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1.
Br J Cancer ; 128(8): 1429-1438, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36639527

RESUMO

Numerous studies have demonstrated the higher biological efficacy of carbon-ion irradiation (C-ions) and their ballistic precision compared with photons. At the nanometre scale, the reactive oxygen species (ROS) produced by radiation and responsible for the indirect effects are differentially distributed according to the type of radiation. Photon irradiation induces a homogeneous ROS distribution, whereas ROS remain condensed in clusters in the C-ions tracks. Based on this linear energy transfer-dependent differential nanometric ROS distribution, we propose that the higher biological efficacy and specificities of the molecular response to C-ions rely on a 'stealth-bomber' effect. When biological targets are on the trajectories of the particles, the clustered radicals in the tracks are responsible for a 'bomber' effect. Furthermore, the low proportion of ROS outside the tracks is not able to trigger the cellular mechanisms of defence and proliferation. The ability of C-ions to deceive the cellular defence of the cancer cells is then categorised as a 'stealth' effect. This review aims to classify the biological arguments supporting the paradigm of the 'stealth-bomber' as responsible for the biological superiority of C-ions compared with photons. It also explains how and why C-ions will always be more efficient for treating patients with radioresistant cancers than conventional radiotherapy.


Assuntos
Neoplasias , Humanos , Espécies Reativas de Oxigênio , Neoplasias/radioterapia , Fótons/uso terapêutico , Íons , Carbono
2.
Int J Mol Sci ; 23(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35055060

RESUMO

Squamous cell carcinoma is the most common type of head and neck cancer (HNSCC) with a disease-free survival at 3 years that does not exceed 30%. Biomarkers able to predict clinical outcomes are clearly needed. The purpose of this study was to investigate whether a short-term culture of tumour fragments irradiated ex vivo could anticipate patient responses to chemo- and/or radiotherapies. Biopsies were collected prior to treatment from a cohort of 28 patients with non-operable tumours of the oral cavity or oropharynx, and then cultured ex vivo. Short-term biopsy slice culture is a robust method that keeps cells viable for 7 days. Different biomarkers involved in the stemness status (CD44) or the DNA damage response (pATM and γ-H2AX) were investigated for their potential to predict the treatment response. A higher expression of all these markers was predictive of a poor response to treatment. This allowed the stratification of responder or non-responder patients to treatment. Moreover, the ratio for the expression of the three markers 24 h after 4 Gy irradiation versus 0 Gy was higher in responder than in non-responder patients. Finally, combining these biomarkers greatly improved their predictive potential, especially when the γ-H2AX ratio was associated with the CD44 ratio or the pATM ratio. These results encourage further evaluation of these biomarkers in a larger cohort of patients.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais , Carcinoma de Células Escamosas/metabolismo , Histonas/metabolismo , Receptores de Hialuronatos/metabolismo , Neoplasias Bucais/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Biópsia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Dano ao DNA , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Histonas/genética , Humanos , Receptores de Hialuronatos/genética , Imuno-Histoquímica , Masculino , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Prognóstico , Curva ROC
3.
Med Sci Monit ; 27: e934116, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34728593

RESUMO

Hypoxia involves neoplastic cells. Unlike normal tissue, solid tumors are composed of aberrant vasculature, leading to a hypoxic microenvironment. Hypoxia is also known to be involved in both metastasis initiation and therapy resistance. Radiotherapy is the appropriate treatment in about half of all cancers, but loco-regional control failure and a disease recurrence often occur due to clinical radioresistance. Hypoxia induces radioresistance through a number of molecular pathways, and numerous strategies have been developed to overcome this. Nevertheless, these strategies have resulted in disappointing results, including adverse effects and limited efficacy. Additional clinical studies are needed to achieve a better understanding of the complex hypoxia pathways. This review presents an update on the mechanisms of hypoxia in radioresistance in solid tumors and the potential therapeutic solutions.


