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1.
Eur J Med Chem ; 237: 114399, 2022 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-35468516

RESUMEN

Searching for new small molecules as photosensitizing agents, we have developed a class of twenty-five pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepines with a good substitution pattern defining a versatile synthetic pathway to approach the title ring system. All compounds were evaluated for their photocytotoxicity on a triple negative human breast cancer cell line (MDA-MB-231) in the dark and under UVA light (2.0 J/cm2). The most effective compounds exhibited a photoantiproliferative activity with IC50 values up to nanomolar ranges. Interestingly, these new developed compounds showed high selectivity towards cancerous cells with respect to non-cancerous ones. Moreover, four representative derivatives demonstrated to be phototoxic also against an additional human HER2 positive breast cancer cell line (HCC1954), and against the HER2 positive vesical cancer cell line (T24) harboring Hras mutation. Mechanistic studies performed in triple negative MDA-MB-231 cancer cells revealed the ability of the compounds to increase reactive oxygen species (ROS) production and to induce a thiol redox stress, thus triggering cancer cell death through apoptosis. Apoptotic cell death was also induced in highly aggressive and metastatic HER2 positive Hras mutated T24-treated bladder cancer cells. Overall, our data confirm that these new small photosensitizing agents may represent very promising candidates for phototherapy application against highly aggressive and resistant cancers.


Asunto(s)
Antineoplásicos , Indolizinas , Neoplasias de la Mama Triple Negativas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Azepinas/farmacología , Línea Celular Tumoral , Humanos , Indolizinas/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo
2.
Aging (Albany NY) ; 13(1): 89-103, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33424011

RESUMEN

Skin is the essential barrier of the human body which performs multiple functions. Endogenous factors, in concert with external assaults, continuously affect skin integrity, leading to distinct structural changes that influence not only the skin appearance but also its various physiological functions. Alterations of the barrier functions lead to an increased risk of developing disease and side reactions, thus the importance of maintaining the integrity of the epidermal barrier and slowing down the skin aging process is evident. Salvia haenkei (SH) has been recently identified as a potential anti-senescence agent; its extract is able to decrease the level of senescent cells by affecting the IL1α release and reducing reactive oxygen species (ROS) generation. In this study, SH extract was tested on human keratinocyte cell line (HaCaT) exposed to stress factors related to premature aging of cells such as free radicals and ultraviolet B radiation. We confirmed that SH acts as scavenger of ROS and found its ability to restore the skin barrier integrity by reinforcing the cytoskeleton structure, sealing the tight junctions and increasing the migration rate of cells. Given these results, this work becomes relevant, identifying Salvia haenkei as a compound useful for anti-aging skin treatment in clinical performance.


Asunto(s)
Queratinocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Piel/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Humanos , Salvia
3.
Biomolecules ; 11(2)2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33504020

RESUMEN

Photodynamic therapy (PDT) is frequently used to treat non-muscle invasive bladder cancer due its low toxicity and high selectivity. Since recurrence often occurs, alternative approaches and/or designs of combined therapies to improve PDT effectiveness are needed. This work aimed to evaluate the cytotoxicity of 4,6,4'-trimethylangelicin (TMA) photoactivated by blue light (BL) on human bladder cancer T24 cells and investigate the mechanisms underlying its biological effects. TMA/BL exerted antiproliferative activity through the induction of apoptosis without genotoxicity, as demonstrated by the expression levels of phospho-H2AX, an indicator of DNA double-stranded breaks. It also modulated the Wnt canonical signal pathway by increasing the phospho-ß-catenin and decreasing the nuclear levels of ß-catenin. The inhibition of this pathway was due to the modulation of the GSK3ß phosphorylation state (Tyr 216) that induces a proteasomal degradation of ß-catenin. Indeed, a partial recovery of nuclear ß-catenin expression and reduction of its phosphorylated form after treatment with LiCl were detected. As demonstrated by RT-PCR and cytofluorimetric analysis, TMA/BL also decreased the expression of CD44v6, a marker of cancer stem cells. Taken together, our data suggest that TMA photoactivated by BL may represent an interesting option for the photochemotherapy of noninvasive bladder carcinomas, since this treatment is able to inhibit key pathways for tumour growth and progression in the absence of genotoxic effects.


Asunto(s)
Carcinoma/tratamiento farmacológico , Furocumarinas/química , Fotoquimioterapia/métodos , Fototerapia/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular , Supervivencia Celular , Progresión de la Enfermedad , Histonas/metabolismo , Humanos , Receptores de Hialuranos/metabolismo , Técnicas In Vitro , Luz , Fibras Ópticas , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Transducción de Señal , Vejiga Urinaria/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
4.
Eur J Med Chem ; 39(5): 411-9, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15110967

RESUMEN

1,4,8-Trimethylfuro[2,3-h]quinolin-2(1H)-one (compound 5a) is the most interesting derivative among some new furoquinolinones prepared with the aim of moderating the strong toxic effects of 1,4,6,8-tetramethyl derivative (FQ), a powerful potential drug for photomedicine. Compound 5a showed a photobiological activity lower than FQ, but considerable higher than 8-MOP, the furocoumarin used in clinical photomedicine; contrary to classic furocoumarins, 5a induced a strong inhibition of protein synthesis in mammalian cells. Genotoxicity and skin erythema induction, the main side effects of both FQ and 8-MOP photosensitization, are virtually absent with 5a. This behavior seems to be connected to its particular reaction mechanism: differently from furocoumarin derivatives, 5a induced low levels of DNA-protein and no inter-strands cross-links, but formed covalent RNA-protein linkages, lesions not observed with known furocoumarins. Moreover, compound 5a generated reactive oxygen species to a considerable extent. For these features, compound 5a appears to be a new photosensitizing agent whose special activity deserves to be deeply investigated.


Asunto(s)
Furanos/farmacología , Furanos/toxicidad , Furocumarinas/farmacología , Furocumarinas/toxicidad , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/toxicidad , Quinolonas/farmacología , Quinolonas/toxicidad , Animales , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cricetinae , ADN/efectos de los fármacos , ADN/metabolismo , Replicación del ADN/efectos de los fármacos , Relación Dosis-Respuesta en la Radiación , Evaluación Preclínica de Medicamentos , Furanos/síntesis química , Furocumarinas/síntesis química , Células HeLa/efectos de los fármacos , Humanos , Ratones , Estructura Molecular , Fotobiología , Fármacos Fotosensibilizantes/síntesis química , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Quinolonas/síntesis química , ARN/efectos de los fármacos , ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Piel/efectos de los fármacos , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos
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