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1.
Artigo em Inglês | MEDLINE | ID: mdl-31628482

RESUMO

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

2.
PLoS One ; 13(9): e0203639, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30235224

RESUMO

BACKGROUND: Low-grade gliomas affect younger adults and carry a favorable prognosis. They include a variety of biological features affecting clinical behavior and treatment. Having no guidelines on treatment established, we aim to describe clinical and treatment patterns of low-grade gliomas across the largest cancer database in the United States. METHODS: We analyzed the National Cancer Database from 2004 to 2015, for adult patients with a diagnosis of World Health Organization grade II diffuse glioma. RESULTS: We analyzed 13,621 cases with median age of 41 years. Over 56% were male, 88.4% were white, 6.1% were black, and 7.6% Hispanic. The most common primary site location was the cerebrum (79.9%). Overall, 72.2% received surgery, 36.0% radiation, and 27.3% chemotherapy. Treatment combinations included surgery only (41.5%), chemotherapy + surgery (6.6%), chemotherapy only (3.1%), radiation + chemotherapy + surgery (10.7%), radiation + surgery (11.5%), radiation only (6.1%), and radiotherapy + chemotherapy (6.7%). Radiation was more common in treatment of elderly patients, 1p/19q co-deletion (37.3% versus 24.3%, p<0.01), and tumors with midline location. Median survival was 11 years with younger age, 1p/19q co-deletion, and cerebrum location offered survival advantage. CONCLUSIONS: Tumor location, 1p/19q co-deletion, and age were the main determinants of treatment received and survival, likely reflecting tumor biology differences. Any form of treatment was preferred over watchful waiting in the majority of the patients (86.1% versus 8.1%). Survival of low-grade gliomas is higher than previously reported in the majority of clinical trials and population-based analyses. Our analysis provides a real world estimation of treatment decisions, use of molecular data, and outcomes.


Assuntos
Glioma/tratamento farmacológico , Glioma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Feminino , Glioma/metabolismo , Glioma/radioterapia , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Antioxid Redox Signal ; 29(13): 1237-1272, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325444

RESUMO

SIGNIFICANCE: Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. CRITICAL ISSUES: The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment. FUTURE DIRECTIONS: Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
5.
Radiol Case Rep ; 12(1): 31-33, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28228873

RESUMO

Brachytherapy consists of placing radioactive sources into or adjacent to tumors, to deliver conformal radiation treatment. The technique is used for treatment of primary malignancies and for salvage in recurrent disease. Permanent prostate brachytherapy seeds are small metal implants containing radioactive sources of I-125, Pd-103, or Cs-131 encased in a titanium shell. They can embolize through the venous system to the lungs or heart and subsequently be detected by cardiovascular computed tomography. Cardiovascular imagers should be aware of the appearance of migrated seeds, as their presence in the chest is generally benign, so that unnecessary worry and testing are avoided. We report a case of a patient who underwent brachytherapy for prostate cancer and developed a therapeutic seeds embolus to the right ventricle.

6.
Cancer Res ; 77(6): 1345-1356, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108513

RESUMO

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings. Cancer Res; 77(6); 1345-56. ©2017 AACR.


Assuntos
Ácido Ascórbico/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Próstata/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Radiossensibilizantes/farmacologia , Fator de Transcrição RelB/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Nus , Estresse Oxidativo/efeitos da radiação , Próstata/citologia , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Neuroophthalmology ; 41(5): 287-290, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29339965

RESUMO

Radiation optic neuropathy (RON) is an iatrogenic complication that causes severe, irreversible vision loss within months to years following radiation to lesions close to the visual pathway. The authors describe a case of RON in glioblastoma after radio-sensitisation with temozolomide with sequential involvement of both optic nerves. This case provides a timeline for clinical and imaging findings with RON and specifically resolution of nerve enhancement. The authors also highlight the potential of an increase in incidence of RON in glioblastoma with advances in survival seen with greater use of second-line chemotherapy and even re-radiation.