Assuntos
Hipóxia/complicações , Hipóxia/fisiopatologia , Neoplasias/complicações , Neoplasias/radioterapia , Tolerância a Radiação , Feminino , Humanos , Masculino
4.
Lasers Med Sci ; 36(7): 1445-1454, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33169275

RESUMO

Photobiomodulation-based (PBM-based) therapies show promising results in mucositis and dermatitis treatment by stimulating wound healing mechanisms such as cell proliferation and migration. The aim of the present study is to investigate the in vitro effects of CareMin650 on the proliferation and migration of two different types of cells, namely cancer and non-cancer cells, with or without X-ray radiation. Study design used PBM through a combination of 0-3-6 J/cm2 doses-with or without X-ray radiation-on the proliferation and migration capabilities of a keratinocyte cell line (HaCaT) and a squamous cell carcinoma line (SCC61). PBM is delivered by a new woven optical fiber device, namely CareMin650 prototype (light emission by LEDs (light-emitting diodes), peak at 660 nm, irradiance of 21.6 mW/cm2). The effectiveness of PBM to increase HaCaT proliferation and migration (with or without X-ray radiation) supports the capability of PBM to favor wound healing. It also highlights that PBM does not provide any anti-radiation effect to previously X-rays radiated SCC (p < 0.001). Such data supports the beneficial effect of PBM delivered by an optical fiber device to heal wounds, without promoting cancer development.


Assuntos
Carcinoma de Células Escamosas , Terapia com Luz de Baixa Intensidade , Carcinoma de Células Escamosas/radioterapia , Proliferação de Células , Humanos , Queratinócitos , Fibras Ópticas , Raios X
5.
Int J Mol Sci ; 22(20)2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34681703

RESUMO

Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.


Assuntos
Epigênese Genética/efeitos da radiação , Mitocôndrias/metabolismo , Radiação Ionizante , Transdução de Sinais/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Humanos , Mitocôndrias/genética , Mitocôndrias/efeitos da radiação , Dinâmica Mitocondrial/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo
6.
BMC Oral Health ; 21(1): 220, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926421

RESUMO

BACKGROUND: Oral mucositis (OM) is a severe complication cancer patients undergo when treated with chemoradiotherapy. Photobiomodulation (PBM) therapy also known as low-level laser therapy has been increasingly used for the treatment of such oral toxicity. The aim of this review is to discuss the mechanisms of photobiomodulation (PBM) regarding OM prevention and treatment, and more precisely to focus on the effect of PBM on tumor and healthy cells. METHODS: MEDLINE/PubMed, and google scholar were searched electronically. Selected studies were focusing on PBM effects on tumor and healthy cells. RESULTS: PBM interactions with the tissue and additional mechanism in OM therapy were detailed in this review. Moreover, this review highlighted a controversy about the carcinogenic effect of PBM. Indeed, Many studies reported that PBM could enhance malignant cell proliferation; suggesting that PBM would have no protective effect. In addition to acting on cancer cells, PBM may damage healthy cells. CONCLUSION: More prospective studies are needed to assess the effect of PBM on cancer cells in order to improve its use for OM prevention and treatment.


Assuntos
Terapia com Luz de Baixa Intensidade , Neoplasias , Estomatite , Quimiorradioterapia , Humanos , Estudos Prospectivos , Estomatite/etiologia , Estomatite/prevenção & controle
7.
Br J Cancer ; 123(3): 339-348, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581341

RESUMO

Radiotherapy is a pivotal component in the curative treatment of patients with localised cancer and isolated metastasis, as well as being used as a palliative strategy for patients with disseminated disease. The clinical efficacy of radiotherapy has traditionally been attributed to the local effects of ionising radiation, which induces cell death by directly and indirectly inducing DNA damage, but substantial work has uncovered an unexpected and dual relationship between tumour irradiation and the host immune system. In clinical practice, it is, therefore, tempting to tailor immunotherapies with radiotherapy in order to synergise innate and adaptive immunity against cancer cells, as well as to bypass immune tolerance and exhaustion, with the aim of facilitating tumour regression. However, our understanding of how radiation impacts on immune system activation is still in its early stages, and concerns and challenges regarding therapeutic applications still need to be overcome. With the increasing use of immunotherapy and its common combination with ionising radiation, this review briefly delineates current knowledge about the non-targeted effects of radiotherapy, and aims to provide insights, at the preclinical level, into the mechanisms that are involved with the potential to yield clinically relevant combinatorial approaches of radiotherapy and immunotherapy.


