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.

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