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1.
Curr Oncol ; 30(3): 2812-2824, 2023 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-36975427

RESUMEN

BACKGROUND: Intraoperative radiotherapy (IORT) is a therapeutic de-escalation option in older women with low-risk early breast cancer (EBC). A qualitative study was implemented to describe EBC physicians' points of view on IORT as a de-escalation option. METHODS: Recorded face-to-face and telephone semi-structured interviews were conducted among diverse physicians from seven French comprehensive cancer centers. Interview transcripts were grouped as corpus to construct a typology. Thematic analysis was performed. RESULTS: Positions toward IORT were contrasted between the 16 participating physicians. Five fully supported IORT as a de-escalation option, four were not in favor, and seven had a more reserved or neutral opinion. Points of divergence concerned treatment efficacy, treatment duration, side effects and sequelae, psychological impact, compliance with adjuvant endocrine therapy, logistical constraints, financial cost, and availability of other techniques of partial breast irradiation. Physicians in favor of IORT emphasized direct benefits for the patient, and those against pointed the lack of specific guidelines, risk of lost opportunity in older women with long life expectancy, and challenges of shared decision making. CONCLUSIONS: Despite national policies to preserve cancer patients' quality of life and increase their participation in medical decision making, therapeutic de-escalation using IORT is not consensual among physicians. Further efforts are needed to promote patient-centered care.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Anciano , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Calidad de Vida , Radioterapia Adyuvante/métodos , Mastectomía Segmentaria/métodos , Resultado del Tratamiento
2.
Cell Biol Toxicol ; 28(4): 239-53, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22491967

RESUMEN

In this study, we have compared several features of cell death triggered by classical inducers of apoptotic pathways (etoposide and tumour necrosis factor (TNF)-α) versus exogenous reactive oxygen species (ROS; hydrogen peroxide (H2O2), tert-butyl hydroperoxide (t-BHP)) or a ROS generator (paraquat). Our aim was to characterize relationships that exist between ROS, mitochondrial perturbations, Bcl-2 and caspases, depending on source and identity of ROS. First, we have found that these five inducers trigger oxidative stress, mitochondrial membrane permeabilization (MMP), cytochrome c (cyt c) release from mitochondria and cell death. In each case, cell death could be inhibited by several antioxidants, showing that it is primarily ROS dependent. Second, we have highlighted that during etoposide or TNF-α treatments, intracellular ROS level, MMP and cell death are all regulated by caspases and Bcl-2, with caspases acting early in the process. Third, we have demonstrated that H2O2-induced cell death shares many of these characteristics with etoposide and TNF-α, whereas t-BHP induces both caspase-dependent and caspase-independent cell death. Surprisingly, paraquat-induced cell death, which harbours some characteristics of apoptosis such as cyt c release and caspase-3 activation, is not modulated by Bcl-2 and caspase inhibitors, suggesting that paraquat also triggers non-apoptotic cell death signals. On the one hand, these results show that endogenous or exogenous ROS can trigger multiple cell death pathways with Bcl-2 and caspases acting differentially. On the other hand, they suggest that H2O2 could be an important mediator of etoposide and TNF-α-dependent cell death since these inducers trigger similar phenotypes.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Peróxido de Hidrógeno/metabolismo , Mitocondrias/efectos de los fármacos , Oxidantes/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Antioxidantes/farmacología , Citocromos c/metabolismo , Etopósido/farmacología , Células HeLa , Humanos , Peróxido de Hidrógeno/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Paraquat/farmacología , Permeabilidad/efectos de los fármacos , Transporte de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , terc-Butilhidroperóxido/farmacología
3.
BMC Cell Biol ; 10: 50, 2009 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-19555499

