RESUMO
BACKGROUND: Breast cancer stem cells (BCSCs) have a critical role in progression of breast cancer by inducing angiogenesis. Several therapeutic strategies have been designed for the treatment of breast cancer by specifically preventing angiogenesis. But there is a dearth of study regarding the treatment procedure which can specifically target and kill the BCSCs and cause lesser harm to healthy cells of the body. A plant-based bioactive compound Quinacrine (QC) specifically kills cancer stem cells (CSCs) without harming healthy cells and also inhibits cancer angiogenesis but the detailed mechanistic study of its anti-CSCs and anti-angiogenic activity is yet to explore. HYPOTHESIS: Earlier report showed that both cMET and ABCG2 play an essential role in cancer angiogenesis. Both are present on the cell surface of CSCs and share an identical ATP-binding domain. Interestingly, QC a plant based and bioactive compound which was found to inhibit the function of CSCs marker cMET and ABCG2. These relevant evidence led us to hypothesize that cMET and ABCG2 may interact with each other and induce the production of angiogenic factors, resulting in activation of cancer angiogenesis and QC might disrupt the interaction between them to stop this phenomena. METHODS: Co-immunoprecipitation assay, immunofluorescence assay, and western blotting were performed by using ex vivo patient-derived breast cancer-stem-cells (PDBCSCs) and human umbilical vein endothelial cells (HUVECs). In silico study was carried out to check the interaction between cMET and ABCG2 in presence or absence of QC. Tube formation assay using HUVECs and in ovo Chorioallantoic membrane (CAM) assay using chick fertilized eggs were performed to monitor angiogenesis. In vivo patient-derived xenograft (PDX) mice model was used to validate in silico and ex vivo results. RESULTS: Data revealed that in a hypoxic tumor microenvironment (TME), cMET and ABCG2 interact with each other and upregulate HIF-1α/VEGF-A axis to induce breast cancer angiogenesis. In silico and ex vivo study showed that QC disrupted the interaction between cMET and ABCG2 to inhibit the angiogenic response in endothelial cells by reducing the secretion of VEGF-A from PDBCSCs within the TME. Knockdown of cMET, ABCG2 or both, significantly downregulated the expression of HIF-1α and reduced the secretion of pro-angiogenic factor VEGF-A in the TME of PDBCSCs. Additionally, when PDBCSCs were treated with QC, similar experimental results were obtained. CONCLUSION: In silico, in ovo, ex vivo and in vivo data confirmed that QC inhibited the HIF-1α/VEGF-A mediated angiogenesis in breast cancer by disrupting the interaction between cMET and ABCG2.
Assuntos
Neoplasias da Mama , Quinacrina , Humanos , Animais , Camundongos , Feminino , Quinacrina/farmacologia , Quinacrina/metabolismo , Quinacrina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , Células-Tronco Neoplásicas/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismoRESUMO
BACKGROUND: The Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that manifests as a rapidly progressive dementia syndrome. Currently, CJD has no cure, and many patients die within the first year, but some drugs are being studied as options for managing this condition. OBJECTIVE: To evaluate the effectiveness of pharmacological treatments offered to patients with CJD as a means to increase survival and reduce cognitive deterioration. METHODS: A systematic review of the literature was performed using 4 independent reviewers and 1 extra reviewer to resolve possible divergences in the search and analysis of papers indexed in MedLINE (PubMed), SciELO and Lilacs databases. The Medical Subject Heading (MeSH) terms used were: prion diseases, Creutzfeldt-Jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine, and pentosan polysulfate, with the Boolean operators AND and OR. This search included controlled clinical trials, uncontrolled clinical trials, and case series published from the year 2000 onwards, in the English language. RESULTS: A total of 85 papers were found using the descriptors used. At the end of the selection analyses, 9 articles remained, which were analyzed fully and individually. CONCLUSIONS: None of the drugs evaluated proved significantly effective in increasing survival in patients with CJD. Flupirtine appears to have a beneficial effect in reducing cognitive deterioration in patients with CJD. However, additional studies are needed to establish better evidence and therapeutic options for the management of patients with CJD.