Assuntos
Efeito Espectador , Neoplasias/radioterapia , Evasão Tumoral/efeitos da radiação , Imunidade Adaptativa/efeitos da radiação , Animais , Humanos , Imunidade Inata/efeitos da radiação , Neoplasias/imunologia , Radioimunoterapia
8.
Int J Mol Sci ; 21(19)2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33003449

RESUMO

We investigated the potential involvement of ceramide-enriched membrane domains in radiation-induced targeted and nontargeted effects using head and neck squamous cell carcinoma with opposite radiosensitivities. In radiosensitive SCC61 cells, the proportion of targeted effects was 34% and nontargeted effects killed 32% of cells. In contrast, only targeted effects (30%) are involved in the overall death of radioresistant SQ20B cells. We then demonstrated in SCC61 cells that nontargeted cell response was driven by the formation of the radiation-induced ceramide-enriched domain. By contrast, the existence of these platforms in SQ20B cells confers a permissive region for phosphatidylinositol-3-kinase (PI3K)/AKT activation. The disruption of lipid raft results in strong inhibition of PI3K/AKT signaling, leading to radiosensitization and apparition of nontargeted effects. These results suggest that ceramide-enriched platforms play a significant role in targeted and nontargeted effects during radiotherapy and that drugs modulating cholesterol levels may be a good alternative for improving radiotherapy effectiveness.


Assuntos
Ceramidas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Colesterol/genética , Terapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
9.
Br J Cancer ; 117(4): 583-587, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28683471

RESUMO

BACKGROUND: Urothelial bladder cancer (UBC) is characterised by a high risk of recurrence. Patient monitoring is currently based on iterative cystoscopy and on urine cytology with low sensitivity in non-muscle-invasive bladder cancer (NMIBC). Telomerase reverse transcriptase (TERT) is frequently reactivated in UBC by promoter mutations. METHODS: We studied whether detection of TERT mutation in urine could be a predictor of UBC recurrence and compared this to cytology/cystoscopy for patient follow-up. A total of 348 patients treated by transurethral bladder resection for UBC were included together with 167 control patients. RESULTS: Overall sensitivity was 80.5% and specificity 89.8%, and was not greatly impacted by inflammation or infection. TERT remaining positive after initial surgery was associated with residual carcinoma in situ. TERT in urine was a reliable and dynamic predictor of recurrence in NMIBC (P<0.0001). In univariate analysis, TERT positive-status after initial surgery increased risk of recurrence by 5.34-fold (P=0.0004). TERT positive-status was still associated with recurrence in the subset of patients with negative cystoscopy (P=0.034). CONCLUSIONS: TERT mutations in urine might be helpful for early detection of recurrence in UBC, especially in NMIBC.


Assuntos
Carcinoma de Células de Transição/urina , Recidiva Local de Neoplasia/urina , Vigilância da População/métodos , Telomerase/urina , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Cistoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasia Residual , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Estudos Prospectivos , Telomerase/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urina/citologia
10.
Br J Cancer ; 116(10): 1340-1349, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28407653

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) are resistant to standard treatments, partly due to cancer stem cells (CSCs) localised in hypoxic niches. Compared to X-rays, carbon ion irradiation relies on better ballistic properties, higher relative biological effectiveness and the absence of oxygen effect. Hypoxia-inducible factor-1α (HIF-1α) is involved in the resistance to photons, whereas its role in response to carbon ions remains unclear. METHODS: Two HNSCC cell lines and their CSC sub-population were studied in response to photons or carbon ion irradiation, in normoxia or hypoxia, after inhibition or not of HIF-1α. RESULTS: Under hypoxia, compared to non-CSCs, HIF-1α is expressed earlier in CSCs. A combined effect photons/hypoxia, less observed with carbon ions, results in a synergic and earlier HIF-1α expression in both subpopulations. The diffuse ROS production by photons is concomitant with HIF-1α expression and essential to its activation. There is no oxygen effect in response to carbon ions and the ROS localised in the track might be insufficient to stabilise HIF-1α. Finally, in hypoxia, cells were sensitised to both types of radiations after HIF-1α inhibition. CONCLUSIONS: Hypoxia-inducible factor-1α plays a main role in the response of CSCs and non-CSCs to carbon ion and photon irradiations, which makes the HIF-1α targeting an attractive therapeutic challenge.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Radioterapia com Íons Pesados , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fótons/uso terapêutico , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Sobrevivência Celular , Inativação Gênica , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação , Espécies Reativas de Oxigênio/metabolismo , Transfecção , Hipóxia Tumoral
11.
Future Oncol ; 13(8): 679-693, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28076966

RESUMO

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Everolimo/administração & dosagem , Everolimo/farmacocinética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
12.
Nanomedicine ; 13(8): 2655-2660, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28779947

RESUMO

Hadrontherapy presents the major advantage of improving tumor sterilization while sparing surrounding healthy tissues because of the particular ballistic (Bragg peak) of carbon ions. However, its efficacy is still limited in the most resistant cancers, such as grade III-IV head and neck squamous cell carcinoma (HNSCC), in which the association of carbon ions with gadolinium-based nanoparticles (AGuIX®) could be used as a Trojan horse. We report for the first time the radioenhancing effect of AGuIX® when combined with carbon ion irradiation in human tumor cells. An increase in relative biological effectiveness (1.7) in three HNSCC cell lines (SQ20B, FaDu, and Cal33) was associated with a significant reduction in the radiation dose needed for killing cells. Radiosensitization goes through a higher number of unrepaired DNA double-strand breaks. These results underline the strong potential of AGuIX® in sensitizing aggressive tumors to hadrontherapy and, therefore, improving local control while lowering acute/late toxicity.


