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1.
Curr Med Chem ; 16(15): 1821-30, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19442148

RESUMEN

Cancer cells show an up-regulation of glycolysis, they readily take up vitamin C, and they appear more susceptible to an oxidative stress than the surrounding normal cells. Here we compare, analyse and discuss these particular hallmarks by performing experiments in murine hepatomas (TLT cells) and freshly isolated mouse hepatocytes. The results show that rates of lactate formation are higher in TLT cells as compared to mouse hepatocytes, but their ATP content represents less than 25% of that in normal cells. The uptake of vitamin C is more important in hepatoma cells as compared to normal hepatocytes. This uptake mainly occurs through GLUT1 transporters. Hepatoma cells have less than 10% of antioxidant enzyme activities as compared to normal hepatocytes. This decrease includes not only the major antioxidant enzymes, namely catalase, superoxide dismutase and glutathione peroxidase, but also the GSH content. Moreover, catalase is almost not expressed in hepatoma cells as shown by western blot analysis. We explored therefore a selective exposure of cancer cells to an oxidative stress induced by pro-oxidant mixtures containing pharmacological doses of vitamin C and a redox active compound such as menadione (vitamin K(3)). Indeed, the combination of vitamin C (which accumulates in hepatoma cells) and a quinone undergoing a redox cycling (vitamin K(3)) leads to an oxidative stress that kills cancer cells in a selective manner. This differential sensitivity between cancer cells and normal cells may have important clinical applications, as it has been observed with other pro-oxidants like Arsenic trioxide, isothiocyanates, Adaphostin.


Asunto(s)
Neoplasias/patología , Estrés Oxidativo , Animales , Línea Celular Tumoral , Humanos , Ratones , Neoplasias/metabolismo
2.
Anticancer Agents Med Chem ; 11(2): 213-21, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21395522

RESUMEN

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.


Asunto(s)
Ácido Ascórbico/farmacología , Neoplasias/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Quinonas/farmacología , Antineoplásicos , Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Humanos , Neoplasias/metabolismo , Quinonas/uso terapéutico
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