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1.
Mol Ther ; 30(5): 1979-1993, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35167974

RESUMO

As of December 2021, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single-chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the Delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Because of their high efficiency, remarkable stability, resilience to nebulization, and low cost of production, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Humanos , Fragmentos de Imunoglobulinas , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus
2.
Chem Commun (Camb) ; 57(7): 867-870, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33433550

RESUMO

Antitumor hydroxamates SAHA and Dacinostat have been linked to cetuximab and trastuzumab through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure. These antibody drug conjugates (ADCs) were able to inhibit HDAC in several tumour cell lines. The cetuximab based ADCs block human lung adenocarcinoma cell proliferation, demonstrating that bioconjugation with antibodies is a suitable approach for targeted therapy based on hydroxamic acid-containing drugs. This work also shows that ADC-based delivery might be used to overcome the classical pharmacokinetic problems of hydroxamic acids.


Assuntos
Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/química , Imunoconjugados/química , Células A549 , Proliferação de Células/efeitos dos fármacos , Cetuximab/química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Imunoconjugados/metabolismo , Trastuzumab/química
3.
Bioorg Med Chem ; 27(15): 3248-3253, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31208798

RESUMO

Tenatumomab is an anti-tenascin murine monoclonal antibody previously used in clinical trials for delivering radionuclides to tumors by both pre-targeting (biotinylated Tenatumomab within PAGRIT) and direct 131Iodine labeling approaches. Here we present the synthesis and in vitro characterization of three Tenatumomab conjugates to bifunctional chelating agents (NHS-DOTA, NCS-DOTA and NCS-DTPA). Results indicate ST8198AA1 (Tenatumomab-DOTAMA, derived by conjugation of NHS-DOTA), as the most promising candidate in terms of conjugation rate and yield, stability, antigen immunoreactivity and affinity. Labeling efficiency of the different chelators was investigated with a panel of cold metals indicating DOTAMA as the best chelator. Labeling of Tenatumomab-DOTAMA was then optimized with several metals and stability performed confirms suitability of this conjugate for further development. ST8198AA1 represents an improvement of the previous antibody forms because the labeling with radionuclides like 177Lu or 64Cu would allow theranostic applications in patients bearing tenascin expressing tumors.


Assuntos
Compostos Heterocíclicos com 1 Anel/farmacologia , Neoplasias/tratamento farmacológico , Tenascina/antagonistas & inibidores , Nanomedicina Teranóstica , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 1 Anel/química , Humanos , Estrutura Molecular , Neoplasias/genética , Relação Estrutura-Atividade , Tenascina/genética
4.
Front Oncol ; 9: 1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32039017

RESUMO

Targeted therapy using monoclonal antibodies conjugated to toxins is gaining space in the treatment of cancer. Here, we report the anti-tumor effect of a new antibody drug conjugate (ADC) delivering a HDAC inhibitor to ErbB2+ solid tumors. Trastuzumab was partially reduced with tris [2-carboxyethyl] phosphine (TCEP) and conjugated to ST7464AA1, the active form of the prodrug HDAC inhibitor ST7612AA1, through a maleimide-thiol linker to obtain the Antibody Drug Conjugate (ADC) ST8176AA1. The average drug/antibody ratio (DAR) was 4.5 as measured by hydrophobic interaction chromatography (HIC). Binding of ST8176AA1 to ErbB2 receptor and internalization in tumor cells were investigated by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), cytofluorimetry, and High Content Screening (HCS) Imaging. The biological activity of the ADC was evaluated in vitro and in vivo by measuring cell proliferation/cell cycle, apoptosis/DNA damage, tubulin, and histone acetylation and modulation of Epithelial/Mesenchymal Transition (EMT) markers. Receptor binding and internalization of ST8176AA1 were confirmed to be similar to trastuzumab. Higher anti-tumor activity of ST8176AA1 compared to trastuzumab was observed in vitro in tumor cell lines. Such higher activity correlated with increased acetylation of histones and alfa-tubulin as a consequence of HDAC inhibitor-mediated epigenetic modulation that also induced increased expression of ErbB2 and estrogen receptor in triple negative breast cancer cells. Consistently with in vitro data, ST8176AA1 exhibited higher tumor growth inhibition than trastuzumab in xenograft models of ovary and colon carcinoma and in two patient-derived xenograft (PDX) models of pancreatic carcinoma. Immunohistochemistry analysis of tumor masses showed lower expression of the proliferation marker Ki67 and higher expression of cleaved caspase-3 in mice treated with the ADC compared to those treated with trastuzumab and results correlated with increased acetylation of both histones and tubulin. Collectively, present data indicate that ADC ST8176AA1 can target epigenetic modulation to ErbB2+ tumors. Interestingly, the amount of HDACi estimated to be delivered at the ST8176AA1 effective dose would correspond to ~1/1,000 of ST7612AA1 effective dose. Therefore, ST8176AA1 is an attractive new therapeutic candidate because it exhibits increased anti-tumor potency compared to trastuzumab by exerting epigenetic modulation at a much safer dose compared to standard HDACi-based therapeutic protocols.