ANTECEDENTES: A doença de Creutzfeldt-Jakob (DCJ) é uma encefalopatia espongiforme que se manifesta como síndrome demencial rapidamente progressiva. Atualmente, a DCJ não possui cura e muitos pacientes morrem no primeiro ano de doença, mas alguns medicamentos vêm sendo estudados como opções no manejo desta condição. OBJETIVO: Avaliar a eficácia dos tratamentos farmacológicos oferecidos aos pacientes com DCJ no aumento de sobrevida e na redução da deterioração cognitiva. MéTODOS: Foi realizada uma revisão sistemática da literatura utilizando 4 revisores independentes e 1 extra para resolver divergências eventuais na busca e na análise de trabalhos indexados nas bases de dados MedLINE (via PubMed), SciELO e Lilacs. Os termos Medical Subjects Heading (MeSH) utilizados foram: prion diseases, creutzfeldt jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine e pentosan polysulfate, com os operadores booleanos AND e OR. Essa pesquisa incluiu ensaios clínicos controlados, não controlados e séries de casos, publicados a partir do ano 2000 no idioma inglês. RESULTADOS: Ao todo, foram encontrados 85 trabalhos através dos descritores utilizados. Ao final das análises de seleção, restaram 9 artigos, que foram analisados na íntegra individualmente. CONCLUSõES: Nenhuma das drogas avaliadas se mostrou significativamente eficaz no aumento da sobrevida dos pacientes com DCJ. A flupirtina parece ter um efeito benéfico na redução da deterioração cognitiva dos pacientes com DCJ. Entretanto, estudos adicionais são necessários para o estabelecimento de melhores evidências e opções terapêuticas para o manejo dos pacientes com DCJ.
Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Aminopiridinas , Síndrome de Creutzfeldt-Jakob/tratamento farmacológico , Síndrome de Creutzfeldt-Jakob/psicologia , Doxiciclina/uso terapêutico , Humanos , Poliéster Sulfúrico de Pentosana/uso terapêutico , Quinacrina/uso terapêuticoRESUMO
The poor prognosis of glioblastoma requires new innovative treatment strategies. We and others have shown that targeting tumor as well as angiogenesis in glioblastoma are effective therapeutic strategies. In line with these efforts, this work reveals that Quinacrine, an antimalarial drug, is a dual inhibitor of angiogenesis and glioblastoma. Using multiple glioblastoma cell lines, we found that Quinacrine inhibited proliferation and induced apoptosis in these cells, and acted in synergy with Temozolomide. Quinacrine potently inhibited tubular structure formations of glioblastoma microvascular endothelial cell (GMVEC) isolated from glioblastoma patients, especially for early stage tubular structure formation. Although Quinacrine induces apoptosis in GMVEC, the anti-angiogenic activity of Quinacrine is independent of its pro-apoptotic activity in GMVECs. Quinacrine inhibits glioblastoma angiogenesis and growth in vivo, and acts synergistically with Temozolomide in inhibiting glioblastoma growth in mice. Mechanistically, we found that Quinacrine acts on glioblastoma through inducing oxidative stress, impairing mitochondrial function and activating AMP-activated protein kinase (AMPK). Our work is the first to demonstrate the anti-angiogenic activity of Quinacrine. Our findings highlight Quinacrine as an attractive candidate to support treatment of glioblastoma.