8.
Otol Neurotol ; 37(9): 1406-10, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27466892

RESUMO

OBJECTIVES: The objectives were to evaluate the audiological outcomes, response of symptoms, and response of tumor volume in patients with glomus jugulare tumors treated solely with single fraction gamma knife radiosurgery. STUDY DESIGN: Single institution retrospective review. SETTING: Academic, tertiary referral center. PATIENTS: The diagnosis code for glomus jugulare was used to identify patients. Only those who underwent gamma knife radiosurgery were included. Those previously treated with any modality were excluded. A total of 12 patients were included for the tumor response and symptom response data and 7 of those were included in the audiometric analysis. MAIN OUTCOMES MEASURES: Audiometric data at most recent follow-up compared with presentation, subjective improvement in pulsatile tinnitus, and change in tumor volume at most recent follow-up compared with pretreatment. RESULTS: The average time to most recent follow-up was 27.6 months. There was no significant change in pure-tone average or word recognition. Pulsatile tinnitus completely resolved or improved in 80% of patients. Cranial neuropathies were stable or improved. A single patient experienced facial nerve paresis 2 years after treatment, which resolved with steroid treatment. Tumor control was 100% and the average change in tumor volume was a decrease of 37%. CONCLUSION: Single modality gamma knife radiosurgery treatment of glomus jugulare tumors seems to be safe. Treatment results in decreased tumor volume and improved pulsatile tinnitus in most patients. There was no significant progression of hearing loss after treatment. Lower cranial nerve function remains stable in all patients.


Assuntos
Tumor do Glomo Jugular/radioterapia , Radiocirurgia/métodos , Adulto , Idoso , Feminino , Seguimentos , Tumor do Glomo Jugular/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
9.
J Autoimmun ; 59: 43-52, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25744251

RESUMO

Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity-modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Biomarcadores/metabolismo , Mapeamento de Epitopos/métodos , Granulomatose com Poliangiite/imunologia , Mieloblastina/metabolismo , Regulação Alostérica/imunologia , Sítios de Ligação de Anticorpos/imunologia , Progressão da Doença , Seguimentos , Granulomatose com Poliangiite/enzimologia , Humanos , Mieloblastina/imunologia
10.
Cogn Process ; 16(4): 319-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25630854

RESUMO

Is conceptual space continuous? The answer to this question depends on how concepts are represented in the brain. Vector space representations, which ground conceptual states in the instantaneous firing rates of neurons, have successfully captured cognitive dynamics in a broad range of domains. There is a growing body of evidence, however, that conceptual information is encoded in spatiotemporal patterns of neural spikes, sometimes called polychronous neuronal groups (PNGs). The use of PNGs to represent conceptual states, rather than employing a continuous vector space, introduces new challenges, including issues of temporally extended representations, meaning through symbol grounding, compositionality, and representational similarity. In this article, we explore how PNGs support discontinuous transitions between concepts. While the continuous dynamics of vector space approaches require such transitions to activate intermediate and blended concepts, PNGs offer the means to change the activation of concepts discretely, introducing a form of conceptual dynamics unavailable to vector space models.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Formação de Conceito/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Animais , Humanos , Rede Nervosa
11.
Antioxid Redox Signal ; 20(9): 1481-500, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24093432

RESUMO

SIGNIFICANCE: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency. RECENT ADVANCES: Ionizing radiation (IR)-generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from cell death to development of radioresistance. CRITICAL ISSUES: Tumors are heterogeneous and dynamic communication occurs between stromal and prostate cancer cells, and complicated redox-regulated mechanisms exist in the tumor microenvironment. Thus, antioxidant and anti-inflammatory strategies should be carefully evaluated for each patient at different stages of the disease to maximize therapeutic benefits while minimizing unintended side effects. FUTURE DIRECTIONS: Compared with normal cells, tumor cells are usually under higher oxidative stress and secrete more proinflammatory mediators. Thus, redox status is often less adaptive in tumor cells than in their normal counterparts. This difference can be exploited in a search for new cancer therapeutics and treatment regimes that selectively activate cell death pathways in tumor cells with minimal unintended consequences in terms of chemo- and radio-resistance in tumor cells and toxicity in normal tissues.