5.
Chem Sci ; 9(31): 6490-6496, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30288233

RESUMO

We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC50 equal to 0.07 µM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity in vivo. Two payloads were prepared using cleavable and non-cleavable linkers. After anchoring to cetuximab through amide bond with lysines, the resulting HDAC inhibitor-antibody conjugates showed ability to recognize EGFR and efficient internalization in tumor cells. Both ADCs induced sensible increment of histones 3 and 4 and alpha-tubulin acetylation. Animal models of human solid tumors showed high anti-tumor efficacy of the conjugates without the toxicity generally observed with traditional ADCs delivering highly potent cytotoxic drugs. These compounds, the first ADCs charged with not highly cytotoxic warheads, are potentially suitable for epigenetic modulation, extending the ADC strategy to the targeted delivery of HDAC inhibitors with many possible therapeutic applications beyond cancer.

6.
Eur J Med Chem ; 157: 368-379, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30099257

RESUMO

Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Guanidina/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Tioureia/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Guanidina/administração & dosagem , Guanidina/química , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Células NIH 3T3 , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Tioureia/administração & dosagem , Tioureia/química
7.
Oncotarget ; 8(14): 22590-22605, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28186982

RESUMO

The oxidized version of Avidin, known as AvidinOX, was previously shown to link to tissue proteins upon injection or nebulization, thus becoming a stable receptor for biotinylated therapeutics. AvidinOX is currently under clinical investigation to target radioactive biotin to inoperable tumor lesions (ClinicalTrials.gov NCT02053324). Presently, we show that the anti-ErbB2 monoclonal antibodies Trastuzumab and Pertuzumab can be chemically biotinylated while maintaining their biochemical and biological properties. By using several and diverse experimental conditions, we show that when AvidinOX is conjugated to tumor cells, low antibody concentrations of biotinylated Trastuzumab (bTrast) or Pertuzumab (bPert) prevent internalization of ErbB2, induce endoplasmic reticulum stress, cell cycle arrest and apoptosis leading to inhibition of proliferation and ErbB2 signaling. Moreover, we found that the treatment is able to induce down-modulation of ErbB2 thus bypassing the known resistance of this receptor to degradation. Interestingly, we show that AvidinOX anchorage is a way to counteract agonistic activities of Trastuzumab and Pertuzumab. Present data are in agreement with previous observations from our group indicating that the engagement of the Epidermal Growth Factor Receptor (EGFR) by AvidinOX-bound biotinylated Cetuximab or Panitumumab, leads to potent tumor inhibition both in vitro and in animal models. All results taken together encourage further investigation of AvidinOX-based treatments with biotinylated antibodies directed to the members of the EGFR family.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Avidina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Avidina/química , Biomarcadores Tumorais/metabolismo , Biotinilação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Receptor ErbB-2/imunologia , Transdução de Sinais , Trastuzumab/administração & dosagem , Células Tumorais Cultivadas
8.
Glycobiology ; 26(6): 640-54, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26762172

