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1.
Int J Med Sci ; 18(13): 2799-2813, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220308

RESUMO

Intervertebral disc (IVD) degeneration (IDD) is a multifactorial pathological process associated with low back pain (LBP). The pathogenesis is complicated, and the main pathological changes are IVD cell apoptosis and extracellular matrix (ECM) degradation. Apoptotic cell loss leads to ECM degradation, which plays an essential role in IDD pathogenesis. Apoptosis regulation may be a potential attractive therapeutic strategy for IDD. Previous studies have shown that IVD cell apoptosis is mainly induced by the death receptor pathway, mitochondrial pathway, and endoplasmic reticulum stress (ERS) pathway. This article mainly summarizes the factors that induce IDD and apoptosis, the relationship between the three apoptotic pathways and IDD, and potential therapeutic strategies. Preliminary animal and cell experiments show that targeting apoptotic pathway genes or drug inhibition can effectively inhibit IVD cell apoptosis and slow IDD progression. Targeted apoptotic pathway inhibition may be an effective strategy to alleviate IDD at the gene level. This manuscript provides new insights and ideas for IDD therapy.


Assuntos
Degeneração do Disco Intervertebral/tratamento farmacológico , Disco Intervertebral/patologia , Dor Lombar/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Disco Intervertebral/citologia , Disco Intervertebral/efeitos dos fármacos , Degeneração do Disco Intervertebral/complicações , Dor Lombar/etiologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular/métodos , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Nephrol Dial Transplant ; 36(9): 1664-1674, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32941608

RESUMO

BACKGROUND: Immune checkpoints inhibitors have transformed the prognosis of advanced melanoma but are associated with immune-related adverse events (irAEs). We evaluated the incidence, risk factors and causes of acute kidney injury (AKI) in a monocentric real-life cohort of patients treated with anti-programmed death receptor-1 (anti-PD1) antibodies for advanced melanoma. METHODS: Retrospective collection of medical charts and comprehensive analysis of lab results from patients treated with nivolumab or pembrolizumab for advanced melanoma between 2014 and 2018 was carried out. AKI was defined by Kidney Disease Improving Global Outcomes criteria, and causes were determined by chart review. Overall survival, survival without AKI and impact of AKI on survival were analysed. Risk factors for death and for AKI were identified. RESULTS: Two hundred and thirty-nine patients were included. Forty-one (17%) had at least one episode of AKI. Independent risk factors for AKI were treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), pre-existing chronic kidney disease (CKD) and cumulated doses of anti-PD1. The main cause of AKI was prerenal, and only eight patients (3.3%) developed acute interstitial nephritis; 8% of patients developed CKD. The median overall survival was 13.4 months and was not affected by AKI. In multivariate analysis, the overall mortality was lower in overweight and obese patients and higher in patients treated with proton-pump inhibitors (PPI) or corticosteroids. CONCLUSIONS: AKI is common in patients treated with anti-PD1 for advanced melanoma but is mostly prerenal and favoured by the use of RAASi; renal irAE is rare. PPI and corticosteroids were associated with poor survival in this population, while overweight/obesity was protective.


Assuntos
Injúria Renal Aguda , Anticorpos Monoclonais Humanizados , Melanoma , Nivolumabe , Injúria Renal Aguda/induzido quimicamente , Anticorpos Monoclonais Humanizados/efeitos adversos , Humanos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Receptores de Morte Celular/antagonistas & inibidores , Estudos Retrospectivos
3.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G551-G561, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30735454

RESUMO

Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cytokines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat. NEW & NOTEWORTHY The present study demonstrated that a chemical inhibitor necrostatin-1 (Nec-1) or receptor-interacting protein kinase(RIP1) knock down targeted at necroptosis inhibition accelerated liver injury of following sepsis. For fundamental research, these results warrant further investigation of the potential link between Nec-1 administration and the cellular apoptosis following sepsis induced liver injury. For applied research, these results suggest the potential harmful effect of Nec-1 on future sepsis treatment.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Imidazóis/farmacocinética , Indóis/farmacocinética , Hepatopatias , Necroptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sepse , Animais , Modelos Animais de Doenças , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Hepatopatias/fisiopatologia , Camundongos , Necroptose/efeitos dos fármacos , Necroptose/fisiologia , Proteínas Quinases/metabolismo , Ratos , Receptores de Morte Celular/antagonistas & inibidores , Sepse/complicações , Sepse/metabolismo , Fatores de Tempo
4.
Arch Pharm Res ; 42(1): 76-87, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30610617

