RESUMO
INTRODUCTION: Autophagy is an intracellular process of self-digestion involving the lysosomal degradation of cytoplasmic organelles and macromolecules. It occurs at low basal levels to perform housekeeping functions and is dramatically augmented upon nutrient depletion or exposure to other stresses, thus maintaining cellular homeostasis and energy balance and providing cytoprotective responses to adverse conditions. Mounting evidence that autophagy malfunction contributes to the pathogenesis of diverse human diseases has stimulated efforts to identify pharmacological agents that modulate autophagy in potentially beneficial ways. Here, we review the progresses accomplished toward this goal in recent years, as reflected by the patent literature. AREAS COVERED: Patent applications published from 2008 to mid-2012 that pertain to the pharmacological modulation of autophagy are reviewed and their potential therapeutic utilities are discussed. EXPERT OPINION: Of 40 patents related to autophagy, 21 claim novel enhancers or inhibitors of autophagy. One of the most promising applications of these compounds concerns cancer therapy, a few of them being already considered for clinical evaluation. Further work is, however, needed to identify compounds that target unique molecular effectors/regulators of autophagy to selectively modulate its various stages in different tissues and to design therapeutic interventions applicable to a broad variety of dysfunctional autophagy-associated disorders.
Assuntos
Autofagia/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Animais , Homeostase , Humanos , Lisossomos/metabolismo , Organelas/metabolismo , Patentes como AssuntoRESUMO
Radiotherapy (RT) allows for tumor control through the cytotoxic action of ionizing radiation (IR). Although modern technologies permit precise IR delivery to the tumor mass while minimizing exposure of surrounding healthy tissues, the efficacy of RT remains limited by the intrinsic or acquired radioresistance of many tumors. There is thus an ongoing search for agents that augment the sensitivity of tumor cells to IR cytotoxicity, with recent interest in targeting components of signaling pathways involved in tumor growth and radioresistance. Here, we review the evidence suggesting that disabling one of these components, the mechanistic target of rapamycin (mTOR) kinase, may enhance RT efficacy. This molecule constitutes the catalytic subunit of the mTORC1 and mTORC2 protein complexes, which regulate cell growth and other processes implicated in tumorigenesis. Much work has focused on mTORC1 because it is selectively blocked by the microbial product rapamycin and its analogs (collectively designated rapamycins) that are approved for cancer treatment, and is frequently hyperactivated in malignant cells. In several, but not all human cancer cell lines, rapamycins increased IR cytotoxicity in vitro, apparently through multiple mechanisms, including the promotion of autophagic cell death. Rapamycins also potentiated fractionated RT in tumor xenograft models, in part by suppressing tumor angiogenesis. Synthetic kinase inhibitors that simultaneously target PI3K and both mTOR complexes also enhanced RT in vitro and in vivo, but with greater efficiency than rapamycins. These encouraging data have led to early clinical trials of rapamycins and catalytic mTOR inhibitors combined with RT in various cancers.
Assuntos
Neoplasias/metabolismo , Neoplasias/radioterapia , Radiossensibilizantes/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sirolimo/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Citocinas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Animais , Citocinas/imunologia , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/fisiopatologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/fisiopatologia , Transdução de Sinais/imunologiaRESUMO
Protein Design Labs is developing fontolizumab, a humanized anti-interferon gamma monoclonal antibody, for the potential treatment of autoimmune diseases. By February 2003, the company was actively seeking to outlicense the development and commercialization rights to fontolizumab outside of the US and Canada.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Interferon gama/antagonistas & inibidores , Interferon gama/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais Humanizados , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desenho de Fármacos , Indústria Farmacêutica/organização & administração , Humanos , Interferon gama/químicaRESUMO
Mitsubishi Pharma Corp and Novartis AG are developing fingolimod, an orally active immunosuppressant affecting lymphocyte re-circulation, for the potential prevention of transplant rejection and the treatment of autoimmune diseases, including multiple sclerosis. Fingolimodis a synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate receptor agonist.
Assuntos
Imunossupressores/uso terapêutico , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Administração Oral , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos/métodos , Cloridrato de Fingolimode , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Metanálise como Assunto , Propilenoglicóis/administração & dosagem , Propilenoglicóis/química , Esfingosina/administração & dosagem , Esfingosina/química , Esfingosina/uso terapêuticoRESUMO
Bristol-Myers Squibb is developing the fusion protein abatacept for the potential treatment of various immunological disorders, including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. Abatacept is undergoing phase III clinical trials.
Assuntos
Antígenos de Diferenciação/administração & dosagem , Antígenos de Diferenciação/metabolismo , Doenças Autoimunes/tratamento farmacológico , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Ativação Linfocitária/efeitos dos fármacos , Antígenos CD , Antígenos de Diferenciação/genética , Doenças Autoimunes/imunologia , Antígeno B7-1/imunologia , Antígenos CD28/imunologia , Antígeno CTLA-4 , Ensaios Clínicos como Assunto , Avaliação de Medicamentos , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/imunologiaRESUMO
ISAtx-247 is a ciclosporin A analog under development by Isotechnika and Roche as an immunosuppressant for the potential prevention of organ rejection after transplantation, and for the potential treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis and type 1 diabetes. A phase II renal transplantation study had been completed by June 2003.