RESUMO

Heparanase is a ß-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (IC50 ≈ 3 nM) and showed, at higher concentrations, a Hill coefficient consistent with the engagement of two molecules of inhibitor. A homology model of human heparanase GS3 construct was built and used for docking experiments with inhibitor fragments. The model has high structural similarity with the recently reported crystal structure of human heparanase. Different interaction schemes are proposed, which support the hypothesis of a complex binding mechanism involving the recruitment of one or multiple roneparstat chains, depending on its concentration. In particular, docking solutions were obtained in which (i) a single roneparstat molecule interacts with both heparin-binding domains (HBDs) of heparanase or (ii) two fragments of roneparstat interact with either HBD-1 or HBD-2, consistent with the possibility of different inhibitor:enzyme binding stoichiometries. This study provides unique insights into the mode of action of roneparstat as well as clues of its interaction with heparanase at a molecular level, which could be exploited to design novel potential inhibitor molecules.


Assuntos
Inibidores Enzimáticos/química , Glucuronidase/química , Heparina/análogos & derivados , Polissacarídeos/química , Acidobacteria/química , Acidobacteria/enzimologia , Motivos de Aminoácidos , Sítios de Ligação , Sequência de Carboidratos , Fondaparinux , Glucuronidase/antagonistas & inibidores , Glucuronidase/metabolismo , Heparina/química , Humanos , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Polissacarídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica
9.
Oncotarget ; 7(1): 914-28, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26575422

RESUMO

For locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC), the current clinical use of Cetuximab in chemo/radiotherapy protocols is often associated to severe systemic toxicity. Here we report in vitro data in human FaDu pharynx SCC cells, showing that inactive concentrations of biotinylated Cetuximab (bCet) become active upon anchorage to AvidinOX on the surface of tumor cells. AvidinOX-anchored bCet induces apoptosis and DNA damage as well as specific inhibition of signaling, degradation and abrogation of nuclear translocation of EGFR. In the mouse model of FaDu cancer, we show that intra-tumor injection of AvidinOX allows anti-tumor activity of an otherwise inactive, intraperitoneally delivered, low dose bCet. Consistently with in vitro data, in vivo tumor inhibition is associated to induction of apoptosis, DNA damage and reduced angiogenesis. AvidinOX is under clinical investigation for delivering radioactive biotin to inoperable tumors (ClinicalTrials.gov NCT02053324) and present data support its use for the local treatment of HNSCC in combination with systemic administration of low dose bCet.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Avidina/administração & dosagem , Biotinilação , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Immunoblotting , Imuno-Histoquímica , Camundongos Nus , Neovascularização Patológica/prevenção & controle , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
10.
Oncotarget ; 6(8): 5735-48, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25671299

RESUMO

ST7612AA1 (property of Sigma-Tau), a thioacetate-ω (γ-lactam amide) derivative, is a potent, second generation, oral pan-histone deacetylase inhibitor (HDACi). Aim of the study was to assess the efficacy of ST7612AA1 in solid and haematological tumors, and to characterize its mechanism of action. In vitro, ST7612AA1 potently inhibited different class I and class II HDACs, leading to restore the balance of both histone and non-histone protein acetylation. In vivo, it induced significant anti-tumor effects in xenograft models of lung, colon, breast and ovarian carcinomas, leukemia and lymphoma. This was likely due to the modulation of different HDAC substrates and induction of transcriptional changes with respect to several genes involved in key processes, such as cell cycle regulation, DNA damage checkpoints, immune response, cell adhesion and epithelial-to-mesenchymal transition. PK analysis confirmed the pro-drug nature of ST7612AA1, which is rapidly absorbed and converted to ST7464AA1 after a single oral dose in mice. ST7612AA1 was selected from a novel generation of oral HDAC inhibitors. Its high efficacy correlated with its potent and selective inhibitory activity of HDAC and was combined with a favorable pharmacodynamics profile. These aspects support a clinical development of ST7612AA1 towards a broad spectrum of human solid and haematologic malignancies.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Pirrolidinonas/farmacologia , Animais , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 5(19): 9239-55, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25238453