Assuntos
Glioblastoma , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Camundongos , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo , Quinacrina/farmacologia , Quinacrina/uso terapêutico , Temozolomida/farmacologiaRESUMO
OBJECTIVE: The pathogenesis of cutaneous lupus erythematosus (CLE) is multifactorial, and CLE is difficult to treat due to the heterogeneity of inflammatory processes among patients. Antimalarials such as hydroxychloroquine (HCQ) and quinacrine (QC) have long been used as first-line systemic therapy; however, many patients do not respond to treatment with antimalarials and require systemic immunosuppressants that produce undesirable side effects. Given the complexity and the unpredictability of responses to antimalarial treatments in CLE patients, we sought to characterize the immunologic profile of patients with CLE stratified by subsequent treatment outcomes to identify potential biomarkers of inducible response. METHODS: We performed mass cytometry imaging of multiple immune cell types and inflammation markers in treatment-naive skin biopsy samples from 48 patients with CLE to identify baseline immunophenotypes that may predict the response to antimalarial therapy. Patients were stratified according to their response to treatment with antimalarials, as HCQ responders, QC responders, or nonresponders. RESULTS: HCQ responders demonstrated increased CD4+ T cells compared to the QC responder group. Patients in the nonresponder group were found to have decreased Treg cells compared to QC responders and increased central memory T cells compared to HCQ responders. QC responders expressed increased phosphorylated stimulator of interferon genes (pSTING) and interferon-κ (IFNκ) compared to HCQ responders. Phosphorylated STING and IFNκ were found to be localized to conventional dendritic cells (cDCs), and the intensity of pSTING and IFNκ staining was positively correlated with the number of cDCs on a tissue and cellular level. Neighborhood analysis revealed decreased regulatory cell interactions in nonresponder patients. Hierarchical clustering revealed that nonresponder patients could be further differentiated based on expression of pSTAT2, pSTAT3, pSTAT4, pSTAT5, phosphorylated interferon regulatory factor 3 (pIRF3), granzyme B, pJAK2, interleukin-4 (IL-4), IL-17, and IFNγ. CONCLUSION: These findings indicate differential immune cell compositions between patients with CLE, offering guidance for future research on precision-based medicine and treatment response.
Assuntos
Antimaláricos , Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Sistêmico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Granzimas , Humanos , Hidroxicloroquina/efeitos adversos , Imunossupressores/uso terapêutico , Fator Regulador 3 de Interferon , Interferons , Interleucina-17 , Interleucina-4 , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Quinacrina/farmacologia , Quinacrina/uso terapêuticoRESUMO
Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Quinacrina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Citarabina/farmacologia , Citarabina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Cultura Primária de Células , Quinacrina/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Parkinson's disease is a neurodegenerative disorder characterised by nigrostriatal dopaminergic degeneration, and intracellular α-synuclein aggregation. Current pharmacological treatments are solely symptomatic so there is a need to identify agents that can slow or stop dopaminergic degeneration. One proposed class of therapeutics are neurotrophic factors which promote the survival of nigrostriatal dopaminergic neurons. However, neurotrophic factors need to be delivered directly to the brain. An alternative approach may be to identify pharmacological agents which can reach the brain to stimulate neurotrophic factor expression and/or their signalling pathways in dopaminergic neurons. BMP2 is a neurotrophic factor that is expressed in the human substantia nigra; exogenous BMP2 administration protects against dopaminergic degeneration in in vitro models of PD. In this study, we investigated the neurotrophic potential of two FDA-approved drugs, quinacrine and niclosamide, that are modulators of BMP2 signalling. We report that quinacrine and niclosamide, like BMP2, significantly increased neurite length, as a readout of neurotrophic action, in SH-SY5Y cells and dopaminergic neurons in primary cultures of rat ventral mesencephalon. We also show that these effects of quinacrine and niclosamide require the activation of BMP-Smad signalling. Finally, we demonstrate that quinacrine and niclosamide are neuroprotective against degeneration induced by the neurotoxins, MPP+ and 6-OHDA, and by viral-mediated overexpression of α-synuclein in vitro. Collectively, this study identifies two drugs, that are safe for use in patients' to 'are approved for human use, that exert neurotrophic effects on dopaminergic neurons through modulation of BMP-Smad signalling. This rationalises the further study of drugs that target the BMP-Smad pathway as potential neuroprotective pharmacotherapy for Parkinson's disease.
Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Niclosamida/farmacologia , Quinacrina/farmacologia , alfa-Sinucleína/toxicidade , Animais , Proteína Morfogenética Óssea 2/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Neurônios Dopaminérgicos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/prevenção & controle , Neuritos/metabolismo , Neuroproteção/fisiologia , Neurotoxinas/toxicidade , Niclosamida/uso terapêutico , Quinacrina/uso terapêutico , Ratos , Proteínas Smad/metabolismoRESUMO
BACKGROUND: There is a limited evidence base for the treatment of cutaneous sarcoidosis. OBJECTIVE: To describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease. METHODS: Data were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness. RESULTS: In total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission. CONCLUSION: HCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.
