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1.
J Cachexia Sarcopenia Muscle ; 15(1): 55-66, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38064183

RESUMO

BACKGROUND: Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse. Age-related imbalance of protein synthesis and degradation, mainly regulated by AKT/mTOR pathway, leads to progressive loss of muscle mass. Maintenance of anabolic and regenerative capacities of skeletal muscles may be regarded as a therapeutic option for sarcopenia and other muscle wasting diseases. Our previous studies have demonstrated that BIO101, a pharmaceutical grade 20-hydroxyecdysone, increases protein synthesis through the activation of MAS receptor involved in the protective arm of renin-angiotensin-aldosterone system. The purpose of the present study was to assess the anabolic and pro-differentiating properties of BIO101 on C2C12 muscle cells in vitro and to investigate its effects on adult and old mice models in vivo. METHODS: The effects of BIO101 on C2C12 differentiation were assessed using myogenic transcription factors and protein expression of major kinases of AKT/mTOR pathway by Western blot. The in vivo effects of BIO101 have been investigated in BIO101 orally-treated (50 mg/kg/day) adult mice (3 months) for 28 days. To demonstrate potential beneficial effect of BIO101 treatment in a sarcopenic mouse model, we use orally treated 22-month-old C57Bl6/J mice, for 14 weeks with vehicle or BIO101. Mice body and muscle weight were recorded. Physical performances were assessed using running capacity and muscle contractility tests. RESULTS: Anabolic properties of BIO101 were confirmed by the rapid activation of AKT/mTOR, leading to an increase of C2C12 myotubes diameters (+26%, P < 0.001). Pro-differentiating effects of BIO101 on C2C12 myoblasts were revealed by increased expression of muscle-specific differentiation transcription factors (MyoD, myogenin), resulting in increased fusion index and number of nuclei per myotube (+39% and +53%, respectively, at day 6). These effects of BIO101 were like those of angiotensin (1-7) and were abolished with the use of A779, a MAS receptor specific antagonist. Chronic BIO101 oral treatment induced AKT/mTOR activation and anabolic effects accompanied with improved physical performances in adult and old animals (maximal running distance and maximal running velocity). CONCLUSIONS: Our data suggest beneficial anabolic and pro-differentiating effects of BIO101 rendering BIO101 a potent drug candidate for treating sarcopenia and possibly other muscle wasting disorders.


Assuntos
Doenças Musculares , Sarcopenia , Camundongos , Animais , Sarcopenia/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Atrofia Muscular/patologia , Serina-Treonina Quinases TOR/metabolismo , Mioblastos/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologia
2.
J Mol Endocrinol ; 68(2): 77-87, 2021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34825653

RESUMO

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysteroid receptors (EcR/RXR complex) and at least one membrane GPCR receptor (DopEcR). It also displays numerous pharmacological effects in mammals, where its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERß receptor. The goal of this study was to better understand 20E mechanism of action in mammals. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) were used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with angiotensin(1-7), the endogenous ligand of MAS. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using siRNA or pharmacological inhibitors. 17ß-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin(1-7) antagonists. A mechanism involving cooperation between the MAS receptor and a membrane-bound palmitoylated estrogen receptor is proposed. The possibility to activate the MAS receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and, indeed, the proposed mechanism may explain the close similarity between the effects of angiotensin(1-7) and 20E. Our findings open up many possible therapeutic developments involving stimulation of the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.


Assuntos
Ecdisterona/metabolismo , Proto-Oncogene Mas/metabolismo , Sistema Renina-Angiotensina , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ecdisterona/química , Ecdisterona/farmacologia , Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Ligação Proteica , Proto-Oncogene Mas/agonistas , Proto-Oncogene Mas/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Esteroides/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos
3.
Pacing Clin Electrophysiol ; 43(2): 223-233, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31876292