RESUMO

Lung cancer, as well as lung metastases from distal primary tumors, could benefit from aerosol treatment. Unfortunately, because of lung physiology, clearance of nebulized drugs is fast, paralleled by unwanted systemic exposure. Here we report that nebulized AvidinOX can act as an artificial receptor for biotinylated drugs. In nude and SCID mice with advanced human KRAS-mutated A549 metastatic lung cancer, pre-nebulization with AvidinOX enables biotinylated Cetuximab to control tumor growth at a dose lower than 1/25,000 the intravenous effective dose. This result correlates with a striking, specific and unpredictable effect of AvidinOX-anchored biotinylated Cetuximab, as well as Panitumumab, observed on a panel of tumor cell lines, leading to inhibition of dimerization and signalling, blockade of endocytosis, induction of massive lysosomal degradation and abrogation of nuclear translocation of EGFR. Excellent tolerability, together with availability of pharmaceutical-grade AvidinOX and antibodies, will allow rapid clinical translation of the proposed therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Avidina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Administração por Inalação , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab , Endocitose/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Lisossomos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Panitumumabe , Multimerização Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
12.
Int J Oncol ; 45(4): 1421-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25096516

RESUMO

4-Amino substituted resorcino-isoxazole (SST0116CL1) (property of Sigma-Tau Research Switzerland S.A.) is a potent, second generation, small-molecule heat shock protein 90 inhibitor (Hsp90i). SST0116CL1 binds to the ATP binding pocket of Hsp90, and interferes with Hsp90 chaperone function thus resulting in client protein degradation and tumor growth inhibition. The aim of the study was to assess SST0116CL1 in various solid and haematological tumors. The antitumor properties of SST0116CL1 were assessed using in vitro cell proliferation and client protein degradation assays and in vivo different tumor xenograft models. Pharmacokinetic (PK) data were also generated in tumor-bearing mice to gain an understanding of optimal dosing schedules and regimens. SST0116CL1 was shown to inhibit recombinant Hsp90α and to induce the destabilization of different client proteins, often overexpressed and constitutively activated in different types of hematological or solid human tumors. In preclinical in vivo studies, it was revealed to induce antitumor effects in murine models of leukemia and of gastric and ovarian carcinoma. A modulation of PD biomarkers in terms of downregulation of Hsp90 client proteins in tumor-bearing mice was found. SST0116CL1 is a new clinical candidate for cancer therapy. The antitumor property of SST0116CL1, likely due to direct inhibition of the Hsp90 enzymatic activity, may prove to be a critical attribute as the compound enters phase I clinical trials.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Resorcinóis/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Med Chem ; 53: 64-75, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22538015

RESUMO

A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/química , Naftoquinonas/química , Naftoquinonas/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Feminino , Proteínas de Choque Térmico HSP90/química , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Moleculares , Naftoquinonas/síntese química , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Clin Cancer Res ; 16(15): 3944-53, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20562210

RESUMO

PURPOSE: Acetyl-L-carnitine (ALC) plays a relevant role in energy metabolism and stress response because of its function in the complex metabolic system regulating the acetyl-CoA levels that provide a source of acetyl groups for metabolic and acetylation-regulated processes. Because acetylation may influence p53 activity/stability and, therefore, the response to platinum compounds, this study was designed to investigate the effect of ALC in combination with platinum compounds. EXPERIMENTAL DESIGN: The antiproliferative and antitumor activity studies were done in a panel of human tumor cell lines with functional or defective p53. The antimetastatic drug efficacy was investigated in the s.c. growing H460/M tumor subline, which is able to generate lung metastases. RESULTS: ALC enhanced the sensitivity to cisplatin of tumor cells with functional p53. The sensitization by ALC was reflected in an improved in vivo antitumor efficacy of the combination over cisplatin alone in wild-type p53 lung tumors. ALC did not increase the cisplatin efficacy in the p53-mutant SW620 tumor. ALC exhibited a significant antimetastatic activity, and this effect was better exploited in combination with the histone deacetylase inhibitor, ST3595. The in vivo ALC/cisplatin combination caused the activation of p53, associated with protein acetylation and induction of target genes. CONCLUSIONS: ALC was effective in enhancing the antitumor potential of platinum compounds in wild-type p53 tumors. ALC, alone and in combination with a histone deacetylase inhibitor, exhibited an outstanding antimetastatic activity. Both effects, likely mediated by protein acetylation, may have implications for platinum-based therapy and combinations with histone deacetylase inhibitors.