RESUMO

Programmed cell death is critical to the physiological function of multi-cellular organisms, controlling development, immunity, inflammation, and cancer progression. Death receptor (DR)-mediated regulation of a protease functions as a second messenger to initiate a death signal cascade to induce apoptosis or necroptosis. Recently, it has become clear that post-translational modifications (PTMs) of signaling components in the DR complex are highly complex, temporally controlled, and tightly regulated, and play an important role in cell death signaling. This review focuses on the molecular mechanisms and pathophysiological consequences of PTMs on the formation of the DR signaling complex, especially with respect to tumor necrosis factor receptor 1 (TNFR1). Furthermore, characterization of the role of PTMs in spatially different TNFR1 complexes (complexes I and II), especially with respect to the role of ubiquitination and phosphorylation of receptor interacting protein 1 (RIP1) in programmed cell death in cancer cells, will be reviewed. By integrating recently gained insight of the functional importance of PTMs in complex I or II, this review discusses how the concerted action of PTMs results in life or death upon DR ligation. Finally, the emerging concept of a sequential cell death checkpoint by the PTMs of RIP1, which may reveal novel therapeutic opportunities for the treatment of some cancers, will be discussed.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Receptores de Morte Celular/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/genética
5.
Cell Death Differ ; 26(9): 1631-1645, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30442947

RESUMO

Different forms of regulated cell death-like apoptosis and necroptosis contribute to the pathophysiology of clinical conditions including ischemia-reperfusion injury, myocardial infarction, sepsis, and multiple sclerosis. In particular, the kinase activity of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) is crucial for cell fate in inflammation and cell death. However, despite its involvement in pathological conditions, no pharmacologic inhibitor of RIPK1-mediated cell death is currently in clinical use. Herein, we screened a collection of clinical compounds to assess their ability to modulate RIPK1-mediated cell death. Our small-scale screen identified the anti-epilepsy drug Phenhydan® as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan® blocked activation of necrosome formation/activation as well as death receptor-induced NF-κB signaling by influencing the membrane function of cells, such as lipid raft formation, thus exerting an inhibitory effect on pathophysiologic cell death processes. By targeting death receptor signaling, the already FDA-approved Phenhydan® may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death.


Assuntos
Apoptose/efeitos dos fármacos , Inflamação/tratamento farmacológico , Necroptose/efeitos dos fármacos , Fenitoína/farmacologia , Animais , Anticonvulsivantes/farmacologia , Apoptose/genética , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Células HT29 , Humanos , Inflamação/genética , Inflamação/patologia , Camundongos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/genética , Células NIH 3T3 , Necroptose/genética , Fenitoína/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/genética , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Sepse/tratamento farmacológico , Sepse/genética
6.
J Cell Physiol ; 233(10): 6538-6549, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29741789

RESUMO

Despite advances in the diagnosis and treatment of colorectal cancer (CRC), it remains a major cause of cancer related death globally. There are currently no chemotherapeutic agents that have been found to eradicate the disease without adverse effects. A defect in the death receptor signaling pathway is a feature of CRC. The ligand of these receptors belongs to the tumor necrosis factor family, and that are particularly expressed by cells of the immune system, and that induce apoptosis in a caspase dependent manner. The fact that malignant cells are particularly sensitive to these ligands, compared to normal cells, has led to work on the assessment of compounds that activate this pathway in the treatment of CRC. Phase I trials have shown that these death receptor agonists are safe. Phase II and III trials are currently investigating the efficacy of these therapeutic agents in the treatment of CRC. In this review, we describe the biochemical death receptor signaling pathway and its relationship to CRC. We also summarize the current clinical studies that are targeting this signaling pathway in CRC treatment.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Receptores de Morte Celular/genética , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Receptores de Morte Celular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
7.
Oncotarget ; 7(40): 65660-65668, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27582540