RESUMO

AIM: To develop an algorithm for optimization of rate-adaptive pacing settings in heart failure patients with preserved ejection fraction (HFpEF) and permanent cardiac pacing. METHODS: This is a prospective randomized controlled study. A total of 54 patients with HFpEF, permanent atrial fibrillation (AF), and VVIR pacing were randomized to an intervention group with optimization of rate-adaptation parameters by using cardiopulmonary exercise testing (CPET) and pacemaker stress echocardiography (PASE), and to a control group with conventional programming. CPET, 6-min walk test (6-mwt), echocardiography (echo), Duke Activity Status Index (DASI), and Minnesota questionnaire (MLHFQ) were performed at baseline and after 3 months. PASE was used to exclude exercise-induced ischemia and to determine safe upper sensor rate. Pacing parameters were corrected to achieve optimal heart rate increments of 3-6 bpm for 1 mL/min/kg of VO2 (oxygen uptake). RESULTS: After 3 months, the intervention group demonstrated significant improvement of VO2 peak by 1.64 ± 1.6 mL/min/kg, anaerobic threshold by 1.33 ± 1.3 mL/min/kg, exercise time by 170 ± 98 s, 6-mwt distance by 75 ± 63 m (P < .0001 for all), DASI by 5.23 points (P = .009), MLHFQ-score (reduction by 9 points, P < .0001), and echo parameters (decrease in LA volume from 108 (84; 132) to 95 (85; 130) mL, P = .026; E/e' from 11.7 ± 3.2 to 10.4 ± 2.9, P = .025; systolic pulmonary artery pressure (SPAP) from 44 ± 14 to 39 ± 12 mm Hg, P = .001) compared to the control group. CONCLUSION: An algorithm incorporating CPET and PASE for optimal programming of rate-adaptation parameters is a valuable tool to improve exercise capacity in HFpEF patients with permanent AF and VVIR pacing who remain exercise intolerant after conventional programming.


Assuntos
Algoritmos , Estimulação Cardíaca Artificial/métodos , Tolerância ao Exercício/fisiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Idoso , Ecocardiografia , Teste de Esforço , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Estudos Prospectivos , Volume Sistólico , Inquéritos e Questionários , Teste de Caminhada
4.
Oncotarget ; 7(25): 38467-86, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27509260

RESUMO

Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Everolimo/farmacologia , Indóis/farmacologia , Neoplasias Renais/tratamento farmacológico , Pirróis/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Axitinibe , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/farmacologia , Indazóis/farmacologia , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Distribuição Aleatória , Sunitinibe , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Oncotarget ; 6(25): 21614-27, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26057634

RESUMO

Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-ß receptor (TßR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-ß yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-ß signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Células Hep G2 , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Sorafenibe , Sunitinibe , Fator de Crescimento Transformador beta1/antagonistas & inibidores
6.
Eur J Cancer ; 50(14): 2463-77, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25042151

RESUMO

BACKGROUND: Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic ß-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor. METHODS: We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008. RESULTS: In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first. CONCLUSION: This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent.


Assuntos
Calixarenos/farmacologia , Neoplasias/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Galectina 1/antagonistas & inibidores , Células HT29 , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Front Chem ; 2: 20, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24822174

RESUMO

Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.

8.
Eur J Med Chem ; 81: 181-91, 2014 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-24836070

RESUMO

A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HT29 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
9.
Eur J Med Chem ; 74: 41-9, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24445311

RESUMO

High-throughput screening (HTS) hit 1 was previously identified as an inhibitor of the Akt/mTOR (Akt/mammalian target of rapamycin) signaling, which is a major target in oncology. The cytotoxicity of 1 was determined on a panel of human cancer cells lines with an IC50 comprised between 30 and 140 µM. Subsequent structure--activity relationship (SAR) studies led us to the identification of compounds that displayed an enhanced cytotoxicity. We demonstrated also that these molecules directly bind to mTOR complex 1 (mTORC1) and inhibit its kinase activity.


Assuntos
Benzofuranos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Benzofuranos/química , Linhagem Celular Tumoral , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
10.
Cancer Treat Rev ; 40(2): 307-19, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23953240

RESUMO

Galectins belong to a family of carbohydrate-binding proteins with an affinity for ß-galactosides. Galectin-1 is differentially expressed by various normal and pathologic tissues and displays a wide range of biological activities. In oncology, galectin-1 plays a pivotal role in tumor growth and in the multistep process of invasion, angiogenesis, and metastasis. Evidence indicates that galectin-1 exerts a variety of functions at different steps of tumor progression. Moreover, it has been demonstrated that galectin-1 cellular localization and galectin-1 binding partners depend on tumor localization and stage. Recently, galectin-1 overexpression has been extensively documented in several tumor types and/or in the stroma of cancer cells. Its expression is thought to reflect tumor aggressiveness in several tumor types. Galectin-1 has been identified as a promising drug target using synthetic and natural inhibitors. Preclinical data suggest that galectin-1 inhibition may lead to direct antiproliferative effects in cancer cells as well as antiangiogenic effects in tumors. We provide an up-to-date overview of available data on the role of galectin-1 in different molecular and biochemical pathways involved in human malignancies. One of the major challenges faced in targeting galectin-1 is the translation of current knowledge into the design and development of effective galectin-1 inhibitors in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Galectina 1/antagonistas & inibidores , Galectina 1/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/uso terapêutico , Calixarenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/prevenção & controle , Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tiogalactosídeos/farmacologia , Regulação para Cima
11.
Mar Drugs ; 11(3): 944-59, 2013 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-23519149

RESUMO

Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 µM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings.


