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1.
N Engl J Med ; 382(16): 1507-1519, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32187462

RESUMO

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Doenças Cardiovasculares , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Injeções Subcutâneas/efeitos adversos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Fatores de Risco
3.
Ann Lab Med ; 40(2): 155-163, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31650732

RESUMO

BACKGROUND: LINC01234, a long noncoding RNA (lncRNA), is overexpressed in several cancers, including colorectal cancer (CRC). We investigated the role of LINC01234 in CRC development and confirmed its correlation with Krüppel-like factor 6 (KLF6), a tumor suppressor gene that is dysregulated in CRC. METHODS: We tested mRNA levels using quantitative reverse transcription PCR (qRT-PCR). Tissue samples from patients with CRC, inflammatory bowel disease (IBD), hyperplastic polyp, and adenoma were included. Correlations between clinicopathological parameters, overall survival (OS) rate, and LINC01234 were analyzed using Kruskal-Wallis H test. Additionally, cell proliferation, apoptosis, and tumor formation in nude mice were tested to investigate the mechanism of LINC01234. Western blotting was used to determine protein levels. RESULTS: LINC01234 expression was significantly upregulated in CRC tissues and CRC cell lines than in non-tumor tissues and normal epithelial cells, respectively. LINC01234 was associated with high tumor stage, larger tumor size, and metastasis. Patients with higher LINC01234 expression showed reduced OS. Cell proliferation was inhibited by LINC01234 knockdown, whereas apoptosis was enhanced. Mice injected with SW480 cells with LINC01234 knockdown displayed decreased tumor volume, weight, and Ki-67 levels compared with those injected with control cells. KLF6 was negatively regulated by LINC01234. Overexpression of KLF6 showed effects similar to those observed following LINC01234 knockdown on cell proliferation and apoptosis. CONCLUSIONS: LINC01234 could be a prognostic biomarker in CRC patients. Upregulation of LINC01234 in CRC promotes tumor development through negative regulation of KLF6.


Assuntos
Neoplasias Colorretais/patologia , Fator 6 Semelhante a Kruppel/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Fator 6 Semelhante a Kruppel/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Taxa de Sobrevida , Transplante Heterólogo , Regulação para Cima
4.
Cell Mol Biol Lett ; 24: 69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867046

RESUMO

With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.


Assuntos
Neuropatias Amiloides/terapia , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos , Neuropatias Amiloides/genética , Neuropatias Amiloides/metabolismo , Neuropatias Amiloides/patologia , Animais , Técnicas de Transferência de Genes , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Terapia de Alvo Molecular/métodos , Estabilidade de RNA , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA não Traduzido/antagonistas & inibidores , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Complexo de Inativação Induzido por RNA/genética , Complexo de Inativação Induzido por RNA/metabolismo
5.
Expert Opin Pharmacother ; 20(18): 2223-2228, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31566422

RESUMO

Introduction: Hereditary transthyretin-mediated amyloidosis (ATTRv; v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the TTR gene. Mutations promoting proteolytic remodeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.Areas covered: The authors discuss patisiran, the first approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant. This compound demonstrated a safe clinical profile in phase I and II studies and showed a significant clinical effect in a phase III (APOLLO) trial in ATTRv patients. An open-label-extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.Expert opinion: The patisiran program has demonstrated that substantial TTR concentration reduction is associated with significant and sustained improvement in polyneuropathy scores, quality-of-life profile and several outcome measures that capture the systemic burden of the disease. The drug resulted safe also in long term follow-up studies while its efficacy for ATTR with cardiomyopathy is under investigation.


Assuntos
Neuropatias Amiloides Familiares/terapia , RNA Interferente Pequeno/uso terapêutico , Cardiomiopatias/terapia , Humanos , Mutação , Polineuropatias/terapia , Qualidade de Vida , Interferência de RNA
6.
Dtsch Med Wochenschr ; 144(20): 1438-1443, 2019 10.
Artigo em Alemão | MEDLINE | ID: mdl-31594020