Assuntos
Carbono/uso terapêutico , Carcinoma de Células Escamosas/radioterapia , Gadolínio/uso terapêutico , Neoplasias de Cabeça e Pescoço/radioterapia , Nanopartículas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Modelos Moleculares
13.
Mol Cancer ; 14: 134, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26183089

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most frequent and aggressive type of adult brain tumor. Most GBMs express telomerase; a high level of intra-tumoral telomerase activity (TA) is predictive of poor prognosis. Thus, telomerase inhibitors are promising options to treat GBM. These inhibitors increase the response to radiotherapy (RT), in vitro as well as in vivo. Since typical treatments for GBM include RT, our objective was to evaluate the efficiency of Imetelstat (TA inhibitor) combined with RT. FINDINGS: We used a murine orthotopic model of human GBM (N = 8 to11 mice per group) and µMRI imaging to evaluate the efficacy of Imetelstat (delivered by intra-peritoneal injection) alone and combined with RT. Using a clinically established protocol, we demonstrated that Imetelstat significantly: (i) inhibited the TA in the very center of the tumor, (ii) reduced tumor volume as a proportion of TA inhibition, and (iii) increased the response to RT, in terms of tumor volume regression and survival increase. CONCLUSIONS: Imetelstat is currently evaluated in refractory brain tumors in young patients (without RT). Our results support its clinical evaluation combined with RT to treat GBM.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Indóis/farmacologia , Niacinamida/análogos & derivados , Tolerância a Radiação/efeitos dos fármacos , Telomerase/antagonistas & inibidores , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Modelos Animais de Doenças , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Camundongos , Niacinamida/farmacologia , Oligonucleotídeos , Telomerase/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Future Oncol ; 11(10): 1511-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25963428

RESUMO

Optimal development of targeted drug combinations is one of the future challenges to be addressed. Computerization and mathematical models able to describe biological phenomena and to simulate the effects of changes in experimental conditions may help find solutions to this issue. We propose the concept of 'multiparameter trials', where biological, radiological and clinical data required for modeling purpose are collected and illustrated by the ongoing academic EVESOR trial. The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors. It may embody the 'proof of concept' of model-based drug development of anticancer agent combinations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Everolimo/administração & dosagem , Everolimo/farmacocinética , Humanos , Modelos Teóricos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
15.
Nanomedicine ; 11(1): 247-57, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24983891

RESUMO

Gadolinium based nanoparticles (GBNs, diameter 2.9±0.2nm), have promising biodistribution properties for theranostic use in-vivo. We aimed at demonstrating the radiosensitizing effect of these GBNs in experimental radioresistant human head and neck squamous cell carcinoma (SQ20B, FaDu and Cal33 cell lines). Combining 0.6mM GBNs with 250kV photon irradiation significantly decreased SQ20B cell survival, associated with an increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, and the inhibition of cell proliferation, each contributing to the commitment of late apoptosis. Similarly, radiation resistance was overcome for SQ20B stem-like cells, as well as for FaDu and Cal33 cell lines. Using a SQ20B tumor-bearing mouse model, combination of GBNs with 10Gy irradiation significantly delayed tumor growth with an increase in late apoptosis and a decrease in cell proliferation. These results suggest that GBNs could be envisioned as adjuvant to radiotherapy for HNSCC tumors.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Gadolínio/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Nanopartículas/química , Radiossensibilizantes/química , Animais , Apoptose , Carcinoma de Células Escamosas/patologia , Caspase 2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Dano ao DNA , Feminino , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/patologia , Histonas/química , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Microscopia de Fluorescência , Nanomedicina , Radioterapia
16.
BJU Int ; 113(2): 333-42, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24053469