Assuntos
Acetilcarnitina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mol Pharmacol ; 73(5): 1434-43, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18292206

RESUMO

We report here the finding of a new pharmacological activity of a well known antagonist of peroxisome proliferator-activated receptors (PPARs). PPARs belong to the family of nuclear receptors playing a relevant role in mammalian physiology and are currently believed to represent a major target for the development of innovative drugs for metabolic and inflammatory diseases. In the present study, the application of reporter animal technology was instrumental to obtain the global pharmacological profiling indispensable to unraveling 3-(1-(4-chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoic acid (MK-886)-selective PPAR modulator (SPPARM) activity not underlined by previous traditional, cell-based studies. The results of this study, demonstrating the usefulness of reporter mice, may open new avenues for the development of innovative drugs for cardiovascular, endocrine, neural, and skeletal systems characterized by limited side effects.


Assuntos
Indóis/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Imagem Corporal Total/métodos , Animais , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Ligantes , Luciferases/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/agonistas , PPAR alfa/antagonistas & inibidores , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Elementos de Resposta , Transdução de Sinais/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacos
16.
Bioorg Med Chem ; 16(5): 2473-88, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18083578

RESUMO

Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonismo Inverso de Drogas , Receptores Adrenérgicos beta 3/metabolismo , Adenilil Ciclases/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Humanos , Estrutura Molecular , Receptores Adrenérgicos beta 3/genética , Estereoisomerismo , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 40(2): 143-54, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15694649

RESUMO

Clofibrate is a lipid-profile modifying agent belonging to the fibrate class of drugs. Fibrates are known to exhibit their beneficial effects by activating peroxisome proliferator-activated receptor-alpha (PPARalpha) and used in the treatment of dyslipidemia and atherosclerosis and for the prevention of heart failure. Hereby, the preparation of two new sets of clofibrate analogues, ethyl 2-(4-chlorophenoxy)-3-oxoalkanoates and ethyl 2-(4-chlorophenoxy)-3-hydroxyalkanoates is described starting from commercially available 3-oxoalkanoates in fair to good yields. Treatment of 3-oxoalkanoates with SO2Cl2 yielded the corresponding 2-chloro-3-oxoalkanoates, that were then converted into 2-(4-chlorophenoxy)-3-oxoalkanoates by reacting with sodium or caesium 4-chlorophenate. Reduction of the keto group with NaBH4 afforded the corresponding 2-(4-chlorophenoxy)-3-hydroxyalkanoates in very high yields and with variable diastereoselectivity. Biological evaluation of the compounds was performed by a transactivation assay in a transiently transfected monkey kidney fibroblast cell line. The newly synthesised clofibrate analogues failed to show noticeable levels of PPAR activation at concentrations where clofibrate showed an evident activity, suggesting that the structural modifications caused the loss of PPAR activity.


Assuntos
Clofibrato/síntese química , Ésteres/síntese química , Hipolipemiantes/síntese química , PPAR alfa/agonistas , Fatores de Transcrição/efeitos dos fármacos , Animais , Linhagem Celular , Clofibrato/análogos & derivados , Clofibrato/farmacologia , Ésteres/farmacologia , Fibroblastos/citologia , Haplorrinos , Hipolipemiantes/farmacologia , Rim/citologia , Modelos Químicos , Estereoisomerismo , Fatores de Transcrição/metabolismo
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