RESUMO

Rare, progressive, and fatal is a short description for autosomal dominant hereditary transthyretin (TTR) amyloidosis (ATTR). In the absence of a family background, delays in diagnosis are common. ATTR is often represented by a progressive, axonal fiber-length-dependent polyneuropathy (motor, autonomic, sensory). Cardiovascular, gastrointestinal, renal and ocular manifestations are frequently observed. ATTR is caused by mutated serum protein transthyretin (TTRm), which results in amyloid deposits.The three current concepts of ATTR treatment aim to replace, stabilize and reduce TTR synthesis. (i) The mutant TTRm is almost completely replaced in the peripheral blood after orthotopic liver transplantation by the synthesis of the wild-type (TTRwt) in the donor liver. (ii) Low molecular weight compounds stabilize the TTR tetramer and thereby minimize the formation of amyloid precursors. (iii) Gene silencers (mRNA-inhibiting oligonucleotides) reduce liver-secreted TTRm and TTRwt.Liver transplantation (LTx) is an established procedure in ATTR patients. LTx significantly prolongs survival, especially in early stage patients (< 50 years) with variant ATTRV30M. Some non-ATTRV30M variants show a higher mortality after LTx. The progression of the disease can be slowed down but not prevented by LTx. Diflunisal is a low-cost, off-label drug from the NSAID group. Similar to Tafamidis, it stabilizes the TTR tetramer. Tafamidis has been approved for the treatment of stage 1 ATTR since 2011. It is administered orally and used in patients with polyneuropathy and more recently with cardiomyopathy. Inotersen represents an antisense oligonucleotide that is administered subcutaneously (s. c.) once a week. Patisiran acts as a siRNA oligonucleotide administered intravenously (i. v.) every three weeks in combination with premedication. Both gene silencers were approved in 2018 for the treatment of ATTR stages 1 and 2. The new era of TTR gene silencers now affords an update of algorithms used for treatment of ATTR.


Assuntos
Neuropatias Amiloides Familiares/terapia , Progressão da Doença , Humanos , Transplante de Fígado , RNA Interferente Pequeno/uso terapêutico
8.
Chemotherapy ; 64(3): 119-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661694

RESUMO

OBJECTIVE: To investigate whether TRIAP1inhibition affects the ovarian cancer cell resistance to cisplatin (DDP) via the Cyt c/Apaf-1/caspase-9 pathway by in vitro and in vivo experiments. METHODS: CCK8 assay was performed to find out how treatment with both TRIAP1 siRNA and DDP affects the cell viability of SKOV3 cells and DDP-resistant human ovarian carcinoma cell line SKOV3/DDP. SKOV3/DDP cells were transfected with control siRNA or TRIAP1 siRNA before 24 h of treatment with DDP (5 µg/mL). Flow cytometry was employed to detect cell apoptosis and Western blot to examine the expressions of Cyt c/Apaf-1/caspase-9 pathway-related proteins. SKOV3/DDP cells transfected with control siRNA or TRIAP1 siRNA were subcutaneously injected into BALB/c-nu/nu nude mice followed by the intraperitoneal injection of DDP (4 mg/kg). Cyt c/Apaf-1/caspase-9 pathway in transplanted tumors was detected by immunohistochemistry. RESULTS: TRIAP1 expression declined in SKOV3 cells when compared with SKOV3/DDP cells. The proliferation rate was lower in SKOV3/DDP cells transfected with TRIAP1 siRNA combined with treatment of DDP (1, 2, 4, 6, 8, 16, 32 µg/mL) than in those transfected with control siRNA. Moreover, the TRIAP1 siRNA group had an increased SKOV3/DDP cell apoptosis rate with the activation of the Cyt c/Apaf-1/caspase-9 pathway. During DDP treatment, nude mice in TRIAP1 siRNA group had slower growth and smaller size of transplanted tumor than those in control siRNA group, with increased expression of Cyt c, Apaf-1, and caspase-9. CONCLUSION: TRIAP1 inhibition may enhance the sensitivity of SKOV3/DDP cells to cisplatin via activation of the Cyt c/Apaf-1/caspase-9 pathway.


Assuntos
Cisplatino/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fator Apoptótico 1 Ativador de Proteases/genética , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Citocromos c/genética , Citocromos c/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Transplante Heterólogo
10.
Int J Mol Sci ; 20(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470511

RESUMO

Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients.


Assuntos
Aptâmeros de Nucleotídeos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Oligodesoxirribonucleotídeos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Animais , Aptâmeros de Nucleotídeos/genética , Humanos , Oligodesoxirribonucleotídeos/genética , Oligonucleotídeos Antissenso/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/genética , RNA Interferente Pequeno/genética
12.
Mol Med Rep ; 20(4): 3625-3632, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485668