Assuntos
Fármacos Dermatológicos/uso terapêutico , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Azatioprina/uso terapêutico , Protocolos Clínicos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Interleucina-12/antagonistas & inibidores , Interleucina-23/antagonistas & inibidores , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Fenótipo , Estudos Prospectivos , Quinacrina/uso terapêutico , Encaminhamento e Consulta , Indução de Remissão , Centros de Atenção Terciária , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto JovemRESUMO
Quinacrine, also known as mepacrine, has originally been used as an antimalarial drug for close to a century, but was recently rediscovered as an anticancer agent. The mechanisms of anticancer effects of quinacrine are not well understood. The anticancer potential of quinacrine was discovered in a screen for small molecule activators of p53, and was specifically shown to inhibit NFκB suppression of p53. However, quinacrine can cause cell death in cells that lack p53 or have p53 mutations, which is a common occurrence in many malignant tumors including high grade serous ovarian cancer. Recent reports suggest quinacrine may inhibit cancer cell growth through multiple mechanisms including regulating autophagy, FACT (facilitates chromatin transcription) chromatin trapping, and the DNA repair process. Additional reports also suggest quinacrine is effective against chemoresistant gynecologic cancer. In this review, we discuss anticancer effects of quinacrine and potential mechanisms of action with a specific focus on gynecologic and breast cancer where treatment-refractory tumors are associated with increased mortality rates. Repurposing quinacrine as an anticancer agent appears to be a promising strategy based on its ability to target multiple pathways, its selectivity against cancer cells, and the synergistic cytotoxicity when combined with other anticancer agents with limited side effects and good tolerability profile.
Assuntos
Antimaláricos/uso terapêutico , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Quinacrina/uso terapêutico , Animais , HumanosRESUMO
We have recently identified three molecules (tilorone, quinacrine and pyronaridine tetraphosphate) which all demonstrated efficacy in the mouse model of infection with mouse-adapted Ebola virus (EBOV) model of disease and had similar in vitro inhibition of an Ebola pseudovirus (VSV-EBOV-GP), suggesting they interfere with viral entry. Using a machine learning model to predict lysosomotropism these compounds were evaluated for their ability to possess a lysosomotropic mechanism in vitro. We now demonstrate in vitro that pyronaridine tetraphosphate is an inhibitor of Lysotracker accumulation in lysosomes (IC50 = 0.56 µM). Further, we evaluated antiviral synergy between pyronaridine and artesunate (Pyramax®), which are used in combination to treat malaria. Artesunate was not found to have lysosomotropic activity in vitro and the combination effect on EBOV inhibition was shown to be additive. Pyramax® may represent a unique example of the repurposing of a combination product for another disease.
Assuntos
Antivirais/farmacologia , Artesunato/uso terapêutico , Reposicionamento de Medicamentos , Ebolavirus/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Naftiridinas/uso terapêutico , Quinacrina/uso terapêutico , Tilorona/uso terapêutico , Antivirais/uso terapêutico , Combinação de Medicamentos , Sinergismo Farmacológico , Células HeLa , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologia , Humanos , Células MCF-7 , Aprendizado de Máquina , Internalização do Vírus/efeitos dos fármacosRESUMO
BACKGROUND: Malignant pleural effusion (MPE) is a common problem for people with cancer and usually associated with considerable breathlessness. A number of treatment options are available to manage the uncontrolled accumulation of pleural fluid, including administration of a pleurodesis agent (via a chest tube or thoracoscopy) or placement of an indwelling pleural catheter (IPC). This is an update of a review published in Issue 5, 2016, which replaced the original, published in 2004. OBJECTIVES: To ascertain the optimal management strategy for adults with malignant pleural effusion in terms of pleurodesis success and to quantify differences in patient-reported outcomes and adverse effects between interventions. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and three other databases to June 2019. We screened reference lists from other relevant publications and searched trial registries. SELECTION CRITERIA: We included randomised controlled trials of intrapleural interventions for adults with symptomatic MPE, comparing types of sclerosant, mode of administration and IPC use. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on study design, characteristics, outcome measures, potential effect modifiers and risk of bias. The primary outcome was pleurodesis failure rate. Secondary outcomes were adverse events, patient-reported breathlessness control, quality of life, cost, mortality, survival, duration of inpatient stay and patient acceptability. We performed network meta-analyses of primary outcome data and secondary outcomes with enough data. We also performed pair-wise meta-analyses of direct comparison data. If we deemed interventions not jointly randomisable, or we found insufficient available data, we reported results by narrative synthesis. For the primary outcome, we performed sensitivity analyses to explore potential causes of heterogeneity and to evaluate pleurodesis agents administered via a chest tube only. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified 80 randomised trials (18 new), including 5507 participants. We found all except three studies at high or unclear risk of bias for at least one domain. Due to the nature of the interventions, most studies were unblinded. Pleurodesis failure rate We included 55 studies of 21 interventions in the primary network meta-analysis. We estimated the rank of each intervention's effectiveness. Talc slurry (ranked 6, 95% credible interval (Cr-I) 3 to 10) is an effective pleurodesis agent (moderate certainty for comparison with placebo) and may result in fewer pleurodesis failures than bleomycin and doxycycline (bleomycin versus talc slurry: odds ratio (OR) 2.24, 95% Cr-I 1.10 to 4.68; low certainty; ranked 11, 95% Cr-I 7 to 15; doxycycline versus talc slurry: OR 2.51, 95% Cr-I 0.81 to 8.40; low certainty; ranked 12, 95% Cr-I 5 to 18). There is little evidence of a difference between the pleurodesis failure rate of talc poudrage and talc slurry (OR 0.50, 95% Cr-I 0.21 to 1.02; moderate certainty). Evidence for any difference was further reduced when restricting analysis to studies at low risk of bias (defined as maximum one high risk domain in the risk of bias assessment) (pleurodesis failure talc poudrage versus talc slurry: OR 0.78, 95% Cr-I 0.16 to 2.08). IPCs without daily drainage are probably less effective at obtaining a definitive pleurodesis (cessation of pleural fluid drainage facilitating IPC removal) than talc slurry (OR 7.60, 95% Cr-I 2.96 to 20.47; rank = 18/21, 95% Cr-I 13 to 21; moderate certainty). Daily IPC drainage or instillation of talc slurry via IPC are likely to reduce pleurodesis failure rates. Adverse effects Adverse effects were inconsistently reported. We performed network meta-analyses for the risk of procedure-related fever and pain. The evidence for risk of developing fever was of low certainty, but suggested there may be little difference between interventions relative to talc slurry (talc poudrage: OR 0.89, 95% Cr-I 0.11 to 6.67; bleomycin: OR 2.33, 95% Cr-I 0.45 to 12.50; IPCs: OR 0.41, 95% Cr-I 0.00 to 50.00; doxycycline: OR 0.85, 95% Cr-I 0.05 to 14.29). Evidence also suggested there may be little difference between interventions in the risk of developing procedure-related pain, relative to talc slurry (talc poudrage: OR 1.26, 95% Cr-I 0.45 to 6.04; very-low certainty; bleomycin: OR 2.85, 95% Cr-I 0.78 to 11.53; low certainty; IPCs: OR 1.30, 95% Cr-I 0.29 to 5.87; low certainty; doxycycline: OR 3.35, 95% Cr-I 0.64 to 19.72; low certainty). Patient-reported control of breathlessness Pair-wise meta-analysis suggests there is likely no difference in breathlessness control, relative to talc slurry, of talc poudrage ((mean difference (MD) 4.00 mm, 95% CI -6.26 to 14.26) on a 100 mm visual analogue scale for breathlessness; studies = 1; participants = 184; moderate certainty) and IPCs without daily drainage (MD -6.12 mm, 95% CI -16.32 to 4.08; studies = 2; participants = 160; low certainty). Overall mortality There may be little difference between interventions when compared to talc slurry (bleomycin and IPC without daily drainage; low certainty) but evidence is uncertain for talc poudrage and doxycycline. Patient acceptability Pair-wise meta-analysis demonstrated that IPCs probably result in a reduced risk of requiring a repeat invasive pleural intervention (OR 0.25, 95% Cr-I 0.13 to 0.48; moderate certainty) relative to talc slurry. There is likely little difference in the risk of repeat invasive pleural intervention with talc poudrage relative to talc slurry (OR 0.96, 95% CI 0.59 to 1.56; moderate certainty). AUTHORS' CONCLUSIONS: Based on the available evidence, talc poudrage and talc slurry are effective methods for achieving a pleurodesis, with lower failure rates than a number of other commonly used interventions. IPCs provide an alternative approach; whilst associated with inferior definitive pleurodesis rates, comparable control of breathlessness can probably be achieved, with a lower risk of requiring repeat invasive pleural intervention. Local availability, global experience of agents and adverse events (which may not be identified in randomised trials) and patient preference must be considered when selecting an intervention. Further research is required to delineate the roles of different treatments according to patient characteristics, such as presence of trapped lung. Greater attention to patient-centred outcomes, including breathlessness, quality of life and patient preference is essential to inform clinical decision-making. Careful consideration to minimise the risk of bias and standardise outcome measures is essential for future trial design.
