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1.
Anticancer Res ; 41(9): 4239-4248, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475043

RESUMO

BACKGROUND/AIM: Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs. MATERIALS AND METHODS: Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells. RESULTS: HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax. CONCLUSION: HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Promielocítica Aguda/genética , Regulação para Cima , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proliferação de Células , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Células HL-60 , Humanos , Sulfonamidas/farmacologia
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445506

RESUMO

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Triterpenos Pentacíclicos/química , Sulfonamidas/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Antígenos de Neoplasias/química , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Simulação de Acoplamento Molecular , Tolerância a Radiação , Sulfonamidas/síntese química , Sulfonamidas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
3.
J Enzyme Inhib Med Chem ; 36(1): 1874-1883, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340614

RESUMO

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Biologia Computacional/métodos , Isoenzimas/antagonistas & inibidores , Quinazolinas/química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , Sulfonamidas/química
4.
Biomolecules ; 11(7)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34356673

RESUMO

Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.


Assuntos
Antineoplásicos/uso terapêutico , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Celecoxib/efeitos adversos , Celecoxib/análogos & derivados , Celecoxib/farmacologia , Ciclo Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Pirazóis/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/química , Sulfonamidas/farmacologia
5.
Medicine (Baltimore) ; 100(30): e26739, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397713

RESUMO

ABSTRACT: Baricitinib is a Janus kinase (JAK) inhibitor that selectively blocks against JAK1 and JAK2 signaling. This study aimed to determine the effect of baricitinib on disease activity based on musculoskeletal ultrasound in patients with rheumatoid arthritis (RA).A total of 20 patients with RA receiving baricitinib for 24 weeks were assessed. Ultrasound scores of gray scale and power Doppler synovitis, joint effusion, and bone erosion in each patient were assessed between baseline and 24 weeks for 27 affected joints. Disease activity in RA was evaluated using the disease activity score for 28-joint count with erythrocyte sediment rate (DAS28-ESR), simplified disease activity index (SDAI), and clinical disease activity index (CDAI).Treatment with baricitinib for 12 weeks and 24 weeks significantly decreased disease activity composites such as DAS28-ESR, SDAI, and CDAI (P < .001 for all). Treatment with baricitinib for 24 weeks improved ultrasound-detected gray-scale and power Doppler synovitis and joint effusion compared to baseline (P = .002, P = .030, and P = .002, respectively). Bone erosion scores were not different between baseline and 24 weeks (P = .317). There were no differences in ultrasound abnormalities for improvement based on DAS28-ESR. Changes in power Doppler score were significantly associated with changes in DAS28-ESR (ß = 0.590, P = .044), but not SDAI and CDAI.This study demonstrates that baricitinib treatment has a favorable effect on ultrasound-detected abnormalities including synovitis and bone erosion in patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Osso e Ossos/efeitos dos fármacos , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Sinovite/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Azetidinas/farmacologia , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Purinas/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sinovite/diagnóstico por imagem , Ultrassonografia
6.
Cancer Sci ; 112(9): 3645-3654, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288263

RESUMO

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Translocação Genética/genética , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tretinoína/farmacologia
7.
Bioorg Chem ; 114: 105153, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34328851

RESUMO

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively. The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Herpes simplex virus-1(TK- KOS ACVr), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized compounds endowed with good antimicrobial property together with considerable antiviral activity.