Assuntos
Transformação Celular Neoplásica/metabolismo , Mediadores da Inflamação/metabolismo , Oxirredução , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Radiação Ionizante , Animais , Citocinas/metabolismo , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismo
12.
Antioxid Redox Signal ; 20(10): 1567-89, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24094070

RESUMO

SIGNIFICANCE: Ionizing radiation is a vital component in the oncologist's arsenal for the treatment of cancer. Approximately 50% of all cancer patients will receive some form of radiation therapy as part of their treatment regimen. DNA is considered the major cellular target of ionizing radiation and can be damaged directly by radiation or indirectly through reactive oxygen species (ROS) formed from the radiolysis of water, enzyme-mediated ROS production, and ROS resulting from altered aerobic metabolism. RECENT ADVANCES: ROS are produced as a byproduct of oxygen metabolism, and superoxide dismutases (SODs) are the chief scavengers. ROS contribute to the radioresponsiveness of normal and tumor tissues, and SODs modulate the radioresponsiveness of tissues, thus affecting the efficacy of radiotherapy. CRITICAL ISSUES: Despite its prevalent use, radiation therapy suffers from certain limitations that diminish its effectiveness, including tumor hypoxia and normal tissue damage. Oxygen is important for the stabilization of radiation-induced DNA damage, and tumor hypoxia dramatically decreases radiation efficacy. Therefore, auxiliary therapies are needed to increase the effectiveness of radiation therapy against tumor tissues while minimizing normal tissue injury. FUTURE DIRECTIONS: Because of the importance of ROS in the response of normal and cancer tissues to ionizing radiation, methods that differentially modulate the ROS scavenging ability of cells may prove to be an important method to increase the radiation response in cancer tissues and simultaneously mitigate the damaging effects of ionizing radiation on normal tissues. Altering the expression or activity of SODs may prove valuable in maximizing the overall effectiveness of ionizing radiation.


Assuntos
Neoplasias/radioterapia , Superóxido Dismutase/fisiologia , Animais , Efeito Espectador/efeitos da radiação , Hipóxia Celular/efeitos da radiação , Dano ao DNA , Humanos , Neoplasias/enzimologia , Neoplasias/patologia , Oxirredução , Tolerância a Radiação
13.
J Neurosurg ; 119(5): 1166-75, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23600932

RESUMO

OBJECT: Despite the widespread use of Gamma Knife surgery (GKS) for trigeminal neuralgia (TN), controversy remains regarding the optimal treatment dose and target site. Among the published studies, only a few have focused on long-term outcomes (beyond 2 years) using 90 Gy, which is in the higher range of treatment doses used (70-90 Gy). METHODS: The authors followed up on 315 consecutive patients treated with the Leksell Gamma Knife unit using a 4-mm isocenter without blocks. The isocenter was placed on the trigeminal nerve with the 20% isodose line tangential to the pontine surface (18 Gy). At follow-up, 33 patients were deceased; 282 were mailed an extensive questionnaire regarding their outcomes, but 32 could not be reached. The authors report their analysis of the remaining 250 cases. The patients' mean age at the time of survey response and the mean duration of follow-up were 70.8 ± 13.1 years and 68.9 ± 41.8 months, respectively. RESULTS: One hundred eighty-five patients (85.6%) had decreased pain intensity after GKS. Modified Marseille Scale (MMS) pain classifications after GKS at follow-up were: Class I (pain free without medication[s]) in 104 (43.7%), Class II (pain free with medication[s]) in 66 (27.7%), Class III (> 90% decrease in pain intensity) in 23 (9.7%), Class IV (50%-90% decrease in pain intensity) in 20 (8.4%), Class V (< 50% decrease in pain intensity) in 11 (4.6%), and Class VI (pain becoming worse) in 14 (5.9%). Therefore, 170 patients (71.4%) were pain free (Classes I and II) and 213 (89.5%) had at least 50% pain relief. All patients had pain that was refractory to medical management prior to GKS, but only 111 (44.4%) were being treated with medication at follow-up (p < 0.0001). Eighty patients (32.9%) developed numbness after GKS, and 74.5% of patients with numbness had complete pain relief. Quality of life and patient satisfaction on a 10-point scale were reported at mean values (± SD) of 7.8 ± 3.1 and 7.7 ± 3.4, respectively. Most of the patients (87.7%) would recommend GKS to another patient. Patients with prior surgical treatments had increased latency to pain relief and were more likely to continue medicines (p < 0.05). Moreover, presence of altered facial sensations prior to radiosurgery was associated with higher pain intensity, longer pain episodes, more frequent pain attacks, worse MMS pain classification, and more medication use after GKS (p < 0.05). Conversely, increase in numbness intensity after GKS was associated with a decrease in pain intensity and pain length (p < 0.05). CONCLUSIONS: Gamma Knife surgery using a maximum dose of 90 Gy to the trigeminal nerve provides satisfactory long-term pain control, reduces the use of medication, and improves quality of life. Physicians must be aware that higher doses may be associated with an increase in bothersome sensory complications. The benefits and risks of higher dose selection must be carefully discussed with patients, since facial numbness, even if bothersome, may be an acceptable trade-off for patients with severe pain.


