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1.
Mol Ther Nucleic Acids ; 33: 127-141, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37449042

RESUMO

Nanodiamonds are innovative nanocrystalline carbon particles able to deliver chemically conjugated miRNAs. In oncology, the use of miRNA-based therapies may represent an advantage, based on their ability to simultaneously target multiple intracellular oncogenic targets. Here, nanodiamonds were tested and optimized to deliver miR-34a, a miRNA playing a key role in inhibiting tumor development and progression in many cancers. The physical-chemical properties of nanodiamonds were investigated suggesting electrical stability and uniformity of structure and size. Moreover, we evaluated nanodiamond cytotoxicity on two breast cancer cell models and confirmed their excellent biocompatibility. Subsequently, nanodiamonds were conjugated with miR-34a, using the chemical crosslinker polyethyleneimine; real-time PCR analysis revealed a higher level of miR-34a in cancer cells treated with the different formulations of nanodiamonds than with commercial transfectant. A significant and early nanodiamond-miR-34a uptake was recorded by FACS and fluorescence microscopy analysis in MCF7 and MDA-MB-231 cells. Moreover, nanodiamond-miR-34a significantly inhibited both cell proliferation and migration. Finally, a remarkable anti-tumor effect of miR-34a-conjugated nanodiamonds was observed in both heterotopic and orthotopic murine xenograft models. In conclusion, this study provides a rationale for the development of new therapeutic strategies based on use of miR-34a delivered by nanodiamonds to improve the clinical treatment of neoplasms.

2.
Eur J Med Chem ; 228: 113971, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34772529

RESUMO

Hybrid molecules targeting simultaneously DNA polymerase α (POLA1) and histone deacetylases (HDACs) were designed and synthesized to exploit a potential synergy of action. Among a library of screened molecules, MIR002 and GEM144 showed antiproliferative activity at nanomolar concentrations on a panel of human solid and haematological cancer cell lines. In vitro functional assays confirmed that these molecules inhibited POLA1 primer extension activity, as well as HDAC11. Molecular docking studies also supported these findings. Mechanistically, MIR002 and GEM144 induced acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. Oral administration of these inhibitors confirmed their antitumor activity in in vivo models. In human non-small cancer cell (H460) xenografted in nude mice MIR002 at 50 mg/kg, Bid (qd × 5 × 3w) inhibited tumor growth (TGI = 61%). More interestingly, in POLA1 inhibitor resistant cells (H460-R9A), the in vivo combination of MIR002 with cisplatin showed an additive antitumor effect with complete disappearance of tumor masses in two animals at the end of the treatment. Moreover, in two human orthotopic malignant pleural mesothelioma xenografts (MM473 and MM487), oral treatments with MIR002 and GEM144 confirmed their significant antitumor activity (TGI = 72-77%). Consistently with recent results that have shown an inverse correlation between POLA1 expression and type I interferon levels, MIR002 significantly upregulated interferon-α in immunocompetent mice.


Assuntos
Antineoplásicos/farmacologia , DNA Polimerase I/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Polimerase I/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Bioorg Chem ; 104: 104253, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920362

RESUMO

Atypical retinoids (AR) or retinoid-related molecules (RRMs) represent a promising class of antitumor compounds. Among AR, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (adarotene), has been extensively investigated. In the present work we report the results of our efforts to develop new adarotene-related atypical retinoids endowed also with POLA1 inhibitory activity. The effects of the synthesized compounds on cell growth were determined on a panel of human and hematological cancer cell lines. The most promising compounds showed antitumor activity against several tumor histotypes and increased cytotoxic activity against an adarotene-resistant cell line, compared to the parent molecule. The antitumor activity of a selected compound was evaluated on HT-29 human colon carcinoma and human mesothelioma (MM487) xenografts. Particularly significant was the in vivo activity of the compound as a single agent compared to adarotene and cisplatin, against pleural mesothelioma MM487. No reduction of mice body weight was observed, thus suggesting a higher tolerability with respect to the parent compound adarotene.


