Tesis doctoral de Oscar Gonzalez Moreno
Prostate cancer (pca) is the leading cause of cancer in men and the second cause of death in western countries. Prevention trials using antioxidant-enriched diets are currently underway and selenium is one of the most promising chemopreventing agents. To study selenium-mediated cancer treatment, we have used c3(1)/tag mice-derived prostate cancer cell lines treated either with methylselenic acid (msa) or sodium selenite. Mtt cytotoxicity assays showed that msa was much more effective than sodium selenite in inducing cell growth inhibition and apoptosis. Microarray analysis using affymetrix showed that the number of genes with an altered expression in tumor cells was significantly higher (p<0.01) than that found in non-tumoral cells. Pathways analyses using ingenuity¿ revealed a decreased expression of genes involved in metabolism (fabp5, cyba), signal transduction (erk, akt), angiogenesis (neuropilin-1, flt-4), and transcription (creb). Combination therapies using low doses of etoposide and taxotere (docetaxel¿) plus low doses of msa revealed a strong enhancement of cell growth inhibition and apoptosis in tumor cells. Moreover, in vivo xenografts using pr-14 cells, demonstrated that msa enhanced dramatically the chemotherapeutical effect of etoposide, resulting in 80% tumor growth inhibition. Pca prevention preclinical trials using tramp mice fed with low and high selenium-containing diets (0.08 and 0.24ppm respectively), showed that high selenium diets are not able to reduce or prevent pin an tumor developed in these mice. Recently the selct clinical trial which has been finished in january 2009, has found no benefit on pca prevention by supranutritional administration of selenium, vit e or a combination of both. selenoprotein-p (sepp) transports selenium to the tissues. Sepp expression is downregulated in pca. When c3(1)/tag-derived cells were treated with h2o2, the tumoral cells pr-14 and pr-14c1 (with low sepp expression) were highly sensitive to cell growth inhibition induced by oxidative damage, but not the pin-like pr-111 cell line (with high sepp expression). Tumoral cells pr-14 showed high ros levels that increased significantly with h2o2 treatment. Administration of purified sepp was able to prevent ros induction in these cells. When sepp expression was inhibited in pr-111 cells, a significant increase in cell growth inhibition and ros levels, compared to control cells was found. Purified sepp was able to prevent ros induction in these cells as found for pr-14 cells. These results showed that sepp protects prostate cells from oxidative damage. Cross tramp mice with seppko+/- mice and evaluation of pin or tumor lesions appearance showed no differences with respect to tramp mice. This results demonstrate that downregulation of sepp does not accelerate pca in this animal model.
Datos académicos de la tesis doctoral «Role of selenium and selenoprotein-p in prostate cancer treatment and prevention«
- Título de la tesis: Role of selenium and selenoprotein-p in prostate cancer treatment and prevention
- Autor: Oscar Gonzalez Moreno
- Universidad: Navarra
- Fecha de lectura de la tesis: 24/03/2009
Dirección y tribunal
- Director de la tesis
- Alfonso Calvo Gonzalez
- Tribunal
- Presidente del tribunal: julia Bujan varela
- adela Lopez de cerain salsamendi (vocal)
- Luis Santamaría solis (vocal)
- lutz Schomburg (vocal)