Administration of coenzyme-Q plus antithrombotics could sensitize glioblastoma cells to the effect of chemotherapeuticals
Abstract
Many evidences indicate that the ability of glioblastoma (GBM) cells to invade and resist chemo and radiotherapy is mostly due to phenotypic changes, from proliferative to migratory ones, which it is intimately linked to a hypoxic transition, initiated by oxygen deprivation after a vaso-occlusive event. Under these conditions, the transcription factor HIF-1? is expressed and triggers a neovascularization response that induces endothelial hyperplasia and the formation of a high density of aberrant, non-functional and leaky micro vessels. These vessels contribute to a positive feedback in the coagulation cascade, allowing blood extravasation and contact with tumor cells, resulting in a sustained coagulation. Moreover, HIF-1? overexpression is also linked to GBM cells resistance to chemo- and radiotherapy. Indeed, HIF-1? is upregulated by an increase in the level of free oxygen and nitrogen radicals. This is the molecular signal that turns on the hypoxic response, but it is also responsible for the resistance to therapies. The exacerbated level of oxidative stress present in GBM cells is accompanied by the rising of antioxidant enzyme activity, as a cellular attempt to restore redox homeostasis. In the clinical practice, the consequence for this particular cellular setting is the inefficiency of radiotherapy and some chemotherapeuticals such as temozolomide, whose mechanism is to target the cells by inducing an increase in free radicals. As GBM cells are endowed with a powerful antioxidant machinery, free radicals induced by both therapies are rapidly detoxified and result ineffective. Here we put forward a new strategy to sensitize GBM to the effect of chemotherapeuticals, by using the antioxidant CoQ, to reduce the cellular level of antioxidant enzymes, and antithrombotics, to diminish vaso-occlusive events; we explore how both compounds can act synergistically on the neovascularization process. To this aim, we will use murine preclinical GBM models, in parallel to biochemical, molecular, cellular and biomathematical approaches, to gain deeper insight into the pathophysiology of the disease and to develop innovative and efficient therapeutic approaches.
Financial:
James S. Mc. Donnell Foundation (USA) (2012-2014)
Participating entity:
Universidad de Castilla-La Mancha
Principal investigator:
Investigators:
10
Duration:
1 año
Amount:
50.000 $