RESUMO

The aim of this study was to explore the synergistic effect of signal transducer and activator of transcription 3 (STAT3)­targeted small interfering (si)RNA and AZD0530 against glioblastoma in vitro and in vivo. Glioblastoma cell lines U87 and U251 were divided into four groups and treated with control, LV­STAT3 siRNA, AZD0530, and combined LV­STAT3 siRNA with AZD0530, respectively. The proliferation and apoptotic capacity of glioblastoma cells was assessed by Cell Counting Kit­8 and double staining flow cytometry assays, respectively. Additionally, the potential effect of LV­STAT3 siRNA and AZD0530 on glioblastoma was evaluated in vivo. Images were captured of the tumor formation in mice every week. Following three weeks of treatment, NMR scan and immunohistochemistry were performed. The treatment of combined LV­STAT3 siRNA and AZD0530 was more effective in inhibiting proliferation and inducing apoptosisof glioblastoma cells in comparison with the treatment of either LV­STAT3 siRNA or AZD0530 alone. Although LV­STAT3 siRNA or AZD0530 treatment alone suppressed tumor growth in mice, the combined treatment had a more significant effect than the treatment of LV­STAT3 siRNA or AZD0530 alone. According to the results of both in vitro and in vivo assays, a combined therapy of LV­STAT3 siRNA with AZD0530 could enhance therapeutic effects on glioblastoma, supporting the idea that the combination of LV­STAT3 siRNA and AZD0530 could serve as a novel and effective strategy to combat glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Quinazolinas/uso terapêutico , Terapêutica com RNAi , Fator de Transcrição STAT3/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Glioblastoma/genética , Glioblastoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos
13.
Br J Anaesth ; 123(4): 439-449, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383364

RESUMO

BACKGROUND: Nerve growth factor (NGF) has been implicated in hyperalgesia by sensitising nociceptors. A role for NGF in modulating myocardial injury through ischaemic nociceptive signalling is plausible. We examined whether inhibition of spinal NGF attenuates myocardial ischaemia-reperfusion injury and explored the underlying mechanisms. METHODS: In adult rats, lentivirus-mediated short-hairpin RNA targeted at reducing NGF gene expression (NGF-shRNA) or a transient receptor potential vanilloid 1 (TRPV1) antagonist (capsazepine) was injected intrathecally before myocardial ischaemia-reperfusion. Infarct size (expressed as the ratio of area at risk) and risk of arrhythmias were quantified. Whole-cell clamp patch electrophysiology was used to record capsaicin currents in primary dorsal root ganglion neurones. The co-expression of substance P (SP) and calcitonin gene-related peptide (CGRP), plus activation of TRPV1, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also quantified. RESULTS: NGF levels increased by 2.95 (0.34)-fold in dorsal root ganglion and 2.12 (0.27)-fold in spinal cord after myocardial ischaemia-reperfusion injury. Intrathecal injection of NGF-shRNA reduced infarct area at risk from 0.58 (0.02) to 0.37 (0.02) (P<0.01) and reduced arrhythmia score from 3.67 (0.33) to 1.67 (0.33) (P<0.01). Intrathecal capsazepine was similarly cardioprotective. NGF-shRNA suppressed expression of SP/CGRP and activation of Akt/ERK and TRPV1 in spinal cord. NGF increased capsaicin current amplitude from 144 (42) to 840 (132) pA (P<0.05), which was blocked by the TRPV1 antagonist 5'-iodoresiniferatoxin. Exogenous NGF enhanced capsaicin-induced Akt/ERK and TRPV1 activation in PC12 neuroendocrine tumour cells in culture. CONCLUSIONS: Spinal NGF contributes to myocardial ischaemia-reperfusion injury by mediating nociceptive signal transmission.


Assuntos
Terapia Genética/métodos , Lentivirus/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fator de Crescimento Neural/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Arritmias Cardíacas/prevenção & controle , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Cardiotônicos/administração & dosagem , Cardiotônicos/uso terapêutico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Injeções Espinhais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/prevenção & controle , Fator de Crescimento Neural/biossíntese , Células PC12 , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
14.
Int J Pharm ; 569: 118594, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394184

RESUMO

Nucleic acid-based therapy has shown great promise in accelerating bone regeneration as well as other diseases. Nucleic acids used in gene therapy mainly are either plasmid DNA (pDNA) or RNAs. Although pDNA therapy has been extensively studied for decades with encouraging preclinical and clinical results, side effects, and low efficiency associated with nuclear trafficking are hard to bypass. Unlike pDNA, RNAs (mRNA, siRNA, miRNA) exert their function in the cytoplasm, thereby being more efficient in hard-to-transfect cells such as primary osteoblasts. RNA interference-based gene silencing represents a negative regulation which knockdown the expression of antagonists that impair osteogenesis process. In contrary, mRNA therapy for osteogenesis represents a positive regulation which delivers mRNA encoding growth factors to accelerate bone regeneration. This review presents a comprehensive summary of the mRNA and siRNA-based therapies and the targets for bone regeneration in case of bone defect and osteoporosis.


