-peptide low-micromolar neurotensin receptor 1 (NTSR1) full agonists, discovered through structural optimization of the known NTSR1 partial agonist 1. In vitro cellular screenings, based on an intracellular Ca(2+) mobilization assay, revealed our best hit molecule 8 (SR-12062) to have an EC50 of 2 µM at NTSR1 with full agonist behaviour (Emax=100%), showing a higher efficacy and ∼90-fold potency improvement compared to parent compound 1 (EC50=178 µM; Emax=17%).


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Receptores de Neurotensina/agonistas , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 22(12): 3890-4, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22617492

RESUMO

A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.


Assuntos
Antipsicóticos/síntese química , Piperidinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Antipsicóticos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Receptores de Orexina , Piperidinas/farmacocinética , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-Atividade , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
10.
Drug Discov Today Technol ; 7(1): e37-e42, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21218149

RESUMO

G protein-coupled receptors (GPCR) are the major site of action for endogenous hormones and neurotransmitters. Early drug discovery efforts focused on determining whether ligands could engage G protein coupling and subsequently activate or inhibit cognate "second messengers." Gone are those simple days as we now realize that receptors can also couple ßarrestins. As we delve into the complexity of ligand-directed signaling and receptosome scaffolds, we are faced with what may seem like endless possibilities triggered by receptor-ligand mediated events.

11.
J Pharmacol Exp Ther ; 306(1): 147-56, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12665544

RESUMO

The neuropeptide Y (NPY) family peptides NPY, peptide YY (PYY), and pancreatic polypeptide (PP) bind to four G protein-coupled receptors (GPCRs): Y1, Y2, Y4, and Y5. A key step in the desensitization and internalization of GPCRs is the association of the receptor with beta-arrestins. In the present study, these receptors were analyzed with respect to their ability to interact with GFP2-tagged beta-arrestin 2 using the new bioluminescence resonance energy transfer 2 method. Agonists induced a concentration-dependent association of beta-arrestin 2 with all four receptors. Whereas the Y1 receptor exhibited the highest maximum response and rapid association (t(1/2) = 3.4 min), the maximal signals for the association of Y2 and Y4 receptors were less than half of that of Y1, and the association rates were much slower. Interestingly, when evaluated at the Y4 receptor, the Y4 agonist 1229U91 [(Ile,Glu,Pro,Dpr,Tyr,Arg, Leu,Arg,Try-NH2)-2-cyclic(2,4'),(2',4)-diamide] was unable to provoke the same maximal response as human PP, suggesting that 1229U91 is a partial agonist. When stimulated by PYY, the Y5 receptor responded with a t(1/2) of 4.6 min and a maximal response approximately 60% of what was observed with Y1. Because beta-arrestins are key components in GPCR internalization, it is interesting to note that the receptor that is known to internalize rapidly (Y1) exhibits the most rapid association with beta-arrestin 2, whereas the receptor that is known to internalize slowly, or not at all (Y2) associates slowly with beta-arrestin 2.


Assuntos
Arrestinas/metabolismo , Medições Luminescentes , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Sequência de Aminoácidos , Animais , Clonagem Molecular , Transferência de Energia , Humanos , Macaca mulatta , Dados de Sequência Molecular , Polipeptídeo Pancreático/metabolismo , Peptídeo YY/metabolismo , Receptores de Neuropeptídeo Y/biossíntese , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Receptores de Neuropeptídeo Y/genética , Homologia de Sequência de Aminoácidos , Fatores de Tempo , beta-Arrestina 2 , beta-Arrestinas
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