RESUMEN

BACKGROUND: The retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis. In cancer cells, ablation of Rb function or its pathway is a consequence of genetic inactivation, viral oncoprotein binding or deregulated hyperphosphorylation. Some recent data suggest that Rb relocation could also account for the regulation of its tumor suppressor activity, as is the case for other tumor suppressor proteins, such as p53. RESULTS: In this reported study, we present evidence that a fraction of the total amount of Rb protein can localize to the mitochondria in proliferative cells taken from both rodent and human cells. This result is also supported by the use of Rb siRNAs, which substantially reduced the amount of mitochondrial Rb, and by acellular assays, in which [35S]-Methionine-labeled Rb proteins bind strongly to mitochondria isolated from rat liver. Moreover, endogenous Rb is found in an internal compartment of the mitochondria, within the inner-membrane. This is consistent with the protection of Rb from alkaline treatment, which destroys any interaction of proteins that are weakly bound to mitochondria. CONCLUSION: Although a few data regarding an unspecific cytosolic localization of Rb protein have been reported for some tumor cells, our results are the first evidence of a mitochondrial localization of Rb. The mitochondrial localization of Rb is observed in parallel with its classic nuclear location and paves the way for the study of potential as-yet-unknown roles of Rb at this site.


Asunto(s)
Mitocondrias/química , Proteína de Retinoblastoma/análisis , Animales , Apoptosis , Fraccionamiento Celular/métodos , Línea Celular , Humanos , Ratones , Mitocondrias/metabolismo , Ratas , Proteína de Retinoblastoma/metabolismo
4.
Biochem Biophys Res Commun ; 387(4): 772-7, 2009 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-19635458

RESUMEN

p53 protein plays a central role in suppressing tumorigenesis by inducing cell cycle arrest or apoptosis through transcription-dependent and -independent mechanisms. Emerging publications suggest that following stress, a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis. However, the localization of p53 under unstressed conditions remains largely unexplored. Here we show that p53 is localized at mitochondria in absence of apoptotic stimuli, when cells are proliferating, localization observed in various cell types (rodent and human). This is also supported by acellular assays in which p53 bind strongly to mitochondria isolated from rat liver. Furthermore, the mitochondria subfractionation study and the alkaline treatment of the mitochondrial p53 revealed that the majority of mitochondrial p53 is present in the membranous compartments. Finally, we identified VDAC, a protein of the mitochondrial outer-membrane, as a putative partner of p53 in unstressed/proliferative cells.


Asunto(s)
Proliferación Celular , Mitocondrias/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular , Humanos , Ratones , Ratas
5.
Cell Cycle ; 12(17): 2781-93, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23966169

RESUMEN

We and others previously reported that endogenous p53 can be located at mitochondria in the absence of stress, suggesting that p53 has a role in the normal physiology of this organelle. The aim of this study was to characterize in unstressed cells the intramitochondrial localization of p53 and identify new partners and functions of p53 in mitochondria. We find that the intramitochondrial pool of p53 is located in the intermembrane space and the matrix. Of note, unstressed HCT116 p53(+/+) cells simultaneously show increased O2 consumption and decreased mitochondrial superoxide production compared with their p53-null counterpart. This data was confirmed by stable H1299 cell lines expressing low levels of p53 specifically targeted to the matrix. Using immunoprecipitation and mass spectrometry, we identified the oligomycin sensitivity-conferring protein (OSCP), a subunit of the F1F0-ATP synthase complex, as a new partner of endogenous p53, specifically interacting with p53 localized in the matrix. Interestingly, this interaction seems implicated in mitochondrial p53 localization. Moreover, p53 localized in the matrix promotes the assembly of F1F0-ATP synthase. Taking into account that deregulations of mitochondrial respiration and reactive oxygen species production are tightly linked to cancer development, we suggest that mitochondrial p53 may be an important regulator of normal mitochondrial and cellular physiology, potentially exerting tumor suppression activity inside mitochondria.


Asunto(s)
Mitocondrias/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo , Adenosina Trifosfatasas/química , Adenosina Trifosfatasas/metabolismo , Secuencia de Aminoácidos , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Respiración de la Célula/genética , Estabilidad de Enzimas , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Membranas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Consumo de Oxígeno , Unión Proteica/genética , Transporte de Proteínas , Especies Reactivas de Oxígeno/metabolismo , Estrés Fisiológico
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