Assuntos
Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Inibidores de Calcineurina , Ensaios Clínicos como Assunto , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Diabetes Mellitus Tipo 1/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Transplante de Rim/imunologia , Ativação Linfocitária/efeitos dos fármacos , Psoríase/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
CXCR6, the receptor for the membrane-anchored chemokine, CXCL16, is expressed on a subset of CCR5-bearing memory T cells, and may play a role in recruiting these cells to sites of inflammation. Here, we set out to determine the effect of T cell activation on CXCR6 expression. Highly purified human peripheral blood T cells were cultured for 7-8 days in presence of IL-2 (400 U/ml) to enhance CXCR6 expression. Overnight stimulation with anti-CD3 mAb+anti-CD28 mAb, which resulted in CD69 induction and cytokine (IL-2 and IFN-gamma) production, reduced cell surface expression of CXCR6 by 85% and that of CCR5 by 76%. The Ca(2+) ionophore, ionomycin (125-500 ng/ml), also markedly diminished CXCR6 expression (85%), but without inducing CD69 expression or cytokine production, and reduced CCR5 expression by only 40%. In contrast, the phorbol esters, PdBu or PMA had little effect on CXCR6 expression (23% reduction) but induced CD69 expression and caused a profound down-regulation (92%) of CCR5 expression. Moreover, CCR7, whose expression was low on CXCR6(+) T cells, was little affected by any of these modes of activation. The down-regulation of CXCR6 expression induced by CD3/CD28 activation was blocked by the broad kinase inhibitor, staurosporine, and by the src kinase inhibitor, PP2, but not by the MEK1 inhibitor, U0106. Most interestingly, the calcineurin inhibitor, FK506, consistently inhibited CD3/CD28-induced CXCR6 down-regulation. FK506 also blocked the decrease of CXCR6 expression caused by ionomycin, whereas staurosporine or PP2 had no effect on this decrease. Altogether, these data indicate that CXCR6 expression is down-regulated, independent of CCR5 or CD69 expression and of cytokine induction, by T cell activation signals that involve predominantly the Ca(2+)-dependent calcineurin pathway.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Calcineurina/imunologia , Ativação Linfocitária/imunologia , Receptores de Citocinas/biossíntese , Receptores Acoplados a Proteínas G , Receptores Virais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Butadienos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Citocinas/imunologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Citometria de Fluxo , Humanos , Imunossupressores , Interleucina-2/imunologia , Lectinas Tipo C , Nitrilas/farmacologia , Pirimidinas/farmacologia , Receptores CCR7 , Receptores CXCR6 , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Receptores de Citocinas/metabolismo , Transdução de Sinais/imunologia , Estaurosporina/farmacologia , Tacrolimo/farmacologiaAssuntos
Imunossupressores , Ativação Linfocitária/efeitos dos fármacos , Depleção Linfocítica , Linfócitos T/efeitos dos fármacos , Tolerância ao Transplante/imunologia , Ensaios Clínicos como Assunto , Epitopos de Linfócito T/efeitos dos fármacos , Epitopos de Linfócito T/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ativação Linfocitária/imunologia , Estrutura Molecular , Linfócitos T/imunologia , Tolerância ao Transplante/efeitos dos fármacosRESUMO
IDEC, in collaboration with Eisai, is developing IDEC-131 (E6040), a humanized monoclonal antibody (mAb) against CD154, the ligand for CD40 also called CD40L or gp39, for the potential treatment of several autoimmune diseases. IDEC-131 is based on technology that IDEC licensed from Dartmouth Medical School where researchers demonstrated the biological effects of the anti-CD154 antibody in animal models of autoimmunity. In January 2001, phase II trials in psoriasis and idiopathic thrombocytopenic purpura (ITP) were initiated. By january 2002, a phase II trial in Crohn's disease was also ongoing. A pilot, multicenter, multiple-dose phase I trial in moderate-to-severe psoriasis was initiated in January 2001. This trial was ongoing in January 2002. IDEC, in collaboration with Dartmouth Medical School had also initiated a phase I trial in multiple sclerosis by March 1999. IDEC-131 was also previously being developed for systemic lupus ezythematosus (SLE), although no further development for this indication has been reported since the disclosure of disappointing phase II results in April 2000. Analysts at Morgan Stanley predicted in February 2002, that the product would be launched in 2005, with sales of US $25 million, rising to US $75 million in 2006.
Assuntos
Anticorpos Monoclonais/farmacologia , Imunossupressores/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Doenças Autoimunes/metabolismo , Doenças Autoimunes/terapia , Ligante de CD40/imunologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Injeções Intravenosas , Ensaios Clínicos Controlados Aleatórios como Assunto , Dermatopatias/metabolismo , Dermatopatias/terapia , Relação Estrutura-AtividadeRESUMO
CAMPATH (CAMPATH-1H, alemtuzumab, MabCAMPATH), is a lymphocyte-depleting humanized monoclonal antibody that was recently approved in the USA and Europe for the treatment of chronic lymphocytic leukemia (CLL). It targets CD52--a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes and on a large proportion of lymphoid cell malignancies--but not on hematopoietic progenitor cells. CAMPATH was shown to be effective against CLL refractory to chemotherapy with an acceptable toxicity profile. CAMPATH is also active against T-cell prolymphocytic leukemia and has been extensively used to prevent graft-versus-host disease associated with bone marrow transplantation. CAMPATH is owned by ILEX Pharmaceuticals LP and distributed by Schering AG and its US affiliate Berlex Laboratories.