Assuntos
Antineoplásicos/farmacologia , Depsipeptídeos/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Depsipeptídeos/administração & dosagem , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , RNA Mensageiro/metabolismo , Receptor Cross-Talk , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo
12.
Cancer Chemother Pharmacol ; 71(5): 1297-307, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23479136

RESUMO

PURPOSE: To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib. METHODS: Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1-20 µM) and second-generation drugs (0.03-20.0 µM) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells. RESULTS: In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (≥1 µM) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, ≥1 µM rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations >0.03 µM in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets. CONCLUSIONS: Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Antineoplásicos/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Everolimo , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Indóis/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Complexos Multiproteicos/antagonistas & inibidores , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirróis/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Sorafenibe , Sunitinibe
13.
Head Neck ; 35(12): 1819-28, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23468253

RESUMO

The human chemokine system includes approximately 48 chemokines and 19 chemokine receptors. The CXCL12/CXCR4 system is one of the most frequently studied that is also found overexpressed in a large variety of tumors. The CXCL12/CXCR4 axis has been increasingly identified as an important target in cancer growth, metastasis, relapse, and resistance to therapy. In this review, we highlight current knowledge of the molecular mechanisms involving chemokines CXCL12/CXCR4 and their consequences in head and neck squamous cell carcinoma (HNSCC). Overexpression of CXCL12/CXCR4 in HNSCC appears to activate cellular functions, including motility, invasion, and metastatic processes. Current findings suggest that CXCR4 and epithelial-mesenchymal transition markers are associated with tumor aggressiveness and a poor prognosis, and may be suitable biomarkers for head and neck tumors with high metastatic potential. Furthermore, knowledge of the role of CXCR4 in HNSCC could influence the development of new targeted therapies for treatment, aimed at improving the prognosis of this disease.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Quimiocina CXCL12/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Receptores CXCR4/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/patologia , Adesão Celular , Movimento Celular , Avaliação Pré-Clínica de Medicamentos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controle , Neovascularização Patológica/metabolismo , Prognóstico , Receptores CXCR4/antagonistas & inibidores
14.
Target Oncol ; 7(3): 173-81, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22923165

RESUMO

Management of advanced pancreatic neuroendocrine tumors (PNETs) is challenging. Chemotherapy has remained for decades the only validated therapeutic option, with debated efficacy. Recently, data from two large placebo-controlled phase III trials have demonstrated that targeted therapies directed against receptor of vascular endothelial growth factor (sunitinib) and mammalian target of rapamycin (mTOR) (everolimus) produced clinically significant improvement in patients with advanced PNETs, resulting in a doubling of progression free survival and leading to their FDA approval. However, as more patients have been treated following the approval of those drugs, reports of early progression, and tumor regrowth following initial responses strongly suggested that primary and acquired resistances may limit the efficacy of targeted therapies in PNETs. In this review, we aim to summarize the current knowledge about primary and acquired resistance to targeted therapies, i.e., antiangiogenic agents and mTOR inhibitors, using data available from preclinical and clinical studies in various malignancies. Herein, we also describe how these general mechanisms of resistance may emerge in PNETs in patients treated with sunitinib and everolimus. Overcoming such resistances is likely to be the next challenge for clinicians in advanced PNETs management, warranting seeking for new anticancer strategies.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Etoposídeo/farmacologia , Everolimo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Indóis/uso terapêutico , Oncologia/métodos , Pirróis/uso terapêutico , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sunitinibe , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Oral Oncol ; 48(12): 1263-71, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22776129