Assuntos
Dor/cirurgia , Radiocirurgia/métodos , Neuralgia do Trigêmeo/cirurgia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dor/fisiopatologia , Medição da Dor , Satisfação do Paciente , Qualidade de Vida/psicologia , Doses de Radiação , Radiocirurgia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
14.
Free Radic Res ; 46(8): 1029-43, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22656864

RESUMO

HLE, a human hepatocellular carcinoma cell line was transiently transfected with normal human MnSOD and MnSOD without a mitochondrial targeting signal (MTS). Mitochondrial reactive oxygen species (ROS), lipid peroxidation and apoptosis were examined as a function of time following 18.8 Gy X-ray irradiation. Our results showed that the level of mitochondrial ROS increased and reached a maximum level 2 hours after X-ray irradiation. Authentic MnSOD, but not MnSOD lacking MTS, protected against mitochondrial ROS, lipid peroxidation and apoptosis. In addition, the levels of mitochondrial ROS were consistently found to always correlate with the levels of authentic MnSOD in mitochondria. These results suggest that only when MnSOD is located in mitochondria is it efficient in protecting against cellular injuries by X-ray irradiation and that mitochondria are the critical sites of X-ray-induced cellular oxidative injuries.


Assuntos
Apoptose/efeitos da radiação , Hepatócitos/efeitos da radiação , Mitocôndrias/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Carcinoma Hepatocelular , Linhagem Celular Tumoral , Corantes Fluorescentes , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Peroxidação de Lipídeos/efeitos da radiação , Neoplasias Hepáticas , Microscopia de Fluorescência , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Sinais Direcionadores de Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Superóxido Dismutase/genética , Transfecção , Raios X
15.
PLoS One ; 7(3): e32905, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22403723

RESUMO

BACKGROUND: Prostate specific antigen (PSA) is traditionally used as an indicator for the presence of prostate cancer (PCa) and radiotherapy is generally used to treat inoperable and locally advanced PCa. However, how cellular PSA level is associated with sensitivity of PCa to radiotherapy is unknown. The previous finding that the RelB-based NF-κB alternative pathway differentially regulates PSA and interleukin-8 (IL-8) in aggressive PCa has directed our attention to the role of RelB in the response of PCa to radiotherapy. METHODOLOGY/PRINCIPAL FINDINGS: RelB and its targets PSA and IL-8 in PCa cells were manipulated by ectopic expression in PCa cells with a low endogenous level of RelB (LNCaP) and by RNAi-based knock-down in PCa cells with a high constitutive level of RelB (PC3). The effects of RelB, PSA and IL-8 on the response of PCa to radiation treatment were examined in vitro and in xenograft tumors. RelB regulates PSA and IL-8 in an inverse manner. When the cellular levels of PSA and IL-8 were directly modulated by genetic manipulations or by the addition of recombinant proteins, the results demonstrate that up-regulation of IL-8 enhanced radioresistance of PCa cells and concurrently down-regulated PSA. In contrast, up-regulation of PSA resulted in reduced radioresistance with concurrent down-regulation of IL-8. CONCLUSION/SIGNIFICANCE: RelB plays a critical role in the response of PCa to radiotherapy and the inverse expression of IL-8 and PSA. The results identify a previously unrecognized relationship between IL-8 and PSA in the response of PCa cells to radiotherapy.