RESUMO

Epigallocatechin gallate (EGCG) is a major polyphenol in green tea. Recent studies have reported that EGCG can inhibit TRAIL-induced apoptosis and activate autophagic flux in cancer cells. However, the mechanism behind these processes is unclear. The present study found that EGCG prevents tumor cell death by antagonizing the TRAIL pathway and activating autophagy flux. Our results indicate that EGCG dose-dependently inhibits TRAIL-induced apoptosis and decreases the binding of death receptor 4 and 5 (DR4 and 5) to TRAIL. In addition, EGCG activates autophagy flux, which is involved in the inhibition of TRAIL cell death. We confirmed that the protective effect of EGCG can be reversed using genetic and pharmacological tools through re-sensitization to TRAIL. The inhibition of autophagy flux affects not only the re-sensitization of tumor cells to TRAIL, but also the restoration of death receptor proteins. This study demonstrates that EGCG inhibits TRAIL-induced apoptosis through the manipulation of autophagic flux and subsequent decrease in number of death receptors. On the basis of these results, we suggest further consideration of the use of autophagy activators such as EGCG in combination anti-tumor therapy with TRAIL.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Catequina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Receptores de Morte Celular/antagonistas & inibidores , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Anticarcinógenos/farmacologia , Catequina/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células Tumorais Cultivadas
8.
Semin Cell Dev Biol ; 39: 20-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25617598

RESUMO

Apoptosis is a form of programmed cell death that plays a critical role in the regulation of various physiological and pathophysiological processes. Since apoptosis is typically disturbed in human cancers, therapeutic targeting of apoptosis represents a promising avenue for the development of novel therapeutic approaches. This strategy is particularly relevant, since many currently used anticancer therapies utilize apoptosis signaling pathways to exert their antitumor activities. A better understanding of these signaling networks and their deregulation in human cancers is anticipated to open new perspectives for the development of apoptosis-targeted therapies for the treatment of cancer.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores de Morte Celular/antagonistas & inibidores , Animais , Humanos , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores
9.
Cell Death Dis ; 5: e1401, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25188511

RESUMO

Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Membrana/metabolismo , Neuroblastoma/patologia , Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/metabolismo , Animais , Antibacterianos/toxicidade , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Adesão Celular , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Doxiciclina/toxicidade , Feminino , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Proteína Proto-Oncogênica N-Myc , Metástase Neoplásica , Estadiamento de Neoplasias , Neuroblastoma/metabolismo , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Transplante Heterólogo , Tretinoína/farmacologia , Regulação para Cima/efeitos dos fármacos
10.
Clin Cancer Res ; 20(15): 3915-20, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24824309

RESUMO

Inhibitor of apoptosis (IAP) proteins are overexpressed in multiple human malignancies, an event that is associated with poor prognosis and treatment resistance. Therefore, IAP proteins represent relevant targets for therapeutic intervention. Second mitochondrial activator of caspases (Smac) is a mitochondrial protein that is released into the cytosol upon the induction of programmed cell death and promotes apoptosis by neutralizing IAP proteins. On the basis of this property, a variety of small-molecule inhibitors have been developed that mimic the binding domain of the native Smac protein to IAP proteins. Evaluation of these Smac mimetics in preclinical studies revealed that they particularly synergize together with agents that trigger the death receptor pathway of apoptosis. Such combinations might therefore be of special interest for being included in the ongoing evaluation of Smac mimetics in early clinical trials.


Assuntos
Materiais Biomiméticos/química , Proteínas Inibidoras de Apoptose/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Mitocondriais/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Oligopeptídeos/química , Receptores de Morte Celular/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/patologia , Prognóstico
11.
Cytokine Growth Factor Rev ; 25(2): 235-43, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24440054

RESUMO

Gastrointestinal bacterial pathogens such as enteropathogenic Escherichia coli, Salmonella and Shigella control inflammatory and apoptotic signaling in human intestinal cells to establish infection, replicate and disseminate to other hosts. These pathogens manipulate host cell signaling through the translocation of virulence effector proteins directly into the host cell cytoplasm, which then target various signaling pathways. Death receptors such as TNFR1, FAS and TRAIL-R induce signaling cascades that are crucial to the clearance of pathogens, and as such are major targets for inhibition by pathogens. This review focuses on what is known about how bacterial gut pathogens inhibit death receptor signaling to suppress inflammation and prevent apoptosis.