Assuntos
Fenóis/síntese química , Sulfonamidas/síntese química , Tolueno/análogos & derivados , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Linhagem Celular , Chlorocebus aethiops , Humanos , Fenóis/química , Fenóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologia , Células Vero , Vírus/classificação , Vírus/efeitos dos fármacos
8.
J Enzyme Inhib Med Chem ; 36(1): 1521-1539, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34266349

RESUMO

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 µM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 µM, respectively) and HER2 (IC50 = 0.13 and 0.07 µM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
9.
J Enzyme Inhib Med Chem ; 36(1): 1563-1572, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34281464

RESUMO

A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 µM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 µM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Polimerização/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
10.
Biochem Biophys Res Commun ; 571: 26-31, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34303192

RESUMO

The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp out of which two retained binding even using molecular dynamic simulations. We propose these two drugs as potential RdRp inhibitors which need further in-depth testing.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Amidas/farmacologia , Antivirais/química , Benzimidazóis/farmacologia , COVID-19/virologia , Carbamatos/farmacologia , Domínio Catalítico , Simulação por Computador , RNA-Polimerase RNA-Dependente de Coronavírus/química , Ciclopropanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Fluorenos/farmacologia , Humanos , Lactamas Macrocíclicas/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Prolina/análogos & derivados , Prolina/farmacologia , Conformação Proteica , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia
11.
J Med Microbiol ; 70(7)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34259620

RESUMO

Introduction. The presence of Candida biofilms in medical devices is a concerning and important clinical issue for haemodialysis patients who require constant use of prosthetic fistulae and catheters.Hypothesis/Gap Statement. This prolonged use increases the risk of candidaemia due to biofilm formation. PH151 and clioquinol are 8-hydroxyquinoline derivatives that have been studied by our group and showed interesting anti-Candida activity.Aim. This study evaluated the biofilm formation capacity of Candida species on polytetrafluoroethylene (PTFE) and polyurethane (PUR) and investigated the synergistic effects between the compounds PH151 and clioquinol and fluconazole, amphotericin B and caspofungin against biofilm cells removed from those materials. Further, the synergistic combination was evaluated in terms of preventing biofilm formation on PTFE and PUR discs.Methodology. Susceptibility testing was performed for planktonic and biofilm cells using the broth microdilution method. The checkerboard method and the time-kill assay were used to evaluate the interactions between antifungal agents. Antibiofilm activity on PTFE and PUR materials was assessed to quantify the prevention of biofilm formation.Results. Candida albicans, Candida glabrata and Candida tropicalis showed ability to form biofilms on both materials. By contrast, Candida parapsilosis did not demonstrate this ability. Synergistic interaction was observed when PH151 was combined with fluconazole in 77.8 % of isolates and this treatment was shown to be concentration- and time-dependent. On the other hand, indifferent interactions were predominantly observed with the other combinations. A reduction in biofilm formation on PUR material of more than 50 % was observed when using PH151 combined with fluconazole.Conclusion. PH151 demonstrated potential as a local treatment for use in a combination therapy approach against Candida biofilm formation on haemodialysis devices.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Contaminação de Equipamentos/prevenção & controle , Fluconazol/farmacologia , Sulfonamidas/farmacologia , Candida/classificação , Candida/fisiologia , Candidíase/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Oxiquinolina/farmacologia , Diálise Renal
12.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299092

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called "progerin" that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.


Assuntos
Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/farmacologia , Piperidinas/efeitos adversos , Progéria/tratamento farmacológico , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/efeitos adversos , Fator de Transcrição STAT1/antagonistas & inibidores , Sulfonamidas/farmacologia , Adolescente , Células Cultivadas , Pré-Escolar , Farnesiltranstransferase/efeitos adversos , Feminino , Humanos , Masculino , Progéria/induzido quimicamente , Progéria/patologia
13.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204950

RESUMO

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia
14.
Gene ; 800: 145842, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34274479