RESUMO

OBJECTIVE: The aim of this study was to evaluate the expression and the prognostic value of chemokine receptor 4 (CXCR4), its cognate ligand the CXCL12, and markers of epithelial-to-mesenchymal transition (EMT) in squamous cell carcinoma (SCC) of the mobile tongue. PATIENTS AND METHODS: Patients with primary SCC of the mobile tongue who underwent surgery in our center were screened retrospectively. Patients without prior treatment, who had pre-surgery TNM staging and available tumor samples, were eligible. Protein expression of CXCL12, CXCR4, CA9, E-cadherin, and vimentin was determined by immunohistochemical staining, scored, and correlated with clinical and pathological parameters and overall survival. Multivariate and Cox proportional hazards analyses were performed. RESULTS: Among 160 patients treated and screened, 47 were analyzed. CXCR4 and CXCL12 expression was high in tumor cells. CXCR4 expression in primary tumor samples was significantly higher in patients with high-grade tumors, lymph node metastases, and microscopic nerve invasion (p ≤ 0.05). There was a non-significant trend towards a correlation between high CXCL12 expression and pathologic tumor stage (p=0.07). Tumors with high CXCR4 expression correlated with poor overall survival (hazard ratio=3.6, 95% confidence interval 1.3-9.7; p=0.011), notably in the CXCR4(high)/vimentin-positive subgroup. Vimentin-positive tumors, characterizing EMT, were associated with lower survival (hazard ratio=4.5, 95% confidence interval 1.6-12.3; p=0.0086). Multivariate analysis confirmed vimentin (but not CXCR4) expression as an independent prognostic factor of poor overall survival (p=0.016). CONCLUSION: Our results suggest that CXCR4 is a marker of tumor aggressiveness and vimentin is an important and independent prognostic factor in patients with SCC of the mobile tongue.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal , Receptores CXCR4/metabolismo , Neoplasias da Língua/metabolismo , Carcinoma de Células Escamosas/patologia , Humanos , Imuno-Histoquímica , Prognóstico , Estudos Retrospectivos , Neoplasias da Língua/patologia
16.
J Med Chem ; 55(11): 5121-9, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22575017

RESUMO

Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, (15)N-(1)H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118.


Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Metabolismo dos Carboidratos , Galectina 1/metabolismo , Testes de Aglutinação , Regulação Alostérica , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Citometria de Fluxo , Galectina 1/antagonistas & inibidores , Galectina 1/genética , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Modelos Moleculares , Ligação Proteica
17.
Mol Cancer Ther ; 10(9): 1709-19, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21750216

RESUMO

Pyriplatin, cis-diammine(pyridine)chloroplatinum(II), a platinum-based antitumor drug candidate, is a cationic compound with anticancer properties in mice and is a substrate for organic cation transporters that facilitate oxaliplatin uptake. Unlike cisplatin and oxaliplatin, which form DNA cross-links, pyriplatin binds DNA in a monofunctional manner. The antiproliferative effects of pyriplatin, alone and in combination with known anticancer drugs (paclitaxel, gemcitabine, SN38, cisplatin, and 5-fluorouracil), were evaluated in a panel of epithelial cancer cell lines, with direct comparison to cisplatin and oxaliplatin. The effects of pyriplatin on gene expression and platinum-DNA adduct formation were also investigated. Pyriplatin exhibited cytotoxic effects against human cell lines after 24 hours (IC(50) = 171-443 µmol/L), with maximum cytotoxicity in HOP-62 non-small cell lung cancer cells after 72 hours (IC(50) = 24 µmol/L). Pyriplatin caused a G(2)-M cell cycle block similar to that induced by cisplatin and oxaliplatin. Induction of apoptotsis and DNA damage response was supported by Annexin-V analysis and detection of phosphorylated Chk2 and H2AX. Treatment with pyriplatin increased CDKN1/p21 and decreased ERCC1 mRNA expression. On a platinum-per-nucleotide basis, pyriplatin-DNA adducts are less cytotoxic than those of cisplatin and oxaliplatin. The mRNA levels of genes implicated in drug transport and DNA damage repair, including GSTP1 and MSH2, correlate with pyriplatin cellular activity in the panel of cell lines. Synergy occurred for combinations of pyriplatin with paclitaxel. Because its spectrum of activity differs significantly from those of cisplatin or oxaliplatin, pyriplatin is a lead compound for developing novel drug candidates with cytotoxicity profiles unlike those of drugs currently in use.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Adutos de DNA/metabolismo , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA Mensageiro
18.
Target Oncol ; 6(2): 119-24, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21533544