Assuntos
Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/imunologia , Apoptose/imunologia , Sistemas de Secreção Bacterianos/imunologia , Escherichia coli/imunologia , Humanos , Inflamação/imunologia , Microbiota/imunologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Salmonella/imunologia , Shigella/imunologia , Transdução de Sinais/imunologia
12.
Oncogene ; 32(2): 259-68, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22310289

RESUMO

Labdane diterpenoids have a broad spectrum of biological activities including antibacterial, antiviral and anti-inflammatory properties. However, little is known about their possible role in the apoptotic cell death machinery. Here, we report that hispanolone derivatives, a group of labdane diterpenoids, induce apoptosis in different tumor cell lines by activating caspase-8 with subsequent participation of mitochondrial signaling. Activation of caspase-8 by hispanolone derivatives was followed by a decrease in mitochondrial membrane potential, the release of apoptotic factors from mitochondria to the cytosol, and activation of caspases-9 and 3. Hispanolone derivatives also led to a time-dependent cleavage of Bid. Inhibition of caspase-8 abrogated these processes, suggesting that the death receptor pathway has a critical role in the apoptotic events induced by hispanolone derivatives. In addition, silencing death receptors with small interfering RNA s or pretreating cells with neutralizing antibodies to Fas ligand, tumor necrosis factor receptor 1 (TNF-R1), and TNF-α receptor 2 (TRAIL) inhibited diterpenoid-induced apoptosis, revealing it to be dependent on these death receptors. Interestingly, hispanolone derivatives had no effect on non-tumor cells. Consistently, in vivo bioluminescence imaging corroborates this antineoplasic effect, as hispanolone derivatives significantly decrease cancer growth in tumor xenograft assays. These data demostrate the antitumoral effects of hispanolone derivatives and provide relevant preclinical validation for the use of these compounds as potent therapeutic agents in cancer treatment.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Receptores de Morte Celular/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Apoptose/genética , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Proteína Ligante Fas/imunologia , Perfilação da Expressão Gênica , Humanos , Células Jurkat , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Interferência de RNA , RNA Interferente Pequeno , Receptores de Morte Celular/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais , Proteína de Domínio de Morte Associada a Receptor de TNF/genética , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo
13.
Anticancer Agents Med Chem ; 13(3): 433-55, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22721391

RESUMO

Apoptosis is a genetically in-built process whereby organisms remove unwanted cells. Apoptosis can serve as a regulatory and defense mechanism in the formation of the shape and size of the human body and also to eradicate surplus amount of cells. The regulation of apoptosis is relevant and differentiates between a normal cells of body and cancer cells by loss of control. Apoptosis being an intricate process regulated by much more than just a biological mechanism. The induction of the apoptosis manifests the control on the tumour size and number of tumour cells hence establishing the application of apoptotic inducers as vital components in the treatment of cancer. During apoptosis, cells die in a controlled and regulated fashion which makes apoptosis distinct from necrosis (uncontrolled cell death). Protein components and regulators for apoptosis signaling pathways can involve the mitochondria (intrinsic pathway) or signal through death receptors (extrinsic pathway). Many different drug and gene therapy approaches are being tested for initiating apoptosis. Resistance to apoptosis is considered a hallmark of cancer. Therapeutic approaches attempted to date include traditional small molecules, antisense oligonucleotides, monoclonal antibodies, recombinant proteins and several classes of chemical compounds discussed in this review. These compounds may serve as precursor molecules for more effective drugs, all aimed at developing clinically effective therapeutics, targeting key apoptosis regulatory mechanism. This review will discuss the current understanding of apoptosis induced by various chemical agents and highlighting the role of apoptosis inducing agents as emerging opportunities for cancer therapy.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/agonistas , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Receptores de Morte Celular/agonistas , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/genética , Receptores de Morte Celular/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia
14.
Cancer Biol Ther ; 13(7): 458-66, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22406997