Assuntos
Antineoplásicos/farmacologia , DNA Polimerase I/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Retinoides/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , DNA Polimerase I/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Retinoides/síntese química , Retinoides/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Molecules ; 25(9)2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32403241

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the production of inflammatory factors. In order to overcome the side effects of currently used anti-inflammatory drugs, several attempts have been made to identify natural products capable of relieving RA symptoms. In this work, a herbal preparation consisting of propolis, pomegranate peel, and Aglianico grape pomace (PPP) extracts (4:1:1) was designed and evaluated for its effect on a murine collagen-induced arthritis (CIA) model. Firstly, the chemical contents of four different Italian propolis collected in the Campania region (Italy) were here reported for the first time. LC-MS analyses showed the presence of 38 constituents, identified in all propolis extracts, belonging to flavonoids and phenolic acids classes. The Pietradefusi extract was the richest one and thus was selected to design the PPP preparation for the in vivo assay. Our results highlight the impact of PPP on RA onset and progression. By using in vivo CIA models, the treatment with PPP resulted in a delayed onset of the disease and alleviated the severity of the clinical symptoms. Furthermore, we demonstrated that early PPP treatment was associated with a reduction in serum levels of IL-17, IL-1b, and IL-17-triggering cytokines.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Preparações de Plantas/farmacologia , Punica granatum/química , Própole/análise , Vitis/química , Animais , Anti-Inflamatórios/química , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/fisiopatologia , Cromatografia Líquida , Colágeno/toxicidade , Feminino , Flavonoides/análise , Hidroxibenzoatos/análise , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos DBA , Preparações de Plantas/química , Própole/química , Própole/farmacologia
5.
PLoS One ; 13(10): e0205018, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30300374

RESUMO

Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase I/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/metabolismo , Feminino , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos , Camundongos Nus , Simulação de Dinâmica Molecular , Neoplasias/patologia , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Transplante Heterólogo
6.
Eur J Med Chem ; 143: 2005-2014, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29150335

RESUMO

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Dissulfetos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores da Topoisomerase I/farmacologia , Tirosina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , DNA Topoisomerases Tipo I/metabolismo , Dissulfetos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Tirosina/química , Tirosina/farmacologia
7.
Oncotarget ; 8(52): 89595-89606, 2017 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-29163773

RESUMO

Despite multimodal treatments comprising, radiation therapy (RT) and chemotherapy with temozolomide (TMZ), the prognosis of glioblastoma multiforme (GBM) remains dismal and consolidated therapy yields a median survival of 14.6 months. Blood Brain Barrier (BBB) mediated chemoresistance and high dose related toxicity make necessary the development of new therapeutic approach to sensitize GBM to TMZ. The aim of the present study was to investigate the potential of the treatment morphine plus TMZ metronmic doses (1,77 and 0,9 mg/kg) in GBM therapy. The effect of morphine, on tumor cell growth and P-glycoprothein (P-gp) activity, was investigate in in vitro models. The results demonstrated that GBM cells growth is not influenced by morphine treatment and, for the first time, we show that morphine is an inhibitor of the activity of P-gp efflux transporter who is markedly expressed on BBB. In vivo, response to the treatments TMZ plus morphine was investigated in an orthotopic nude mice model of GBM. Animals treated with TMZ metronomic doses showed a significant tumor growth inhibition compared to untreated mice and association with morphine appears to improve TMZ efficacy. Moreover, the combination of morphine with lower dose of TMZ result in a cytostatic effect on tumor growth over the period of the pharmacological treatments. In conclusion this novel approach could be a successful strategy to overcome chemoresistance and side effects TMZ mediated, reducing drug dosage and improving long term response, in GBM therapy.