Assuntos
Interleucina-8/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Fator de Transcrição RelB/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Masculino , Camundongos , Neoplasias da Próstata/radioterapia , Tolerância a Radiação , Regulação para Cima
16.
J Neurol Sci ; 308(1-2): 155-7, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21726879

RESUMO

When ALS patients experience oropharyngeal weakness, sialorrhea can become a considerable challenge. Drooling has a profound negative impact in patient's quality of life causing embarrassing social situations. Several therapeutic modalities, including anticholinergic drugs, botulinum toxin injection, and radiotherapy have emerged as treatments for drooling in ALS. This retrospective case series study examined the effect of palliative radiotherapy in controlling problematic oral secretions in 10 ALS patients refractory to medical management. External electron beam radiation was targeted to a single parotid gland unilaterally with a total dose of 1500 cGy in 3 fractions at a depth determined by CT scanning. One patient received additional radiotherapy to the contralateral parotid due to persistent secretions. All patients reported improvement with a reduction in the intensity and amount of drooling. In 5 of 10 patients, anticholinergics were discontinued and were reduced in another two. There were no major side effects of treatment. We conclude that unilateral parotid electron radiotherapy provides satisfactory relief from sialorrhea in ALS patients and should be considered as a therapeutic option for patients who are refractory to medical management.


Assuntos
Esclerose Amiotrófica Lateral/radioterapia , Cuidados Paliativos/métodos , Glândula Parótida/efeitos da radiação , Aceleradores de Partículas , Sialorreia/radioterapia , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glândula Parótida/diagnóstico por imagem , Aceleradores de Partículas/instrumentação , Radiografia , Sialorreia/diagnóstico por imagem , Sialorreia/etiologia
17.
Int J Oncol ; 37(6): 1575-81, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21042727

RESUMO

The preferential use of aerobic glycolysis for energy production by cancer cells, a phenomenon known as the 'Warburg effect', is well recognized and is being considered for therapeutic applications. However, whether inhibition of glycolysis will be effective in all types of cancer is unclear. The current study shows that a glycolytic inhibitor, 2-deoxy-D-glucose (2DG), exhibits the cytotoxic effect on non-small cell lung cancer in a p53-dependent manner. 2DG significantly inhibits ATP production in p53-deficient lung cancer cells (H358) but not in p53-wt cells (A549). In contrast to p53-wt cells, p53-defective cells are unable to compensate for their need of energy via oxidative phosphorylation (OXPHOS) when glycolysis is inhibited. In the presence of p53, increased ROS from OXPHOS increases the expression of p53 target genes known to modulate metabolism, including synthesis of cytochrome c oxidase 2 (SCO2) and TP53-induced glycolysis and apoptosis regulator (TIGAR). Importantly, 2DG selectively induces the expression of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx1) in a p53-dependent manner. The results demonstrate that the killing of cancer cells by the inhibitor of glycolysis is more efficient in cancer cells without functional p53 and that p53 protects against metabolic stress by up-regulation of oxidative phosphorylation and modulation of antioxidants.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citoproteção , Neoplasias Pulmonares/metabolismo , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Adaptação Fisiológica/genética , Trifosfato de Adenosina/metabolismo , Antioxidantes/metabolismo , Proteínas Reguladoras de Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Citoproteção/genética , Desoxiglucose/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação Oxidativa , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Fatores de Tempo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Ann N Y Acad Sci ; 1201: 129-36, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20649549

RESUMO

Radiation therapy is in the front line for treatment of localized prostate cancer. However, a significant percentage of patients have radiation-resistant disease. The NF-kappaB pathway is an important factor for radiation resistance, and the classical (canonical) pathway is thought to confer protection of prostate cancer cells from ionizing radiation. Recently, the alternative (non-canonical) pathway, which is involved in prostate cancer aggressiveness, has also been shown to be important for radiation resistance in prostate cancer. The alternative NF-kappaB pathway component RelB protects prostate cancer cells from the detrimental effects of ionizing radiation, in part, by stimulating expression of the mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD). Blocking RelB activation suppresses MnSOD expression and sensitizes prostate cancer cells to radiation. These results suggest that RelB-mediated modulation of the antioxidant capacity of prostate cancer cells is an important mechanism of radiation resistance. Therefore, targeting RelB activation may prove to be a valuable weapon in the oncologist's arsenal to defeat aggressive and radiation-resistant prostate cancer.