Assuntos
Osteogênese , RNA Mensageiro/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Animais , Regeneração Óssea , Osso e Ossos/metabolismo , Humanos , Transdução de Sinais
15.
Gene ; 719: 144071, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31454539

RESUMO

RNA interference (RNAi) has extensive potential to revolutionize every aspect of clinical application in biomedical research. One of the promising tools is the Small interfering RNA (siRNA) molecules within a cellular component. Principally, siRNA mediated innovative advances are increasing rapidly in support of cancer diagnosis and therapeutic purposes. Conversely, it has some delivery challenges to the site of action within the cells of a target organ, due to the progress of nucleic acids engineering and advance material science research contributing to the exceptional organ-specific targeted therapy. This siRNA based therapeutic technique definitely favors a unique and effective prospect to cancer patients. Herein, the significant drive also takes to review and summarize the major organ specific targets of diverse siRNAs based gene silencing mechanism. This machinery promisingly served as the inhibitor components for cancer development in the human model. Furthermore, the focus is also given to current applications on siRNA based quantifiable therapy leading to the silencing of cancer related gene expression in a sequence dependent and selective manner for cancer treatment. That might be a potent tool against the traditional chemotherapy techniques. Therefore, the siRNA mediated cancer gene therapy definitely require sharp attention like future weapons in opposition to cancer by the method of non-invasive siRNA delivery and effective gene silencing approaches.


Assuntos
Terapia Genética/métodos , Neoplasias/terapia , RNA Interferente Pequeno/uso terapêutico , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Ligação Proteica , RNA Interferente Pequeno/metabolismo
16.
Oncogene ; 38(33): 6095-6108, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31289363

RESUMO

Current anti-angiogenic therapy for cancer is based mainly on inhibition of the vascular endothelial growth factor pathway. However, due to the transient and only modest benefit from such therapy, additional approaches are needed. Deregulation of microRNAs (miRNAs) has been demonstrated to be involved in tumor angiogenesis and offers opportunities for a new therapeutic approach. However, effective miRNA-delivery systems are needed for such approaches to be successful. In this study, miRNA profiling of patient data sets, along with in vitro and in vivo experiments, revealed that miR-204-5p could promote angiogenesis in ovarian tumors through THBS1. By binding with scavenger receptor class B type 1 (SCARB1), reconstituted high-density lipoprotein-nanoparticles (rHDL-NPs) were effective in delivering miR-204-5p inhibitor (miR-204-5p-inh) to tumor sites to suppress tumor growth. These results offer a new understanding of miR-204-5p in regulating tumor angiogenesis.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , MicroRNAs , Neovascularização Patológica/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Epitelial do Ovário/irrigação sanguínea , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Terapia de Alvo Molecular/métodos , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/patologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Mol Sci ; 20(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284594

RESUMO

Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.


Assuntos
Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Aptâmeros de Nucleotídeos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , MicroRNAs/uso terapêutico , RNA Interferente Pequeno/uso terapêutico
18.
Medicina (Kaunas) ; 55(8)2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31357735

RESUMO

The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells' inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.


Assuntos
Antineoplásicos/uso terapêutico , Reparo Gênico Alvo-Dirigido/métodos , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Vírus Oncolíticos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Literatura de Revisão como Assunto , Reparo Gênico Alvo-Dirigido/estatística & dados numéricos
19.
Pharm Dev Technol ; 24(9): 1095-1103, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31204552

RESUMO

This study evaluated the delivery efficiency and antitumor effects of the intrapulmonary administration of antitumor small interfering ribonucleic acid (siRNA)-containing nanoparticles to mice with metastatic lung tumor. Fluorescence-labeled, siRNA-containing nanoparticles were administered using Liquid MicroSprayer® to mice with metastatic lung tumors induced by the murine melanoma cell line B16F10. Fluorescent signals in the whole lung and in the tumor region following the intrapulmonary administration of siRNA-containing nanoparticles were stronger than those following intravenous administration. The intrapulmonary administration of nanoparticles containing a mixture of siRNA against MDM2, c-Myc, and vascular endothelial growth factor (VEGF) significantly improved survival and prolonged the survival of mice with metastatic lung tumor. In addition, after the intrapulmonary or intravenous administration of the mixture, the activity levels of interleukin-6 and -12, markers of systemic toxicity, were similar to those of nontreatment. These results indicate that the antitumor siRNA-containing nanoparticles were delivered efficiently and specifically to tumor cells, effectively silencing the oncogenes in the lung metastasis without any significant systemic toxicity.


Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Melanoma Experimental/patologia , RNA Interferente Pequeno/administração & dosagem , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/instrumentação , Feminino , Neoplasias Pulmonares/genética , Camundongos Endogâmicos C57BL , Nanopartículas/química , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/instrumentação , Fator A de Crescimento do Endotélio Vascular/genética
20.
J Cancer Res Clin Oncol ; 145(8): 1999-2012, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172267

RESUMO

BACKGROUND: The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. METHODS: CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. RESULTS: We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). CONCLUSION: The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.


Assuntos
Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Catepsina K/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Inibidores de Proteases/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Neoplasias Ósseas/genética , Catepsina K/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos SCID , Células PC-3 , Neoplasias da Próstata/genética , Inibidores de Proteases/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
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