Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells.

Quinone-containing molecules have been developed against cancer mainly for their redox cycling ability leading to reactive oxygen species (ROS) formation. We have previously shown that donor-acceptor phenylaminonaphthoquinones are biologically active against a panel of cancer cells. In this report, we explored the mechanisms involved in cancer cell growth inhibition caused by two phenylaminonaphthoquinones, namely Q7 and Q9, with or without ascorbate (ASC). The results show that Q7 and Q9 are both redox cyclers able to form ROS, which strongly inhibit the proliferation of T24 cells. Q9 was a better redox cycler than Q7 because of marked stabilization of the semiquinone radical species arising from its reduction by ascorbate. Indeed, ASC dramatically enhances the inhibitory effect of Q9 on cell proliferation. Q9 plus ASC impairs the cell cycle, causing a decrease in the number of cells in the G2/M phase without involving other cell cycle regulating key proteins. Moreover, Q9 plus ASC influences the MAPK signaling pathways, provoking the appearance of a senescent cancer cell phenotype and ultimately leading to necrotic-like cell death. Because cellular senescence limits the replicative capacity of cells, our results suggest that induction of senescence may be exploited as a basis for new approaches to cancer therapy.

Inhibition of cell proliferation and migration by oxidative stress from ascorbate-driven juglone redox cycling in human bladder-derived T24 cells.

The effects of juglone on T24 cells were assessed in the presence and absence of ascorbate. The EC(50) value for juglone at 24 h decreased from 28.5 µM to 6.3 µM in the presence of ascorbate. In juglone-treated cells, ascorbate increased ROS formation (4-fold) and depleted GSH (65%). N-acetylcysteine or catalase restricted the juglone/ascorbate-mediated effects, highlighting the role of oxidative stress in juglone cytotoxicity. Juglone alone or associated with ascorbate did not cause caspase-3 activation or PARP cleavage, suggesting necrosis-like cell death. DNA damage and the mild ER stress caused by juglone were both enhanced by ascorbate. In cells treated with juglone (1-5 µM), a concentration-dependent decrease in cell proliferation was observed. Ascorbate did not impair cell proliferation but its association with juglone led to a clonogenic death state. The motility of ascorbate-treated cells was not affected. Juglone slightly restricted motility, but cells lost their ability to migrate most noticeably when treated with juglone plus ascorbate. We postulate that juglone kills cells by a necrosis-like mechanism inhibiting cell proliferation and the motility of T24 cells. These effects are enhanced in the presence of ascorbate.

Redox-active quinones and ascorbate: an innovative cancer therapy that exploits the vulnerability of cancer cells to oxidative stress.

Cancer cells are particularly vulnerable to treatments impairing redox homeostasis. Reactive oxygen species (ROS) can indeed play an important role in the initiation and progression of cancer, and advanced stage tumors frequently exhibit high basal levels of ROS that stimulate cell proliferation and promote genetic instability. In addition, an inverse correlation between histological grade and antioxidant enzyme activities is frequently observed in human tumors, further supporting the existence of a redox dysregulation in cancer cells. This biochemical property can be exploited by using redox-modulating compounds, which represent an interesting approach to induce cancer cell death. Thus, we have developed a new strategy based on the use of pharmacologic concentrations of ascorbate and redox-active quinones. Ascorbate-driven quinone redox cycling leads to ROS formation and provoke an oxidative stress that preferentially kill cancer cells and spare healthy tissues. Cancer cell death occurs through necrosis and the underlying mechanism implies an energetic impairment (ATP depletion) that is likely due to glycolysis inhibition. Additional mechanisms that participate to cell death include calcium equilibrium impairment and oxidative cleavage of protein chaperone Hsp90. Given the low systemic toxicity of ascorbate and the impairment of crucial survival pathways when associated with redox-active quinones, these combinations could represent an original approach that could be combined to standard cancer therapy.

[Ureterointestinal anastomosis in ileal conduit in single kidney. New surgical technique]. / Anastomosis ureterointestinal en conducto ileal en monorreno. Nueva técnica quirúrgica.

Introduction of a new approach for uretero-ileal implantation when only one kidney is available. The technique follows the same approach as the Wallace-type re-implantation but in this case the uretero-ileal anastomosis plate is formed with the far en 2-3 cm of ureter. All cases performed with this technique have been highly successfull as reported in this clinical account.

Anastomosis ureterointestinal en conducto ileal en monorreno. Nueva técnica quirúrgica / Ureterointestinal anastomosis in single kidney ileal duct. New surgical technique

Se presenta una nueva modalidad de implantación para aquellos casos en los que existe una sola unidad renal urétero ileal para aquellos en que nos encontramos con una sola unidad renal. La técnica tiene el mismo planteamiento que la técnica de reimplantación tipo Wallace, formando en este caso la placa de anastomosis urétero ileal con los 2-3 últimos cm del uréter. Los casos realizados hasta el momento con dicha técnica han sido satisfactorios como se refiere a lo largo de esta nota clínica (AU)

Low-input cropping for Acid soils of the humid tropics.

A low-input cropping system has been developed at Yurimaguas, Peru, to serve as a transition technology between shifting and continuous cultivation for acid soils of the humid tropics. Principal features are slash-and-burn clearing, rotation of acid-tolerant upland rice and cowpea cultivars, maximum residue return, no tillage, and no lime or fertilizer applications. When yields decline as a result of increasing weed pressure and nutrient deficiencies, a kudzu fallow is grown for 1 year. Subsequent options include fertilizer-based continuous cultivation, pastures, or agroforestry. The system preserves some agroecosystem diversity and contributes toward a sustainable level of production and income for farmers in humid tropical regions.