Endocrine Abstracts

Gliomas constitute the most frequent type of brain tumors and are characterized by a rapid growth and high diffusion through the brain. In particular, astrocytomas are a subtype of malignant gliomas that are graded from low to high aggressiveness (i.e. grade I, II, III and IV), being grade IV (glioblastoma multiforme, GBM) the most malignant type, and one of the most common cancers in the brain and CNS. To date, surgery is the first-line therapy combined with chemotherapy or radiotherapy; however, about two-thirds of patients do not have a survival rate greater than two years after diagnosis. Thus, it is necessary to develop new strategies to identify novel therapeutic targets for these devastating tumor pathologies. Metformin and Simvastatin are drugs commonly used to treat T2D patients and hypercholesterolemia, respectively. Interestingly, both compounds seem to exert anti-tumoral actions individually in different tumor types through AMPK-dependent and -independent pathways. Therefore, the aim of this study was to evaluate the anti-tumoral actions of metformin (10 mM) and simvastatin (10nM), individually and in combination, on key functional parameters (cell proliferation and migration rate) in human primary GBM cell cultures and GBM cell lines (U87 and U118), and to determine the signaling mechanisms behind these actions in GMB cells. We found that metformin and simvastatin alone inhibited cell proliferation in primary GBM cell cultures and GBM cell lines at 48 h and 72 h of incubation. Moreover, co-administration of metformin and simvastatin exerted an additive inhibitory effect on GBM cell proliferation compared to each compound alone. In addition, metformin, but not simvastatin, reduced cell migration in the U118 GBM cell line at 6 h, but not at 24 h, of incubation, whereas, co-administration of metformin and simvastatin significantly reduced the migration capacity of U118 GBM cell line at both incubation times (6 h and 24 h). Further analysis indicated that the anti-tumoral actions of metformin and simvastatin on GBM cells involve both common and distinct signaling pathways and are likely mediated through dissimilar molecular mechanisms. Altogether, our results demonstrate that metformin and simvastatin alone, and especially in combination, exert clear anti-tumoral effects in human primary GBM cell cultures and GBM cell lines, thus suggesting that these compounds deserve to be further explored as novel potential therapeutic tools for the treatment of patients with high-grade astrocytomas.