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Abstract:
Aggressive pituitary tumors are rare but difficult to manage, as there
is no effective chemotherapy to restrict their growth and cause their
shrinkage. Within these tumors, growth-promoting cascades, like the
PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two
inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and
NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary
tumor cells (GH3) and on primary cell cultures ofhumanpituitary tumors
and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro,
NVP-BEZ235 had a potent apoptotic and cytostatic effect that was
characterized by decreased cyclin D/E and Cdk4/2 protein levels and
subsequent accumulation of cells in G1. In vivo, the effect was
transient, with a decrease in mitotic index and increase in apoptosis;
long-term treatment had no significant inhibitory effect on tumor
growth. In contrast, while NVP-BKM120 had little effect in vitro, it
dramatically limited tumor growth in vivo. Increased Akt phosphorylation
observed only in the NVP-BEZ235-treated tumors may explain the
differential response to the two inhibitors. Primary cell cultures of
human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell
viability and decreased hormone secretion, whereas NVP-BKM120 had little
effect. Altogether, these results show a potential for PI3K inhibitors
in the management of aggressive pituitary tumors. (C) 2016 AACR.