RESUMO

OBJECTIVE: To try and identify a molecular signature for pathological staging and/or grading. through microarray analysis. PATIENTS AND METHODS: We performed a prospective multicentre study between September 2007 and May 2008 that included 108 bladder tumours (45 pTa, 35 pT1 and 28>pT1). Microarray analysis was performed using Agilent Technologies Human Whole Genome 4 × 44K oligonucleotide microarrays (Agilent, Santa Clara, CA, USA). A 'dual colour' method was used vs a reference pool of tumours. From the lists of genes provided by the Biometric Research Branch class comparison analyses, we validated the microarray results of 38 selected differentially expressed genes using reverse transcriptase quantitative PCR in another bladder tumour cohort (n = 95). RESULTS: The cluster 'superficial vs invasive stage' correctly classified 92.9% of invasive stages and 66.3% of superficial stages. Among the superficial tumours, the cluster analysis showed that pT1b tumours were closer to invasive stages than pT1a tumours. We also found molecular differences between low and high grade superficial tumours, but these differences were less well defined than the difference observed for staging. CONCLUSIONS: We confirmed that the histopathological classification into subgroups pTa, pT1a and pT1b can be translated into a molecular signature with a continuous progression of deregulation (overexpression or repression of these genes) from superficial (pTa) to more invasive (pT1a then b) stages.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Análise em Microsséries , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França/epidemiologia , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade
17.
Int J Radiat Oncol Biol Phys ; 118(2): 485-497, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37619790

RESUMO

PURPOSE: Stress granules (SGs) are cytoplasmic aggregates in which mRNAs and specific proteins are trapped in response to a variety of damaging agents. They participate in the cellular defense mechanisms. Currently, their mechanism of formation in response to ionizing radiation and their role in tumor-cell radiosensitivity remain elusive. METHODS AND MATERIALS: The kinetics of SG formation was investigated after the delivery of photon irradiation at different doses to head and neck squamous cell carcinoma cell lines with different radiosensitivities and the HeLa cervical cancer cell line (used as reference). In parallel, the response to a canonical inducer of SGs, sodium arsenite, was also studied. Immunolabeling of SG-specific proteins and mRNA fluorescence in situ hybridization enabled SG detection and quantification. Furthermore, a ribopuromycylation assay was used to assess the cell translational status. To determine whether reactive oxygen species were involved in SG formation, their scavenging or production was induced by pharmacologic pretreatment in both SCC61 and SQ20B cells. RESULTS: Photon irradiation at different doses led to the formation of cytoplasmic foci that were positive for different SG markers. The presence of SGs gradually increased from 30 minutes to 2 hours postexposure in HeLa, SCC61, and Cal60 radiosensitive cells. In turn, the SQ20B and FaDu radioresistant cells did not form SGs. These results indicated a correlation between sensitivity to photon irradiation and SG formation. Moreover, SG formation was significantly reduced by reactive oxygen species scavenging using dimethyl sulfoxide in SCC61 cells, which supported their role in SG formation. However, a reciprocal experiment in SQ20B cells that depleted glutathione using buthionine sulfoximide did not restore SG formation in these cells. CONCLUSIONS: SGs are formed in response to irradiation in radiosensitive, but not in radioresistant, head and neck squamous cell carcinoma cells. Interestingly, compared with sodium arsenite-induced SGs, photon-induced SGs exhibited a different morphology and cellular localization. Moreover, photon-induced SGs were not associated with the inhibition of translation; rather, they depended on oxidative stress.


Assuntos
Arsenitos , Neoplasias de Cabeça e Pescoço , Compostos de Sódio , Grânulos de Estresse , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Espécies Reativas de Oxigênio , Hibridização in Situ Fluorescente , Células HeLa , Tolerância a Radiação , Neoplasias de Cabeça e Pescoço/radioterapia
18.
Ann Surg Oncol ; 20(8): 2655-62, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23519518