Assuntos
Metanálise em Rede , Derrame Pleural Maligno/terapia , Pleurodese/métodos , Adulto , Bleomicina/uso terapêutico , Doxiciclina/uso terapêutico , Dispneia/terapia , Febre/etiologia , Humanos , Iodo/uso terapêutico , Derrame Pleural Maligno/etiologia , Derrame Pleural Maligno/mortalidade , Pleurodese/mortalidade , Quinacrina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Talco/uso terapêutico , Falha de TratamentoRESUMO
Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34+ progenitor/stem leukemia cells from CML patients. QC targets RNA polymerase I, which produces ribosomal (r)RNA, involving in protein translation process. Also, QC treatment prolongs CML-like mice survival and inhibits K562 tumor growth in vivo. In conclusion, we demonstrate that QC depletes BCR-ABL protein and suppresses Ph-positive leukemia cells in vitro and in vivo.
Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Quinacrina/uso terapêutico , Animais , Antígenos CD34/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Although antimalarials are the primary treatment for cutaneous lupus erythematosus, not all patients are equally responsive. We investigated whether different inflammatory cell population and cytokine profiles in lesional cutaneous lupus erythematosus skin could affect antimalarial responsiveness, and whether hydroxychloroquine (HCQ) and quinacrine (QC) differentially suppress inflammatory cytokines. Cutaneous lupus erythematosus patients were grouped according to their response to antimalarials (HCQ vs. HCQ+QC). On immunohistochemistry, only the myeloid dendritic cell population was significantly increased in the HCQ+QC group compared to HCQ group. While the IFN scores calculated for the selected type I IFN-regulated genes (LYE6, OAS1, OASL, ISG15, and MX1) were significantly higher in the HCQ group than the HCQ+QC group, the TNF-α level was higher in the HCQ+QC group. QC was more effective than HCQ at inhibiting the toll receptor-mediated production of TNF-α and IL-6 in the peripheral blood mononuclear cells isolated from cutaneous lupus erythematosus patients, whereas QC and HCQ inhibited IFN-α equally. QC also suppressed phospho-NF-κB p65 more profoundly than HCQ. In conclusion, increased myeloid dendritic cell population with higher TNF-α expression might contribute to HCQ refractoriness and a better response to QC. Differential suppressive effects of HCQ and QC could also affect antimalarial responses in cutaneous lupus erythematosus patients.
Assuntos
Antimaláricos/uso terapêutico , Células Dendríticas/imunologia , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Células Dendríticas/metabolismo , Feminino , Humanos , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Cutâneo/patologia , Masculino , Pessoa de Meia-Idade , Quinacrina/uso terapêutico , Pele/citologia , Pele/imunologia , Pele/patologia , Resultado do TratamentoRESUMO
The role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Temozolomida/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Quinacrina/farmacologia , Quinacrina/uso terapêutico , Proteína Sequestossoma-1/metabolismo , Temozolomida/uso terapêutico , Transplante HeterólogoRESUMO
Aim The aim of this study was to evaluate the clinical response to combined therapy with hydroxychloroquine and mepacrine in patients with systemic lupus erythematosus and refractory joint and/or skin disease. Methods Mepacrine was added to 46 systemic lupus erythematosus patients unresponsive to treatment with the following drug combinations: hydroxychloroquine + prednisone + immunosuppressive drugs ( n = 24), hydroxychloroquine + prednisone ( n = 16), hydroxychloroquine + prednisone + retinoids ( n = 2), hydroxychloroquine alone ( n = 1), hydroxychloroquine + one immunosuppressive drug ( n = 1), hydroxychloroquine + prednisone + one immunosuppressive drug + belimumab ( n = 1) or hydroxychloroquine + prednisone + belimumab ( n = 1). The outcome variable was the clinical response, either complete or partial, based on clinical judgement. The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score were additionally used. Results A total of 91% patients showed complete/partial response, with similar rates among those with joint or skin disease. In patients with cutaneous activity, a statistically significant decrease in the CLASI was seen. There also was a statistically significant decrease in the SLEDAI. The mean daily dose of prednisone decreased from 5.8 to 3.4 mg/d ( p = 0.001). Prednisone could be discontinued in 20% of patients. No serious adverse events were seen. Smoking was the only predictor of complete response. Conclusion In the setting of refractory skin and/or joint disease, the addition of mepacrine to previous therapy including hydroxychloroquine was safe and effective in reducing disease activity and decreasing prednisone doses. The fact that smokers responded better opens the door to further studying the combination of mepacrine-hydroxychloroquine as a first-line therapy in such patients.
