A synthetic uracil derivative with antitumor activity through decreasing cyclin D1 and Cdk1, and increasing p21 and p27 in MCF-7 cells

Marchal, Juan A.; Núñez, María; Suárez, Inés; Díaz‐Gavilán, Mónica; Gómez-Vidal, José A.; Boulaiz, Houría; Rodríguez-Serrano, Fernando; Gallo, Miguel Á.; Espinosa, Antonio; Aránega, Amelia; Campos, Joaquı́n M.

doi:10.1007/s10549-006-9450-2

Cited by 26 publications

(10 citation statements)

References 40 publications

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“…The confocal microscopy study confirmed these results (Figure 3f–j). In fact, it is known to be difficult to demonstrate programmed cell death by known apoptosis-inducing agents in the MCF-7 human breast cancer cell line, and only a few cytotoxic agents have been found to act preferentially via an apoptotic mechanism in human breast cancer cells [38,39]. …”

Section: Resultsmentioning

confidence: 99%

Novel Drug Delivery System Based on Docetaxel-Loaded Nanocapsules as a Therapeutic Strategy Against Breast Cancer Cells

Sánchez-Moreno

Boulaiz

Ortega-Vinuesa

et al. 2012

IJMS

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In the field of cancer therapy, lipid nanocapsules based on a core-shell structure are promising vehicles for the delivery of hydrophobic drugs such as docetaxel. The main aim of this work was to evaluate whether docetaxel-loaded lipid nanocapsules improved the anti-tumor effect of free docetaxel in breast cancer cells. Three docetaxel-loaded lipid nanocapsules were synthesized by solvent displacement method. Cytotoxic assays were evaluated in breast carcinoma (MCF-7) cells treated by the sulforhodamine B colorimetric method. Cell cycle was studied by flow cytometry and Annexin V-FITC, and apoptosis was evaluated by using propidium iodide assays. The anti-proliferative effect of docetaxel appeared much earlier when the drug was encapsulated in lipid nanoparticles than when it was free. Docetaxel-loaded lipid nanocapsules significantly enhanced the decrease in IC50 rate, and the treated cells evidenced apoptosis and a premature progression of the cell cycle from G(1) to G(2)-M phase. The chemotherapeutic effect of free docetaxel on breast cancer cells is improved by its encapsulation in lipid nanocapsules. This approach has the potential to overcome some major limitations of conventional chemotherapy and may be a promising strategy for future applications in breast cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Novel Drug Delivery System Based on Docetaxel-Loaded Nanocapsules as a Therapeutic Strategy Against Breast Cancer Cells

Sánchez-Moreno

Boulaiz

Ortega-Vinuesa

et al. 2012

IJMS

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“…23,24 5-FU plays an important role in standard chemotherapy protocols for a range of solid tumors, including breast and colorectal cancers. 20,21 Considering the carcinogenic and mutagenic effects of Cd on healthy living cells, it seems beneficial to use a cancer cellular line, such as MCF-7.…”

Section: Introductionmentioning

confidence: 99%

Cadmium influences the 5-Fluorouracil cytotoxic effects on breast cancer cells

Asara¹,

Marchal²,

Bandiera³

et al. 2012

Eur J Histochem

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The aim of the research was to evaluate a heavy metal, cadmium (Cd), which was used to produce alterations in human breast cancer cell line MCF-7. Moreover, we analyzed both immunohistochemical and ultrastructural alterations induced by the antineoplastic drug, 5-fluorouracil (5-FU), after exposure to different concentrations of cd. Also, we compared the effects of these compounds on actin and tubulin cytoskeleton proteins. Under ultramicroscopic observation, control cells looked polymorphous with filopodia. In cells already treated with small concentrations of Cd, after brief times of incubation, we observed an intense metabolic activity with larger, clearer, and elongated mitochondria characterized by thin and numerous dilated cristae. 5-FU-treated cells showed cytotoxicity signs with presence of pore-like alterations in the cell membrane and evident degeneration of cytoplasm and cell nuclei. The addition of 5-FU (1.5 µM) to the cells treated with Cd (5 µM–20 µM) did not induce significant ultrastructural changes in comparison with cells treated only with Cd. In Cd+5FU-treated cells mitochondria with globular aspect and regular cristae indicated the active metabolic state. In cells treated only with Cd we observed alterations in actin distribution, while tubulin branched out throughout the cytoplasm. With the association of Cd+5FU, we observed less morphological alterations in both tubulin and actin cytoskeleton proteins. Although the mechanism remains unknown at present, our findings suggest that Cd prevents the cytotoxic effect of 5-FU on breast cancer cells. These preliminary results could have an important clinical application in patients with breast cancer.

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“…Although Cyclin D1 is shown to regulate mitochondrial function [24] and MnSOD activity [32], the exact mechanism in Cyclin D1-controlled MnSOD activity is unknown. Here, we found that a substantial amount of Cyclin D1 and CDK4 was localized in mitochondria in HK18 cells after LDIR with a peak accumulation similar to MnSOD enzymatic activation without evident increase in cytosolic fractions (Fig.…”

Section: Resultsmentioning

confidence: 99%

CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection

Jin

Qin

Shi

et al. 2015

Free Radical Biology and Medicine

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Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low dose ionizing radiation (LDIR) present naturally on earth surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. MnSOD, a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in the radioadaptive protection through detoxifying O2·- generated by mitochondrial oxidative phosphorylation. Contrasted to the well-studied mechanisms of SOD2 gene regulation, the mechanisms underlying post-translational regulation of MnSOD for radioprotection remain to be defined. Herein, we demonstrate that Cyclin D1-cyclin-dependent kinase 4 (CDK4) serves as the messenger to deliver the stress signal to mitochondria to boost mitochondrial homeostasis in human skin keratinocytes under LDIR adaptive radioprotection. Cyclin D1/CDK4 is found to relocate to mitochondria at the same time as MnSOD enzymatic activation peaks without significant changes of total MnSOD protein level. The mitochondrial-localized CDK4 directly phosphorylates MnSOD at Serine 106 (S106), causing enhanced MnSOD enzymatic activity and mitochondrial respiration. Expression of mitochondria-targeted dominant negative CDK4 or the MnSOD-S106A mutant reverses LDIR-induced mitochondrial enhancement and adaptive protection. The CDK4-mediated MnSOD activation and mitochondrial metabolism boost are also detected in skin tissues of mice receiving in vivo whole body LDIR. These results demonstrate a unique CDK4-mediated mitochondrial communication that allows cells to sense environmental genotoxic stress and boost mitochondrial homeostasis via enhancing phosphorylation and activation of MnSOD.

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A synthetic uracil derivative with antitumor activity through decreasing cyclin D1 and Cdk1, and increasing p21 and p27 in MCF-7 cells

Cited by 26 publications

References 40 publications

Novel Drug Delivery System Based on Docetaxel-Loaded Nanocapsules as a Therapeutic Strategy Against Breast Cancer Cells

Novel Drug Delivery System Based on Docetaxel-Loaded Nanocapsules as a Therapeutic Strategy Against Breast Cancer Cells

Cadmium influences the 5-Fluorouracil cytotoxic effects on breast cancer cells

CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection

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