RESUMO
Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis (CF), resulting in recurrent respiratory infections and exacerbations. Strategies to rehydrate airway mucus including inhibition of the epithelial sodium channel (ENaC) have the potential to improve mucosal defense by enhancing mucociliary clearance (MCC) and reducing the risk of progressive decline in lung function. In the current work, we evaluated the effects of AZD5634, an ENaC inhibitor that shows extended lung retention and safety profile as compared with previously evaluated candidate drugs, in healthy and CF preclinical model systems. We found that AZD5634 elicited a potent inhibition of amiloride-sensitive current in non-CF airway cells and airway cells derived from F508del-homozygous individuals with CF that effectively increased airway surface liquid volume and improved mucociliary transport (MCT) rate. AZD5634 also demonstrated efficacious inhibition of ENaC in sheep bronchial epithelial cells, translating to dose-dependent improvement of mucus clearance in healthy sheep in vivo. Conversely, nebulization of AZD5634 did not notably improve airway hydration or MCT in CF rats that exhibit an MCC defect, consistent with findings from a first single-dose evaluation of AZD5634 on MCC in people with CF. Overall, these findings suggest that CF animal models demonstrating impaired mucus clearance translatable to the human situation may help to successfully predict and promote the successful translation of ENaC-directed therapies to the clinic.
Assuntos
Fibrose Cística , Canais Epiteliais de Sódio , Humanos , Ratos , Ovinos , Animais , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêutico , Amilorida/farmacologia , Depuração Mucociliar/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística/tratamento farmacológico , Mucosa RespiratóriaRESUMO
RATIONALE: The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure. OBJECTIVES: To evaluate CFTR dysfunction induced by smoking and test its pharmacological reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis. METHODS: Ferrets were exposed for 6â months to cigarette smoke to induce COPD and chronic bronchitis and then treated with enteral GLPG2196 once daily for 1â month. Electrophysiological measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle-tracking microrheology, microcomputed tomography imaging, histopathological analysis and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes. MEASUREMENTS AND MAIN RESULTS: Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced bronchial wall thickening and airway epithelial hypertrophy. CONCLUSIONS: The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathological features of chronic bronchitis in a COPD ferret model.
Assuntos
Bronquite Crônica , Doença Pulmonar Obstrutiva Crônica , Animais , Bronquite Crônica/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Furões/metabolismo , Hipertrofia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Microtomografia por Raio-XRESUMO
The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6â months, with in vivo mucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (-89.0%, p<0.01) and impaired tracheal MCT (-29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6â µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2â mm·min-1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and ciliary beat frequency were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro, and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.
Assuntos
Desidratação , Doença Pulmonar Obstrutiva Crônica , Adulto , Humanos , Depuração Mucociliar , Muco , Fumar/efeitos adversos , ViscosidadeRESUMO
Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR mediated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce-specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.
Assuntos
Fibrose Cística/tratamento farmacológico , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Canais Epiteliais de Sódio/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Depuração Mucociliar/efeitos dos fármacos , Animais , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Difusão de Inovações , Desenho de Fármacos , Bloqueadores do Canal de Sódio Epitelial/efeitos adversos , Canais Epiteliais de Sódio/metabolismo , Predisposição Genética para Doença , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Terapia de Alvo Molecular , Mutação , Fenótipo , Transdução de Sinais/efeitos dos fármacosAssuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Animais , Animais Recém-Nascidos , Células Cultivadas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Modelos Animais de Doenças , Feminino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Sprague-Dawley , Traqueia/metabolismo , Traqueia/fisiopatologiaRESUMO
Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases.
Assuntos
Furões/fisiologia , Transporte de Íons , Animais , Brônquios/citologia , Brônquios/metabolismo , Brônquios/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fenômenos Eletrofisiológicos , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Canais Epiteliais de Sódio/metabolismo , Traqueia/citologia , Traqueia/metabolismo , Traqueia/fisiologiaRESUMO
DNA methylation is a major epigenetic event that affects not only cellular gene expression but that also has the potential to influence bacterial and viral DNA in their host-dependent functions. Adeno-associated virus (AAV) genome contains a high degree of CpG sequences capable of methylation in its terminal repeat sequences, which are the sole elements retained in AAV-based vectors used in gene therapy. The present study determined the influence of methylation status of the host cell on wild type (wt) AAV integration and recombinant (r) AAV transgene expression in HeLa cells. Results of the study indicated that hypo-methylation significantly enhanced both wtAAV chromosomal integration and transgene expression of rAAV. A direct influence of methylation on AAV integration was further confirmed by methylating the AAVS1 integration sites prior to viral infection with DNA trans-complementation assay. These results signify the importance of epigenetic status of target cells as one of the key factors in long-term transgene expression in AAV gene therapy.
RESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell-derived neoplasms of the peripheral nervous system that have recently been shown to possess an autocrine CXCL12/CXCR4 signaling loop that promotes tumor cell proliferation and survival. Importantly, the CXCL12/CXCR4 signaling axis is driven by availability of the CXCL12 ligand rather than CXCR4 receptor levels alone. Therefore, pharmacological reduction of CXCL12 expression could be a potential chemotherapeutic target for patients with MPNSTs or other pathologies wherein the CXCL12/CXCR4 signaling axis is active. AT101 is a well-established BCL-2 homology domain 3 (BH3) mimetic that we recently demonstrated functions as an iron chelator and thus acts as a hypoxia mimetic. In this study, we found that AT101 significantly reduces CXCL12 mRNA and secreted protein in established human MPNST cell lines in vitro. This effect was recapitulated by other BH3 mimetics [ABT-737 (ABT), obatoclax (OBX) and sabutoclax (SBX)] but not by desferrioxamine (DFO), an iron chelator and known hypoxia mimetic. These data suggest that CXCL12 reduction is a function of AT101's BH3 mimetic property rather than its iron chelation ability. Additionally, this study investigates a potential mechanism of BH3 mimetic-mediated CXCL12 suppression: liberation of a negative CXCL12 transcriptional regulator, poly (ADP-Ribose) polymerase I (PARP1) from its physical interaction with BCL-2. These data suggest that clinically available BH3 mimetics might prove therapeutically useful at least in part by virtue of their ability to suppress CXCL12 expression.
Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Gossipol/análogos & derivados , Mimetismo Molecular , Neurilemoma/tratamento farmacológico , Nitrofenóis/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Gossipol/farmacologia , Humanos , Indóis , Neurilemoma/genética , Neurilemoma/metabolismo , Neurilemoma/patologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Glioblastomas (GBMs) are the most common and aggressive primary human malignant brain tumors. 4-Hydroxy tamoxifen (OHT) is an active metabolite of the tamoxifen (TMX) prodrug and a well-established estrogen receptor (ER) and estrogen-related receptor antagonist. A recent study from our laboratory demonstrated that OHT induced ER-independent malignant peripheral nerve sheath tumor (MPNST) cell death by autophagic degradation of the prosurvival protein Kirsten rat sarcoma viral oncogene homolog. Because both MPNST and GBM are glial in cell origin, we hypothesized that OHT could mediate similar effects in GBM. OHT induced a concentration-dependent reduction in cell viability that was largely independent of caspase activation in a human GBM cell line and 2 patient-derived xenolines. Further, OHT induced both cytotoxic autophagy and a concentration-dependent decrease in epidermal growth factor receptor (EGFR) protein levels. A GBM cell line expressing EGFR variant III (EGFRvIII) was relatively resistant to OHT-induced death and EGFRvIII was refractory to OHT-induced degradation. Thus, OHT induces GBM cell death through a caspase-independent, autophagy-related mechanism and should be considered as a potential therapeutic agent in patients with GBM whose tumors express wild-type EGFR.
RESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive Schwann cell-derived sarcomas and are the leading cause of mortality in patients with neurofibromatosis type 1 (NF1). Current treatment modalities have been largely ineffective, resulting in a high rate of MPNST recurrence and poor five-year patient survival. This necessitates the exploration of alternative chemotherapeutic options for MPNST patients. This study sought to assess the cytotoxic effect of the BH3-mimetic AT101 [(-)-gossypol] on MPNST cells in vitro and to identify key regulators of AT101-induced MPNST cell death. We found that AT101 caused caspase-independent, non-apoptotic MPNST cell death, which was accompanied by autophagy and was mediated through HIF-1α induced expression of the atypical BH3-only protein BNIP3. These effects were mediated by intracellular iron chelation, a previously unreported mechanism of AT101 cytotoxicity.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Morte Celular/efeitos dos fármacos , Gossipol/análogos & derivados , Proteínas de Membrana/metabolismo , Neurilemoma/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Gossipol/farmacologia , Gossipol/uso terapêutico , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ferro/metabolismo , Neurilemoma/metabolismo , Neurilemoma/patologia , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologiaRESUMO
Therapy-induced autophagy is recognized as a critical determinant of treatment outcome in cancer patients, primarily as a factor underlying drug resistance. However, recent investigations point toward a context-dependent, death-inducing role for autophagy, the mechanism of which remains largely unknown. Our recent study provides evidence that autophagy can directly mediate cell killing in multiple tumor cell types by facilitating degradation of KRAS/K-Ras, a key survival protein. These findings have broad implications for strategies employing autophagy modulation to target tumor cells.