RESUMO

Treatment of serum-starved quiescent human cells with fetal bovine serum (FBS), epidermal growth factor (EGF), or the phorbol ester (12-O-tetradecanoylphorbol-13-acetate, TPA) activates the RAS-MAPK pathway which initiates a transcriptional program which drives cells toward proliferation. Stimulation of the RAS-MAPK pathway activates mitogen- and stress-activated kinases (MSK) 1 and 2, which phosphorylate histone H3 at S10 (H3S10ph) or S28 (H3S28ph) (nucleosomal response) located at the regulatory regions of immediate-early genes, setting in motion a series of chromatin remodeling events that result in transcription initiation. To investigate immediate-early genes regulated by the MSK, we have completed transcriptome analyses (RNA sequencing) of human normal fibroblast cells (CCD-1070Sk) stimulated with EGF or TPA ± H89, a potent MSK/PKA inhibitor. The induction of many immediate-early genes was independent of MSK activity. However, the induction of immediate-early genes attenuated with H89 also had reduced induction with the PKA inhibitor, Rp-cAMPS. Several EGF-induced genes, coding for transcriptional repressors, were further upregulated with H89 but not with Rp-cAMPS, suggesting a role for MSK in modulating the induction level of these genes.


Assuntos
Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Mitógenos/farmacologia , Linhagem Celular , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , Fator de Crescimento Epidérmico/farmacologia , Fibroblastos/fisiologia , Perfilação da Expressão Gênica , Genes Precoces/efeitos dos fármacos , Humanos , Isoquinolinas/farmacologia , Reprodutibilidade dos Testes , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Sulfonamidas/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Tionucleotídeos/farmacologia
15.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201614

RESUMO

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.


Assuntos
Cromossomos Humanos Par 3/genética , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Monossomia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Sulfonamidas/farmacologia , Análise de Sobrevida , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade
16.
Blood ; 138(3): 234-245, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34292323

RESUMO

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.


Assuntos
Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Células Cultivadas , Humanos , Imunidade Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/imunologia , Espécies Reativas de Oxigênio/imunologia , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Células Tumorais Cultivadas
17.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198834

RESUMO

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug.


Assuntos
Anidrase Carbônica IX/genética , Inibidores da Anidrase Carbônica/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Apoptose/efeitos dos fármacos , Anidrase Carbônica IX/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
18.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204776

RESUMO

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin's ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changes in the behavior of tropomyosin and the troponin-tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movement and the ability of the troponin-tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility.


Assuntos
Contração Muscular/genética , Mutação/genética , Oximas/farmacologia , Sulfonamidas/farmacologia , Tropomiosina/genética , Actinas/metabolismo , Animais , Cálcio/metabolismo , Contração Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Miofibrilas/efeitos dos fármacos , Miofibrilas/metabolismo , Miosinas/metabolismo , Coelhos , Troponina/metabolismo
19.
J Enzyme Inhib Med Chem ; 36(1): 1402-1410, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34157927

RESUMO

A new series of sulphonamide derivatives bearing naphthalene moiety were synthesised and evaluated for their antiproliferative and tubulin polymerisation inhibitory activities. These new compounds were evaluated for their in vitro antiproliferative activity against MCF-7 and A549 by using CCK-8 method. Among all the tested compounds, compound 5c with naphthalen-1-yl moiety exhibited the most potent antiproliferative activity against MCF-7 and A549 cell line, with IC50 values of 0.51 ± 0.03 µM and 0.33 ± 0.01 µM, respectively. The results of tubulin polymerisation assay shown that 5c exhibited a significant ability to inhibit tubulin polymerisation with IC50 value of 2.8 µM. Consistent with its antitubulin activity, 5c can significantly arrest the cell cycle at G2/M phase and induce apoptosis in MCF-7 cancer cells. Molecular docking study indicated that compound 5c inhibited tubulin polymerisation through interacting at the colchicine-binding site of tubulin. Furthermore, 5c exhibited low cytotoxic activity on human normal cell line.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/química , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Moduladores de Tubulina/química
20.
J Med Chem ; 64(12): 8806-8825, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34101446

RESUMO

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.


Assuntos
Receptores de Orexina/agonistas , Sono/efeitos dos fármacos , Sulfonamidas/farmacologia , Vigília/efeitos dos fármacos , Animais , Células CHO , Cricetulus , Feminino , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Receptores de Orexina/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
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