Assuntos
Apoptose , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Superóxido Dismutase/metabolismo , Fator de Transcrição RelB/fisiologia , Antioxidantes/metabolismo , Humanos , Masculino , Mitocôndrias/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Estresse Oxidativo , Neoplasias da Próstata/patologia , Radiação Ionizante , Radioterapia/métodos , Espécies Reativas de Oxigênio
19.
Mol Cancer Ther ; 9(4): 803-12, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20371728

RESUMO

Radiation therapy is an effective treatment for localized prostate cancer. However, when high-risk factors are present, such as increased prostate-specific antigen, elevated Gleason scores and advanced T stage, undetected spreading of the cancer, and development of radiation-resistant cancer cells are concerns. Thus, additional therapeutic agents that can selectively sensitize advanced prostate cancer to radiation therapy are needed. Imatinib mesylate (Gleevec, STI571), a tyrosine kinase inhibitor, was evaluated for its potential to enhance the efficacy of ionizing radiation (IR) against aggressive prostate cancer cells. STI571 significantly enhances the IR-induced cytotoxicity of androgen-independent prostate cancer cells but not of androgen-responsive prostate cancer cells. The differential cytotoxic effects due to STI571 are associated with the nuclear level of RelB in prostate cancer cells. STI571 inhibits IR-induced RelB nuclear translocation, leading to increased radiosensitivity in aggressive androgen-independent PC-3 and DU-145 cells. In contrast, STI571 enhances RelB nuclear translocation in androgen-responsive LNCaP cells. The different effects of STI571 on RelB nuclear translocation are consistent with RelB DNA binding activity and related target gene expression. STI571 inhibits the phosphoinositide 3-kinase-AKT-IkappaB kinase-alpha pathway in PC-3 cells by decreasing the phosphorylation levels of phosphoinositide 3-kinase (Tyr458) and AKT (Ser473), whereas STI571 increases NF-kappaB inducible kinase (Thr559) phosphorylation, leading to activation of IkappaB kinase-alpha in LNCaP cells. These results reveal that STI571 exhibits differential effects on the upstream kinases leading to different downstream effects on the NF-kappaB alternative pathway in prostate cancer cells and suggest that STI571 is effective for the treatment of androgen-independent prostate cancer in the context of high constitutive levels of RelB. Mol Cancer Ther; 9(4); 803-12. (c)2010 AACR.


Assuntos
Piperazinas/farmacologia , Neoplasias da Próstata/metabolismo , Pirimidinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Fator de Transcrição RelB/metabolismo , Androgênios/farmacologia , Benzamidas , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Mesilato de Imatinib , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/efeitos da radiação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Tolerância a Radiação/efeitos da radiação , Radiação Ionizante , Reprodutibilidade dos Testes , Fator de Transcrição RelA/metabolismo
20.
Cancer Res ; 70(7): 2880-90, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20233868

RESUMO

Cancer cells are usually under higher oxidative stress compared with normal cells. We hypothesize that introducing additional reactive oxygen species (ROS) insults or suppressing antioxidant capacity may selectively enhance cancer cell killing by oxidative stress-generating agents through stress overload or stress sensitization, whereas normal cells may be able to maintain redox homeostasis under exogenous ROS by adaptive response. Here, we show that parthenolide, a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. Parthenolide causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H(2)DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, parthenolide activates NADPH oxidase, leading to a decrease in the level of reduced thioredoxin, activation of phosphoinositide 3-kinase/Akt, and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets antioxidant enzyme manganese superoxide dismutase and catalase. Importantly, when combined with radiation, parthenolide further increases ROS levels in PC3 cells whereas it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing reduced glutathione levels. Together, the results show that parthenolide selectively activates NADPH oxidase and mediates intense oxidative stress in prostate cancer cells by both increasing ROS generation and decreasing antioxidant defense capacity. The results support the concept of exploiting the intrinsic differences in the redox status of cancer cells and normal cells as targets for selective cancer killing.


Assuntos
NADPH Oxidases/metabolismo , Neoplasias da Próstata/enzimologia , Radiossensibilizantes/farmacologia , Sesquiterpenos/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Glutationa/metabolismo , Humanos , Masculino , Proteína Oncogênica v-akt/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Transdução de Sinais , Superóxido Dismutase/metabolismo , Tiorredoxinas/metabolismo
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