Inhibition of PI3K/AKT/mTOR Pathway Enhances Temozolomide-Induced Cytotoxicity in Pituitary Adenoma Cell Lines in Vitro and Xenografted Pituitary Adenoma in Female Nude Mice

Abstract

Invasive pituitary adenomas (PAs) are often refractory to standard therapy and salvage treatment with temozolomide (TMZ). Hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway contributes to chemotherapy resistance in many cancers. XL765, a novel dual-PI3K/mTOR inhibitor, has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers. The hyperactive PI3K/AKT/mTOR pathway frequently occurs in invasive PAs. In this study, we investigated whether XL765 sensitizes PA cells to TMZ in vitro and in vivo. Experiments were carried out to evaluate the effect of XL765 and TMZ alone or in combination on cell proliferation and apoptosis of PA cell lines (αT3-1, GH3, and MMQ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice. XL765 and TMZ synergistically inhibited the growth of PA cell lines and induced apoptosis. Combination of XL765 and TMZ synergistically inhibited tumor growth, decreased serum GH and prolactin levels, and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects. In addition, XL765 in combination with TMZ dramatically decreased phosphorylation of AKT and mTOR as well as the expression of Bcl-2. The increased expression of cleaved poly (ADP-ribose) polymerase and Bcl-2-associated X protein along with elevated caspase-3/7 activity were also observed in the combination group. Therefore, dual inhibitors of PI3K and mTOR may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs.