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1.
Anticancer Res ; 41(7): 3287-3292, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230123

RESUMO

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Life Sci ; 280: 119666, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34087279

RESUMO

AIMS: The preclinical evaluation of innovative drugs plays an important role in the new drugs development. As a derivative of pirfenidone (PFD), mefunidone (MFD) has shown better anti-fibrosis and anti-inflammatory activity in both cell lines and animal models. To support the clinical investigations of MFD, the metabolic characterization of MFD was initially evaluated in preclinical models. MAIN METHODS: The potential metabolites of MFD were analyzed by LC-MS/MS methods. The induction effect of MFD on CYP1A2, CYP2B6, and CYP3A4 was performed in primary human hepatocytes, and the inhibition of CYP enzymes by MFD was also evaluated in human liver microsomes. Finally, the pharmacokinetic profiles of MFD were assessed in SD rats after the rats had received multiple doses (62.5 mg/kg) of MFD. KEY FINDINGS: MFD was metabolized in three pathways including oxidation, N-demethylation, and hydroxylation. Except for slight inhibition on the activity of CYP2D6, MFD exerted no effect on other CYP enzymes. Moreover, drug accumulation of MFD was not observed in rats after repeated dosing of MFD. SIGNIFICANCE: MFD was first discovered in preclinical investigations without inducing and inhibiting metabolic enzymes. This work provides some important information about the metabolic characterization of MFD for its further clinical investigations.


Assuntos
Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Hepatócitos/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacocinética , Piridonas/metabolismo , Piridonas/farmacocinética , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Piperazinas/farmacologia , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley
3.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
4.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066693

RESUMO

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 µg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.


Assuntos
Fumar Cigarros/efeitos adversos , Neutrófilos/patologia , Piperazinas/uso terapêutico , Animais , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Humanos , Interleucina-8/biossíntese , Pulmão/patologia , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Pneumonia/tratamento farmacológico , Proteínas Quinases/metabolismo
5.
Molecules ; 26(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065165

RESUMO

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure-activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.


Assuntos
Acrilamida/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Humanos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Piperazinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Relação Estrutura-Atividade
6.
Nat Commun ; 12(1): 3356, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099663

RESUMO

Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors-palbociclib, ribociclib, or abemaciclib-immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.


Assuntos
Ciclina D/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Células MCF-7 , Camundongos , Microscopia de Fluorescência , Piperazinas/farmacologia , Ligação Proteica , Piridinas/farmacologia , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo
7.
Nat Commun ; 12(1): 2705, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976187

RESUMO

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/genética , Processamento de Proteína Pós-Traducional , Receptores Androgênicos/genética , ADP-Ribosilação/efeitos dos fármacos , Adenocarcinoma , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Masculino , Metribolona/farmacologia , Proteínas de Neoplasias/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise de Sobrevida
8.
Chem Biol Interact ; 344: 109510, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33974899

RESUMO

The problem of chemoresistance development is an inescapable flipside of modern oncotherapy, in particular for сolorectal cancer patients. The search for or development of drugs effective against resistant tumors involves the use of model resistant cell lines in vitro. To obtain such lines, we reproduced the development of chemoresistance of human colon adenocarcinoma cells under the treatment with drugs of different mechanisms, a cytostatic (paclitaxel) and a targeted agent (Nutlin-3a, an inhibitor of p53-Mdm2 protein-protein interaction). In each case, we gradually increased the content of the substance in the medium, starting from effective concentrations that do not cause total cell death. When studying the lines resistant to the corresponding drug, we noted a reduced sensitivity to the drug of another mechanism of action. Analysis of the original and resistant lines showed that the cells use the universal efflux defense mechanism. The observed effect can be partially neutralized using inhibitors of the ABC transport proteins, including P-glycoprotein, known for its oncoprotective function. The role of the latter was confirmed by real-time RT-PCR and Western blotting.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imidazóis/farmacologia , Paclitaxel/farmacologia , Piperazinas/farmacologia , Quinolinas/farmacologia , Vanadatos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HCT116 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores
9.
Int J Mol Sci ; 22(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917574

RESUMO

The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Tronco Encefálico/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Neurônios/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Núcleo Espinal do Trigêmeo/metabolismo , Animais , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Feminino , Masculino , Camundongos , Piperazinas/farmacologia , Quinazolinas/farmacologia
10.
J Theor Biol ; 522: 110696, 2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-33794285

RESUMO

BACKGROUND AND OBJECTIVE: p53, an anti-tumour protein, is significantly inactivated in most tumours. A small molecule of nutlin-3a is used to activate its function by repressing (Mouse double minute 2 homolog) Mdm2 protein which inhibits its activity. In cancer patients, a high risk of drug-drug interactions (DDIs) is observed owing to their multi-dosing prescriptions, which may lead them to harmful effects. In the presented work, we have aimed to investigate the effect of pharmacodynamical interaction between two anti-cancer drugs, nutlin-3a and aspirin in the activation of p53 protein. METHODS: We have adapted control system techniques and designed a Proportional-Integral-Derivative (PID) controller. This controller is used to activate p53 protein. A drug interaction parameter is used to incorporate the effect of both drugs. Extensive simulation is performed using two different doses of aspirin, i.e. a low and a high dose of aspirin. RESULTS: The result shows no harmful effects of pharmacodynamical interaction when a low dose is administered along with nutlin-3a. When a high dose of aspirin is administered it acts as input disturbance and leads to undesirable over-expression of p53 protein. This can further harm other growth cells, thus inducing harmful effects. A comparative analysis is also tabulated with different dosing regimens which shows that a combination of nutlin-3a and a low dose of aspirin provides better results than a high dose of aspirin. CONCLUSION: Overall, the work provides an insight to the activation of p53 protein in cancer patients under the presence of pharmacodynamical interaction and might contribute to the effective management of cancer patients.


Assuntos
Aspirina , Proteína Supressora de Tumor p53 , Animais , Apoptose , Aspirina/farmacologia , Linhagem Celular Tumoral , Humanos , Imidazóis , Camundongos , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo
11.
Nat Commun ; 12(1): 1998, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790302

RESUMO

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.


Assuntos
Benzamidas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Xenoenxertos/efeitos dos fármacos , Morfolinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos/metabolismo , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
12.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: covidwho-1138745

RESUMO

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Leucina/química , Leucina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , Simulação por Computador , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Bases de Dados de Proteínas , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Nitrofenóis/química , Nitrofenóis/farmacologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética
13.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925399

RESUMO

Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.


Assuntos
Senescência Celular/fisiologia , Hepacivirus/metabolismo , Replicação Viral/fisiologia , Antivirais/farmacologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Humanos , Fígado/patologia , Fenótipo , Piperazinas/farmacologia , Piridinas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
14.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805656

RESUMO

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Clotrimazol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Imidazóis/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antifúngicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Aprovação de Drogas , Descoberta de Drogas , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteólise , Transdução de Sinais , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia
15.
Molecules ; 26(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809771

RESUMO

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-ß (Aß) aggregation. Some of these hybrids also prevented Aß-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 µM); Aß aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Donepezila/farmacologia , Sulfonamidas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/farmacologia , Humanos , Ligantes , Piperazinas/farmacologia , Piperidinas/farmacologia , Relação Estrutura-Atividade
16.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802860

RESUMO

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Leucina/química , Leucina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , Simulação por Computador , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Bases de Dados de Proteínas , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Nitrofenóis/química , Nitrofenóis/farmacologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética
17.
Asia Pac J Clin Oncol ; 17 Suppl 3: 3-11, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33860646

RESUMO

AIM: Few real-world studies have reported detailed management and dose adjustment strategies of adverse events (AEs) of ovarian cancer (OC) patients treated with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib. This case series aimed to describe olaparib AEs in Chinese OC patients in real-life settings and to explore dose modification strategies. METHODS: We conducted a detailed examination of the clinical records of OC patients who were treated with olaparib at the Gynecologic Oncology Unit in Hong Kong from September 2015 to December 2019, including baseline characteristics, treatment outcomes, AEs, and management strategies, particularly dose modifications. RESULTS: Nineteen patients were included, with a median olaparib treatment duration of 12 (range: 3-30) months. For recurrent platinum-sensitive cases (n = 16), the median progression-free survival was 16.0 months (95% confidence interval: 9.5-22.5). Eighteen (95%) patients experienced AE(s) of any grade, including four (21%) who experienced grade ≥3 AE(s). The most common AEs were as follows: nonhematologic fatigue (68%), nausea (42%), vomiting (26%), decreased appetite (26%), dyspepsia (21%), dizziness (21%), anemia (37%), neutropenia (26%), and thrombocytopenia (21%). Four specific cases involving anemia, lower limb lymphedema, myeloid neoplasm, and erythema nodosum are discussed separately. Eight patients required dose interruption or reduction due to AEs, of which five patients attempted and tolerated dose re-escalation. CONCLUSION: In this study, most AEs were mild, but rare AEs were observed. In OC patients, olaparib AE management with dose reductions followed by re-escalations was feasible, including for anemia.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Neoplasias Ovarianas/complicações , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia
18.
BMC Cancer ; 21(1): 448, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888065

RESUMO

BACKGROUND: The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. METHODS: Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. RESULTS: Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. CONCLUSION: Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.


Assuntos
Antineoplásicos/farmacologia , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Fluoruracila/farmacologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Sinergismo Farmacológico , Células HCT116 , Humanos
19.
Science ; 372(6538): 156-165, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833118

RESUMO

Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.


Assuntos
Antineoplásicos/farmacologia , N-Glicosil Hidrolases/antagonistas & inibidores , N-Glicosil Hidrolases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Apoptose , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Replicação do DNA , DNA de Neoplasias/metabolismo , Desoxicitidina Monofosfato/análogos & derivados , Desoxicitidina Monofosfato/metabolismo , Desoxicitidina Monofosfato/farmacologia , Nucleotídeos de Desoxiuracil/metabolismo , Resistencia a Medicamentos Antineoplásicos , Genes BRCA1 , Humanos , Hidrólise , N-Glicosil Hidrolases/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/genética , Mutações Sintéticas Letais , Timidina/análogos & derivados , Timidina/antagonistas & inibidores , Timidina/metabolismo , Timidina/farmacologia , Uracila-DNA Glicosidase/metabolismo
20.
ACS Chem Biol ; 16(4): 642-650, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33787221

RESUMO

Host-cell cysteine proteases play an essential role in the processing of the viral spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of cysteine proteases that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC50< 74 nM), HeLa/ACE2 (4 nM), Caco-2 (EC90 = 4.3 µM), and A549/ACE2 (<80 nM). Infectivity of Calu-3 cells depended on the cell line assayed. If Calu-3/2B4 was used, EC50 was 7 nM, but in the ATCC Calu-3 cell line without ACE2 enrichment, EC50 was >10 µM. There was no toxicity to any of the host cell lines at 10-100 µM K777 concentration. Kinetic analysis confirmed that K777 was a potent inhibitor of human cathepsin L, whereas no inhibition of the SARS-CoV-2 cysteine proteases (papain-like and 3CL-like protease) was observed. Treatment of Vero E6 cells with a propargyl derivative of K777 as an activity-based probe identified human cathepsin B and cathepsin L as the intracellular targets of this molecule in both infected and uninfected Vero E6 cells. However, cleavage of the SARS-CoV-2 spike protein was only carried out by cathepsin L. This cleavage was blocked by K777 and occurred in the S1 domain of the SARS-CoV-2 spike protein, a different site from that previously observed for the SARS-CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of cathepsin L-mediated viral spike protein processing.


Assuntos
Antivirais/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Fenilalanina/farmacologia , Piperazinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Compostos de Tosil/farmacologia , Animais , Catepsina L/antagonistas & inibidores , Catepsina L/metabolismo , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Testes de Sensibilidade Microbiana , Domínios Proteicos , Proteólise , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus/efeitos dos fármacos
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