Assuntos
Antimaláricos/uso terapêutico , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Artropatias/tratamento farmacológico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Quinacrina/uso terapêutico , Adulto , Antimaláricos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Imunossupressores/efeitos adversos , Artropatias/diagnóstico , Artropatias/imunologia , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Discoide/diagnóstico , Lúpus Eritematoso Discoide/tratamento farmacológico , Lúpus Eritematoso Discoide/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Quinacrina/efeitos adversos , Indução de Remissão , Estudos Retrospectivos , Fumantes , Resultado do TratamentoRESUMO
Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-κB and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-inactivated conditions. Inhibition of p53 by PFT-α or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G2-M phase. QNC increases the binding between p-Chk1/2 and ß-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre;p53+/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53-/- xenografts.Implications: QNC has been used for the past over 70 years without obvious side effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies. Mol Cancer Res; 16(6); 935-46. ©2018 AACR.
Assuntos
Antimaláricos/uso terapêutico , Quinase 1 do Ponto de Checagem/genética , Neoplasias/tratamento farmacológico , Quinacrina/uso terapêutico , RNA Interferente Pequeno/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Antimaláricos/farmacologia , Humanos , Camundongos , Camundongos Nus , Neoplasias/genética , Neoplasias/patologia , Quinacrina/farmacologia , TransfecçãoRESUMO
Quinacrine (QC), a synthetic antimalarial drug, was consistently used worldwide to combat malaria during the last century. Interestingly, later studies revealed that it also displays various additional properties, specifically antitumor activity. QC's antitumor activity occurs via a variety of pathways, including DNA intercalation, angiogenesis inhibition, signal transduction regulation, cell cycle arrest and autophagy induction. In combination with traditional therapies such as chemotherapy and radiotherapy, QC has also displayed synergistic effects against tumors, which may open promising therapeutic avenues. However, the breadth and complexity of its antitumor mechanisms have not yet been fully elucidated. In this review, we have systematically categorized QC's reported antitumor mechanisms from recent studies, to enable a deeper understanding of its antitumor activity.