RESUMO

In the quest for personalized medicine, only a few biological parameters are routinely used to select patients prior to the initiation of anticancer targeted therapies, including mTOR inhibitors. Identifying biological factors that may predict efficacy or resistance to mTOR inhibitors represents an important challenge since rapalogs may exert antitumor effects through multiple mechanisms of action. Despite the fact that no such a factor is currently available, several molecular patterns are emerging, correlating with sensitivity and/or resistance to rapalogs. While activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, overexpression of cyclin D1, and functional apoptosis seem to sensitize tumor cells to rapalogs, Bcl2 overexpression or KRAS mutations are reported to be associated with resistance to mTOR inhibitors in several preclinical models. Translational research aimed at validating those parameters in clinical trials is ongoing.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/metabolismo
19.
Expert Opin Investig Drugs ; 19(8): 919-30, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20569080

RESUMO

IMPORTANCE OF THE FIELD: Contrasting with the broad activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) survival pathway in most cancer, activity of rapalogues appears to be restricted to a few tumor types. AREAS COVERED IN THIS REVIEW: The analysis of molecular activity of the PI3K/AKT/mTOR pathway and resistance mechanisms of rapamycin and rapalogues led to the development of several inhibitory molecules. WHAT THE READER WILL GAIN: New anticancer agents including PI3K inhibitors, dual PI3K/mTOR inhibitors, specific mTOR inhibitors, and AKT inhibitors may have direct inhibitory effects on targets by competing with ATP or may be non-ATP-competitive allosteric modulators of protein functions. In addition, another way of blocking the abnormal activation of the PI3K/AKT/mTOR pathway may be achieved by using HSP90 inhibitors. In this paper we review novel drugs inhibiting the mTOR signaling pathway. TAKE HOME MESSAGE: Several trials are ongoing with novel drugs targeting key kinases involved in the mTOR pathway. Benchmarking those agents with rapalogues in rationally designed preclinical models and conceiving clinical trials in everolimus/temsirolimus-sensitive tumor types may help to identify drugs with a real clinical potential. Understanding mechanisms associated with primary and acquired resistance to rapalogues may help to enlarge indications and provide a rationale for designing combinations that will minimize the risk of developing resistance to rapalogues.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sirolimo/uso terapêutico , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/análogos & derivados , Sirolimo/metabolismo , Serina-Treonina Quinases TOR , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
20.
Mol Cancer Ther ; 9(5): 1308-17, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20406951

RESUMO

Identifying molecular factors of sensitivity and resistance of cancer cells to enzastaurin, a drug inhibiting protein kinase C (PKC) beta, remains a major challenge to improve its clinical development. Investigating the cellular effects of enzastaurin in a panel of 20 human cancer cell lines, we found that most cells displaying oncogenic K-Ras mutations also display resistance to enzastaurin. Wild-type (WT) K-Ras cancer cells displaying high sensitivity to enzastaurin also expressed high mRNA levels of epithelial markers, such as E-cadherin (CDH1), and low mRNA expressions of mesenchymal markers, such as vimentin, N-cadherin (CDH2), and other genes frequently expressed in mesenchymal transition such as ZEB1, TWIST, SLUG, SNAIL, and TGFbeta. WT K-Ras enzastaurin-resistant cells also expressed high levels of mesenchymal markers. Based on this observation, the effects of enzastaurin were investigated in epithelial colon COLO205-S cells that expressed WT Ras/Raf and its derived COLO205-R mesenchymal counterpart selected for resistance to most PKC modulators and displaying oncogenic K-Ras (G13D/exon 2). In COLO205-S cells, inhibition of phosphorylated PKCbeta led to the inactivation of AKT and glycogen synthase kinase 3beta and was associated with apoptosis without significant effect on cell cycle progression. In COLO205-R cells, enzastaurin induced mainly necrosis at high concentrations. In COLO205-R cells, a strong activation of extracellular signal-regulated kinase 1/2 possibly due to oncogenic K-Ras was predominantly associated with transcription of potent antiapoptotic genes, such as BCL2, GADD45B, and CDKN1A, as well as the multidrug resistance gene ABCB1. From this study, colon cancer cells undergoing apoptosis under enzastaurin exposure seem to frequently express a WT Ras and an epithelial phenotype.


Assuntos
Neoplasias do Colo/patologia , Células Epiteliais/patologia , Genes ras/genética , Indóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/patologia , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Indóis/uso terapêutico , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/patologia , Proteína Quinase C beta , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Células Tumorais Cultivadas
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