Assuntos
Autofagia , Citoproteção , Proteólise , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Autofagia/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase C/metabolismo , Proteólise/efeitos dos fármacos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologiaRESUMO
Tamoxifen is widely used to treat estrogen receptor-positive breast cancer. Recent findings that tamoxifen and its derivative 4-hydroxytamoxifen (OHT) can exert estrogen receptor-independent cytotoxic effects have prompted the initiation of clinical trials to evaluate its use in estrogen receptor-negative malignancies. For example, tamoxifen and OHT exert cytotoxic effects in malignant peripheral nerve sheath tumors (MPNST) where estrogen is not involved. In this study, we gained insights into the estrogen receptor-independent cytotoxic effects of OHT by studying how it kills MPNST cells. Although caspases were activated following OHT treatment, caspase inhibition provided no protection from OHT-induced death. Rather, OHT-induced death in MPNST cells was associated with autophagic induction and attenuated by genetic inhibition of autophagic vacuole formation. Mechanistic investigations revealed that OHT stimulated autophagic degradation of K-Ras, which is critical for survival of MPNST cells. Similarly, we found that OHT induced K-Ras degradation in breast, colon, glioma, and pancreatic cancer cells. Our findings describe a novel mechanism of autophagic death triggered by OHT in tumor cells that may be more broadly useful clinically in cancer treatment.
Assuntos
Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Neoplasias de Bainha Neural/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Tamoxifeno/análogos & derivados , Proteínas ras/metabolismo , Autofagia/genética , Caspases/genética , Caspases/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células HCT116 , Humanos , Células MCF-7 , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias de Bainha Neural/enzimologia , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteólise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Tamoxifeno/farmacologia , Proteínas ras/genéticaRESUMO
Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. In tissue samples of NEC, we identified numerous macrophages and a few neutrophils but not many lymphocytes. We hypothesized that these pathoanatomic characteristics of NEC represent a common tissue injury response of the gastrointestinal tract to a variety of insults at a specific stage of gut development. To evaluate developmental changes in mucosal inflammatory response, we used trinitrobenzene sulfonic acid (TNBS)-induced inflammation as a nonspecific insult and compared mucosal injury in newborn vs. adult mice. Enterocolitis was induced in 10-day-old pups and adult mice (n = 25 animals per group) by administering TNBS by gavage and enema. Leukocyte populations were enumerated in human NEC and in murine TNBS-enterocolitis using quantitative immunofluorescence. Chemokine expression was measured using quantitative polymerase chain reaction, immunoblots, and immunohistochemistry. Macrophage recruitment was investigated ex vivo using intestinal tissue-conditioned media and bone marrow-derived macrophages in a microchemotaxis assay. Similar to human NEC, TNBS enterocolitis in pups was marked by a macrophage-rich leukocyte infiltrate in affected tissue. In contrast, TNBS-enterocolitis in adult mice was associated with pleomorphic leukocyte infiltrates. Macrophage precursors were recruited to murine neonatal gastrointestinal tract by the chemokine CXCL5, a known chemoattractant for myeloid cells. We also demonstrated increased expression of CXCL5 in surgically resected tissue samples of human NEC, indicating that a similar pathway was active in NEC. We concluded that gut mucosal injury in the murine neonate is marked by a macrophage-rich leukocyte infiltrate, which contrasts with the pleomorphic leukocyte infiltrates in adult mice. In murine neonatal enterocolitis, macrophages were recruited to the inflamed gut mucosa by the chemokine CXCL5, indicating that CXCL5 and its cognate receptor CXCR2 merit further investigation as potential therapeutic targets in NEC.
Assuntos
Mucosa Intestinal/patologia , Macrófagos/fisiologia , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Western Blotting , Quimiocina CXCL5/fisiologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/fisiologia , Eletroforese em Gel de Gradiente Desnaturante , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Recém-Nascido , Recém-Nascido Prematuro , Inflamação/patologia , Enteropatias/induzido quimicamente , Enteropatias/patologia , Mucosa Intestinal/citologia , Camundongos , Infiltração de Neutrófilos/fisiologia , Reação em Cadeia da Polimerase , Fatores de Risco , Ácido TrinitrobenzenossulfônicoRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Cloroquina/farmacologia , Receptores ErbB/antagonistas & inibidores , Lisossomos/efeitos dos fármacos , Neoplasias de Bainha Neural/tratamento farmacológico , Quinazolinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cloroquina/uso terapêutico , Genes erbB/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias de Bainha Neural/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/uso terapêutico , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
The role of autophagy, traditionally considered a cellular homeostatic and recycling mechanism, has expanded dramatically to include an involvement in discrete stages of tumor initiation and development. Gliomas are the most aggressive and also the most common brain malignancies. Current treatment modalities have only a modest effect on patient outcomes. Resistance to apoptosis, a hallmark of most cancers, has driven the search for novel targets in cancer therapy. The autophagy lysosomal pathway is one such target that is being explored in multiple cancers including gliomas and is a promising avenue for further therapeutic development. This review summarizes our current understanding of the autophagic process and its potential utility as a target for glioma therapy.