RESUMO

The objective of the ONCODEATH consortium [EU Research Consortium "ONCODEATH" (2006-2010)] was to achieve sensitization of solid tumor cells to death receptor related therapies using rational mechanism-based drug combinations of targeted therapies. In this collaborative effort, during a period of 42 mo, cell and animal model systems of defined oncogenes were generated. Exploitation of generated knowledge and tools enabled the consortium to achieve the following research objectives: (1) elucidation of tumor components which confer sensitivity or resistance to TRAIL-induced cell death; (2) providing detailed knowledge on how small molecule Hsp90, Aurora, Choline kinase, BRAF inhibitors, DNA damaging agents, HDAC and DNMT inhibitors affect the intrinsic apoptotic amplification and execution machineries; (3) optimization of combined action of TRAIL with these therapeutics for optimum effects with minimum concentrations and toxicity in vivo. These findings provide mechanistic basis for a pharmacogenomic approach, which could be exploited further therapeutically, in order to reach novel personalized therapies for cancer patients.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Terapia de Alvo Molecular , Receptores de Morte Celular/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Humanos , Receptores de Morte Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Recent Pat Anticancer Drug Discov ; 6(3): 294-310, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21762072

RESUMO

The death receptors CD95, TRAILR1 and TRAILR2 induce cell death in many types of tumor cells. Activation of these receptors has received considerable interest due to its potential use in cancer therapy. In particular the observation that most primary cells are not or only barely TRAIL-sensitive resulted in the development of targeted therapy concepts that base on activation of the TRAIL death receptors by recombinant TRAIL or agonistic antibodies. Indeed, a variety of preclinical studies and several phase I and II clinical trials show that activation of TRAIL death receptors effectively induces apoptosis in cancer cells in vivo without therapy-limiting toxicity on normal cells. Primary tumor cells are often sparsely sensitive for TRAIL death receptor-mediated apoptosis or acquire resistance during therapy. Sensitization/resensitization of tumor cells by chemotherapeutic drugs or radiation can therefore be necessary for TRAIL-based therapies, but this involves the danger of triggering side effects related to the breakage of apoptosis resistance of non-transformed cells. Thus, there is a foreseeable need to develop optimized combination therapies or to locally restrict TRAIL receptor activation to fully exploit the antitumoral potential of TRAIL death receptors in the clinic. Although the high sensitivity of hepatocytes for CD95-mediated apoptosis prohibits therapies resulting in systemic activation of CD95, several studies have shown that this limitation can be overcome by ex vivo treatment regimes or by CD95 activating agonists with cell type-specific activity. This patent review is focused on the death receptor agonists currently under consideration in clinical trials, but also addresses the hurdles that have to be cleared to broaden and to improve the applicability of the currently used clinical concepts related to death receptor activation.


Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Receptor fas/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Humanos , Modelos Biológicos , Neoplasias/metabolismo , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Receptores de Morte Celular/fisiologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/química , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptor fas/química , Receptor fas/metabolismo , Receptor fas/fisiologia
16.
Curr Med Chem ; 17(25): 2713-28, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20586721

RESUMO

Considering that most currently available chemotherapeutic drugs work by inducing cell apoptosis, it is not surprising that many expectations in cancer research come from the therapeutic exploitation of the naturally occurring death pathways. Receptor mediated apoptosis depends upon the engagement of specific ligands with their respective membrane receptors and - within the frame of complex regulatory networks - modulates some key physiological and pathological processes such as lymphocyte survival, inflammation and infectious diseases. A pivotal observation was that some of these pathways may be over activated in cancer under particular circumstances, which opened the avenue for tumor-specific therapeutic interventions. Although one death-related ligand (e.g., tumor necrosis factor, TNF) is currently the basis of effective anticancer regimens in the clinical setting, the systemic toxicity is hampering its wide therapeutic exploitation. However, strategies to split the therapeutic from the toxic TNF activity are being devised. Furthermore, other death receptor pathways (e.g., Fas/FasL, TRAIL/TRAIL receptor) are being intensively investigated in order to therapeutically exploit their activity against cancer. This article summarizes the current knowledge on the molecular features of death receptor pathways that make them an attractive target for anticancer therapeutics. In addition, the results so far obtained in the clinical oncology setting as well as the issues to be faced while interfering with these pathways for therapeutic purposes will be overviewed.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptores de Morte Celular/antagonistas & inibidores , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/farmacologia , Proteínas Reguladoras de Apoptose/uso terapêutico , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Proteína Ligante Fas/farmacologia , Proteína Ligante Fas/fisiologia , Proteína Ligante Fas/uso terapêutico , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Morte Celular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
17.
Cancer Lett ; 293(2): 240-53, 2010 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-20347216

