RESUMEN
Statins, as inhibitors of de-novo synthesis of cholesterol, exert cytotoxic actions on tumor cells. Despite the increasing data on the antitumoral activities of statins, their complete mechanisms of action still remain obscure. Therefore, the present study aims to investigate the mechanisms of lipophilic statin-induced cytotoxicity on B16.F10 murine melanoma cells in vitro. In-vitro effects of two lipophilic statins, simvastatin and lovastatin, and a hydrophilic statin, pravastatin, were investigated with respect to B16.F10 murine melanoma cell proliferation and viability. Our results show that only lipophilic statins exerted strong cytotoxic effects on B16.F10 melanoma cells. To gain further evidence on the pleiotropic effects of statins responsible for their cytotoxicity in B16.F10 cells, we have assessed their proapoptotic effects by Annexin V-fluorescein isothiocyanate/propidium iodide staining and measured tumor cell production of the hypoxia-inducible factor 1α by western blot analysis, nonenzymatic antioxidant levels by an antioxidant colorimetric assay, and superoxide dismutase activity through an indirect method on the basis of inhibition of xanthine oxidase activity. Protein array was also used to assess angiogenic/inflammatory protein production in B16.F10 cells. Our results pointed out that the cytotoxic actions exerted by lipophilic statins were mainly based on the suppressive actions of these drugs on hypoxia-inducible factor 1α expression and nonenzymatic antioxidant levels, as well as because of the inhibition of superoxide dismutase activity in B16.F10 melanoma cells. In addition, the reduction in the angiogenic/inflammatory capacity of tumor cells induced by lipophilic statins can strengthen and support their cytotoxicity.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Melanoma Experimental , Ratones , Necrosis , Oxidación-Reducción , Estrés Oxidativo , Pravastatina/farmacología , Simvastatina/farmacologíaRESUMEN
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RESUMEN
Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in signal transduction. Cilia are anchored inside the cell through basal bodies (BBs), modified centrioles also acting as microtubule-organization centers. Photoreceptors (PRs) are sensory neurons, whose primary cilium forms a highly specialized compartment called the outer segment (OS) responsible for sensing incoming light. Thus, ciliopathies often present with retinal degeneration. Mutations in KIAA0586/TALPID3 (TA3) cause Joubert syndrome, in which 30% of affected individuals develop retinal involvement. To elucidate the function of TALPID3 in PRs, we studied talpid3 zebrafish mutants and identified a progressive retinal degeneration phenotype. The majority of PRs lack OS development due to defects in BB positioning and docking at the apical cell surface. Intracellular accumulation of the photopigment opsin leads to PR cell death of moderate severity. Electroretinograms demonstrate severe visual impairement. A small subset of PRs display normally docked BBs and extended OSs through rescue by maternally-deposited Talpid3. While localization of the small GTPase Rab8a, which plays an important role in BB docking, appears unaffected in talpid3-/- PRs, overexpression of constitutively active Rab8a rescues OS formation, indicating that the role of Ta3 in early ciliogenesis lies upstream of Rab8a activation in PRs.