RESUMO

BACKGROUND: Prognosis of peritoneal surface malignancies is influenced by the adequacy of surgical and chemotherapeutic treatment and by tumor spread at the time of diagnosis. By promoting morphological changes in the mesothelium, inflammatory cytokines reflect tumor biology and could be evaluated as biomarkers. Our objective was to evaluate intraperitoneal levels of IL-6, IL-8, IL-10, TNF-alpha, and sICAM in patients with pseudomyxoma peritonei and peritoneal mesothelioma. METHODS: Serum and peritoneal fluid samples were prospectively collected in patients managed for peritoneal surface malignancies including pseudomyxoma peritonei (PMP), mesotheliomas, and other rare primitive peritoneal cancers (cancer group) and patients who underwent intraperitoneal laparoscopic surgical procedures for benign diseases (noncancer group). Samples were analyzed for IL-6, IL-8, IL-10, TNF-alpha, and sICAM concentrations. Correlations were assessed with tumor spread related clinical scores. RESULTS: In both patient groups, intraperitoneal cytokine levels were higher than serum levels. Cancer patients had significantly higher intraperitoneal cytokine levels than noncancer patients. Peritoneal levels tended to increase in cancer patients with free tumor cells in peritoneal fluid. They were significantly higher in patients with tumor implants ≥2 cm and/or patients with peritoneal carcinomatosis index (PCI) >19. Furthermore, patients with malignant pseudomyxoma peritonei (grades II and III) had higher levels than patients with nonmalignant disease (grade I). CONCLUSIONS: Assessment of intraperitoneal IL-6, IL-8, IL-10, TNF-alpha, and sICAM levels can be performed in patients with peritoneal surface malignancies. They can be considered as both diagnostic and prognostic biomarkers that could be used as useful adjuncts for therapeutic decision making.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Citocinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Mesotelioma/metabolismo , Neoplasias Peritoneais/metabolismo , Pseudomixoma Peritoneal/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Ascítico/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma/patologia , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Peritoneais/patologia , Pseudomixoma Peritoneal/patologia , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
19.
BMC Cancer ; 13: 151, 2013 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-23530619

RESUMO

BACKGROUND: To determine whether ceramide is responsible for the induction of p53-independent early or late apoptosis in response to high- and low-Linear-Energy-Transfer (LET) irradiation. METHODS: Four cell lines displaying different radiosensitivities and p53-protein status were irradiated with photons or 33.4 or 184 keV/µm carbon ions. The kinetics of ceramide production was quantified by fluorescent microscopy or High-Performance-Liquid-Chromatogaphy and the sequence of events leading to apoptosis by flow cytometry. RESULTS: Regardless of the p53-status, both low and high-LET irradiation induced an early ceramide production in radiosensitive cells and late in the radioresistant. This production strongly correlated with the level of early apoptosis in radiosensitive cells and delayed apoptosis in the radioresistant ones, regardless of radiation quality, tumor type, radiosensitivity, or p53-status. Inhibition of caspase activity or ceramide production showed that, for both types of radiation, ceramide is essential for the initiation of early apoptosis in radiosensitive cells and late apoptosis following mitotic catastrophe in radioresistant cells. CONCLUSIONS: Ceramide is a determining factor in the onset of early and late apoptosis after low and high-LET irradiation and is the mediator of the p53-independent-apoptotic pathway. We propose that ceramide is the molecular bridge between mitotic catastrophe and the commitment phase of delayed apoptosis in response to irradiation.


Assuntos
Apoptose/genética , Apoptose/efeitos da radiação , Ceramidas/metabolismo , Radiação Ionizante , Proteína Supressora de Tumor p53/genética , Carbono , Caspases/metabolismo , Linhagem Celular Tumoral , Ceramidas/biossíntese , Relação Dose-Resposta à Radiação , Humanos , Cinética , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Fótons
20.
Int J Mol Sci ; 14(9): 17767-80, 2013 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-23994838

RESUMO

While now recognized as an aid to predict repeat prostate biopsy outcome, the urinary PCA3 (prostate cancer gene 3) test has also been recently advocated to predict initial biopsy results. The objective is to evaluate the performance of the PCA3 test in predicting results of initial prostate biopsies and to determine whether its incorporation into specific nomograms reinforces its diagnostic value. A prospective study included 601 consecutive patients addressed for initial prostate biopsy. The PCA3 test was performed before ≥12-core initial prostate biopsy, along with standard risk factor assessment. Diagnostic performance of the PCA3 test was evaluated. The three available nomograms (Hansen's and Chun's nomograms, as well as the updated Prostate Cancer Prevention Trial risk calculator; PCPT) were applied to the cohort, and their predictive accuracies were assessed in terms of biopsy outcome: the presence of any prostate cancer (PCa) and high-grade prostate cancer (HGPCa). The PCA3 score provided significant predictive accuracy. While the PCPT risk calculator appeared less accurate; both Chun's and Hansen's nomograms provided good calibration and high net benefit on decision curve analyses. When applying nomogram-derived PCa probability thresholds ≤30%, ≤6% of HGPCa would have been missed, while avoiding up to 48% of unnecessary biopsies. The urinary PCA3 test and PCA3-incorporating nomograms can be considered as reliable tools to aid in the initial biopsy decision.


Assuntos
Biópsia/métodos , Antígeno Prostático Específico/análise , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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