8.
Am J Cancer Res ; 6(3): 639-48, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27152241

RESUMO

Morphine may alter the permeability of Blood-Brain Barrier (BBB), enhancing the access of molecules normally unable to cross it, as Doxorubicin (Dox). In addition, morphine seems to mediate the uptake of Dox into the brain by its reduced efflux mediated by P-glycoprotein (P-gp). We evaluated the antitumor efficacy of Dox plus morphine treatment by an orthotopic glioblastoma xenograft model. Foxn1 mice were injected with U87MG-luc cells in the left lobe of the brain and treated with Dox (5 mg/kg and 2.5 mg/kg, weekly) with or without morphine pretreatment (10 mg/kg, weekly). Bioluminescence imaging (BLI) was used to monitoring tumor growth and response to therapy. Additionally, we investigated the role of morphine on the uptake of Dox by MDCKII cells transfected with human MDR1 gene encoding for P-gp. The data demonstrate that only Dox 5 mg/kg determined a significant tumor regression while the lower dose (2.5 mg/kg) was not effective. However, if combined with morphine, the group treated with Dox 2.5 mg/kg showed a decreasing tumor growth. The average BLI for Dox 2.5 mg/kg plus morphine was 5 fold lower than Dox 2.5 mg/kg alone (P=0.0053) and 8 fold lower than vehicle (P=0.0004). Additionally, Dox increased in MDCKII-P-gp transfected cells only in the presence of morphine with a significantly higher level comparing control group (3.84) vs Dox plus morphine group (12.29, P<0.05). Our results indicate that Dox alone and in combination with morphine appear to be effective in controlling the growth of glioblastoma in a xenograft mouse model.

9.
Eur J Immunol ; 42(10): 2632-43, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22777843

RESUMO

Despite convincing evidence for involvement of members of the Toll-like receptor (TLR) family in fungal recognition, little is known of the functional role of individual TLRs in antifungal defenses. We found here that TLR7 was partially required for the induction of IL-12 (IL-12p70) by Candida albicans or Saccharomyces cerevisiae. Moreover, the IL-12p70 response was completely abrogated in cells from 3d mice, which are unable to mobilize TLRs to endosomal compartments, as well as in cells from mice lacking either the TLR adaptor MyD88 or the IRF1 transcription factor. Notably, purified fungal RNA recapitulated IL-12p70 induction by whole yeast. Although RNA could also induce moderate TLR7-dependent IL-23 and tumor necrosis factor-alpha (TNF-α) secretion, TLR7 and other endosomal TLRs were redundant for IL-23 or TNF-α induction by whole fungi. Importantly, mice lacking TLR7 or IRF1 were hypersusceptible to systemic C. albicans infection. Our data suggest that IRF1 is downstream of a novel, nonredundant fungal recognition pathway that has RNA as a major target and requires phagosomal recruitment of intracellular TLRs. This pathway differs from those involved in IL-23 or TNF-α responses, which we show here to be independent from translocation of intracellular TLRs, phagocytosis, or phagosomal acidification.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Células Dendríticas/imunologia , RNA Fúngico/imunologia , Animais , Candida albicans/genética , Citocinas/metabolismo , Células Dendríticas/microbiologia , Suscetibilidade a Doenças , Endossomos/genética , Endossomos/metabolismo , Imunidade , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fagocitose/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/imunologia , Receptor 7 Toll-Like/genética
10.
J Immunol ; 188(4): 1953-60, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22250086

RESUMO

Group B Streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show in this study that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1ß and IL-18. IL-1ß release required both pro-IL-1ß transcription and caspase-1-dependent proteolytic cleavage of intracellular pro-IL-1ß. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1ß mRNA in response to GBS. Pro-IL-1ß cleavage and secretion of the mature IL-1ß form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of ß-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, apoptosis-associated speck-like protein, or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.


Assuntos
Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Inflamassomos/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus agalactiae/imunologia , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Bactérias/biossíntese , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/genética , Caspase 1/metabolismo , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Feminino , Proteínas Hemolisinas/biossíntese , Interleucina-18/biossíntese , Interleucina-18/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR , RNA Mensageiro/biossíntese , Transdução de Sinais , Infecções Estreptocócicas/metabolismo , Streptococcus agalactiae/metabolismo , Streptococcus agalactiae/patogenicidade , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética
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