Assuntos
Antimaláricos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/terapia , Neovascularização Patológica/tratamento farmacológico , Quinacrina/uso terapêutico , Animais , Antimaláricos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Terapia Combinada/métodos , Sinergismo Farmacológico , Humanos , Neoplasias/patologia , Neovascularização Patológica/patologia , Uso Off-Label , Quinacrina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Introduction Preclinical data suggest quinacrine acts as an inhibitor of FACT (facilitates chromatin transcription) complex, which may play a role in TKI (tyrosine kinase inhibitor) resistance. The aim of this Phase I study was to study the safety and assess the maximum tolerated dose of quinacrine in combination with erlotinib in non small cell lung cancer (NSCLC). Methods This was a phase I study with standard 3 + 3 dose escalation design with the primary aim of determining the maximum tolerated dose. Two of 3 patients enrolled at dose level 1 experienced dose limiting toxicity (DLT). The next 6 patients were enrolled at dose level - 1 and none of these 6 patients experienced DLT. The dose of 50 mg of quinacrine every other day with 150 mg of erlotinib was established as the maximum tolerated and the recommended phase II dose. One of 3 patients treated at dose level 1 had stable disease. One of 6 patients treated at dose level - 1 had partial response for 6 months, the rest had progressive disease at the time of first assessment. Conclusion Combination of quinacrine and erlotinib was well tolerated but showed limited efficacy in advanced NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quinacrina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Quinacrina/efeitos adversosRESUMO
INTRODUCTION: Jessner-Kanof disease (JKD), a lymphocytic infiltration of the skin, can be difficult to treat. Mepacrine (quinacrine), an anti-malarial less available in Belgium, may be beneficial. PATIENTS AND METHODS: Two female patients with biopsy-proven and therapy-resistant JKD, not responding to topical and systemic corticosteroids, (hydroxy-)chloroquine and/or dapsone, were treated with mepacrine 100 mg daily. RESULTS: In both patients an amelioration was observed during the first month of treatment, and clinical remission was obtained by the fourth month, without any side-effects. In both cases, the dose could be tapered to three times weekly. DISCUSSION: JKD is strongly related to lupus erythematosus (tumidus), and although spontaneous remissions may occur, it is notoriously difficult to treat. Mepacrine may be initiated as an add-on therapy to (hydroxy-)chloroquine, but also as monotherapy. A dose of 100 mg a day, tapered to weekly doses once remission is obtained, seems feasible. Except for (mild) yellow skin discoloration, the drug has few side-effects, and offers the advantage of not displaying retinal toxicity. CONCLUSION: Mepacrine is still a useful and safe drug for treating cutaneous lupus erythematosus and related skin conditions, such as refractory JKD in particular. Its future availability, also in Belgium, is therefore important.
Assuntos
Inibidores Enzimáticos/uso terapêutico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Quinacrina/uso terapêutico , Adulto , Epiderme/patologia , Feminino , Técnica Direta de Fluorescência para Anticorpo , Humanos , Pessoa de Meia-IdadeRESUMO
Although an effective therapy for prion disease has not yet been established, many advances have been made toward understanding its pathogenesis, which has facilitated research into therapeutics for the disease. Several compounds, including flupirtine, quinacrine, pentosan polysulfate, and doxycycline, have recently been used on a trial basis for patients with prion disease. Concomitantly, several lead antiprion compounds, including compound B (compB), IND series, and anle138b, have been discovered. However, clinical trials are still far from yielding significantly beneficial results, and the findings of lead compound studies in animals have highlighted new challenges. These efforts have highlighted areas that need improvement or further exploration to achieve more effective therapies. In this work, we review recent advances in prion-related therapeutic research and discuss basic scientific issues to be resolved for meaningful medical intervention of prion disease.
Assuntos
Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/tratamento farmacológico , Síndrome de Creutzfeldt-Jakob/história , Aminopiridinas/uso terapêutico , Animais , Modelos Animais de Doenças , Doxiciclina/uso terapêutico , Descoberta de Drogas , História do Século XX , História do Século XXI , Humanos , Poliéster Sulfúrico de Pentosana/uso terapêutico , Quinacrina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Pesquisa Translacional BiomédicaRESUMO
Overcoming drug resistance is a major challenge for cancer therapy. Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) is a potent therapeutic as an activator of apoptosis, particularly in tumor but not in healthy cells. However, its efficacy is limited by the resistance of tumor cell populations to the therapeutic substance. Here, we have addressed this limitation through the development of a controlled release system, matrix-metalloproteinase (MMP)-sensitive and arg-gly-asp-ser (RGDS) peptide functionalized poly (ethylene-glycol) (PEG) particles which are synthesized via visible-light-induced water-in-water emulsion polymerization. Quinacrine (QC), a recently discovered TRAIL sensitizer drug, is loaded into the hydrogel carriers and the influence of this system on the apoptosis of a malignant type of brain cancer, glioblastoma multiforme (GBM), has been investigated in detail. The results suggest that MMP-sensitive particles are cytocompatible and superior to promote TRAIL-induced apoptosis in GBM cells when loaded with QC. Compared to QC and TRAIL alone, combination of QC-loaded PEG hydrogel and TRAIL demonstrates synergistic apoptotic inducing behavior. Furthermore, QC-loaded particles, but not QC or PEG-hydrogels alone, enhance apoptosis as is measured through expression of apoptosis-related genes. This system is promising to significantly improve the efficacy of chemotherapeutic drugs and suggests a combination treatment for GBM therapy.