RESUMO

Tumor Necrosis Factor-alpha Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptors (DR) 4 and 5 have attracted significant attention in recent years due to their ability to selectively induce apoptosis in malignant cells while demonstrating little cytotoxicity in normal cells. Although these candidates are promising in cancer therapy, a number of tumor cells are resistant to TRAIL-mediated apoptosis. We describe the use of a cationic amphipathic lytic peptide, KLA (single letter sequence HHHHHKLAKLAKKLAKLAKC), for the chemosensitization of TRAIL-resistant LNCaP and PC3-PSMA human prostate cancer cells to DR agonistic antibodies. 'Single-agent' treatment with DR agonistic antibodies did not result in loss of viability of these cells confirming the resistance of these cells. However, the combination treatment of KLA followed by DR agonists resulted in greater cell death compared to the individual treatments acting alone, indicating synergistic action between the two components of the combination treatment. The combination of lytic peptide and DR agonists resulted in a significant increase in activated caspase-3 cleavage and cytochrome-C protein levels in cells, indicating a role for the caspase-mediated apoptotic pathway. In addition, KLA treatment also resulted in increased localization of DR5 and lipid rafts in LNCaP cells. Our results demonstrate, for the first time, that lytic peptides can be employed for sensitizing TRAIL-resistant prostate cancer cells to DR-mediated apoptosis resulting in novel combination treatments for the ablation of advanced cancer cells.


Assuntos
Peptídeos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores de Morte Celular/antagonistas & inibidores , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Antineoplásicos , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino
18.
Cancer Res ; 69(16): 6581-9, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19654295

RESUMO

Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this correlated with the up-regulation of TRAIL death receptor (DR) 4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell-type specific, as its expression was also up-regulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species. Inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase but not of Jun NH(2)-terminal kinase abolished the effect of zerumbone on DR induction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DR induction or for enhancement of TRAIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results show that zerumbone can potentiate TRAIL-induced apoptosis through the reactive oxygen species-mediated activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Espécies Reativas de Oxigênio/farmacologia , Receptores de Morte Celular/genética , Sesquiterpenos/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose/genética , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Sesquiterpenos/administração & dosagem , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Células Tumorais Cultivadas
19.
Biochem Pharmacol ; 78(6): 573-82, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19464267

RESUMO

Despite the fact that many cancer cells are sensitive to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, human K562 leukemic cells showed resistance to TRAIL-induced apoptosis. Interestingly, K562/R3 cells, a stable TRAIL-sensitive variant isolated from K562 cells, showed down-regulation of DNA-PK/Akt pathway and a high responsiveness to TRAIL-mediated growth inhibition and apoptosis. We revealed that siRNA-mediated suppression of DNA-PKcs led to decreased phosphorylation of Akt and Bad, a target molecule of Akt, and increased expression of DR4/DR5. Also, we found that suppression of DNA-PKcs using siRNA down-regulated c-FLIP and sensitized K562 cells to TRAIL-induced apoptosis through activation of caspase-8, -9 and -3. In addition, we revealed that treatment with DMNB, a specific inhibitor of DNA-PK, resulted in an increase of DR4/DR5 mRNA levels and their surface expression and a decrease of c-FLIP mRNA levels in K562 cells. DMNB potentiated TRAIL-induced cytotoxicity and apoptosis through inhibition of DNA-PK/Akt pathway and activation of caspase-8, -9 and -3 in K562 cells. This study is the first to show that a protective role of DNA-PK/Akt pathway against TRAIL-induced apoptosis and thus TRAIL in combination with agents that inhibit DNA-PK/Akt pathway would have clinical applicability in treating TRAIL-insensitive human leukemic cells. This model may provide a novel framework for overcoming TRAIL resistance of other cancer cells with agents that inhibit DNA-PK/Akt pathway.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose/fisiologia , Caspases/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Inativação Gênica , Humanos , Células K562 , Masculino , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/genética , Células Tumorais Cultivadas
20.
Mol Cancer Ther ; 7(11): 3546-55, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19001437

RESUMO

Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Apoptose , Glucose/metabolismo , Receptor fas/metabolismo , Anilidas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Transporte Biológico/efeitos dos fármacos , Ciclo Celular , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Perfilação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Receptores de Morte Celular/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
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