Ricerc@Sapienza

Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition
is a predominant feature of the GBM contributing to tumor growth and resistance to conventional
therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness
is considered of great clinical relevance. Previously, we demonstrated that the activation of M2
muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation
in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs
to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved
in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is
however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with
consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates
the expression of stemness markers and miR-210 levels, one of the main regulators of the responses
to hypoxic condition in dierent tumor types. Our data demonstrate that Ape impairs the GSCs
proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of
GSCs to hypoxia