title: 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.
authors: Department of Neurosurgery, Peking Union Medical College Hospital, Beijing 100730, China.
authors: Congxin
authors: C
authors: Dai
authors: Bo
authors: B
authors: Zhang
authors: Xiaohai
authors: X
authors: Liu
authors: Sihai
authors: S
authors: Ma
authors: Yakun
authors: Y
authors: Yang
authors: Yong
authors: Y
authors: Yao
authors: Ming
authors: M
authors: Feng
authors: Xinjie
authors: X
authors: Bao
authors: Guilin
authors: G
authors: Li
authors: Janxin
authors: J
authors: Wang
authors: Kai
authors: K
authors: Guo
authors: Wenbin
authors: W
authors: Ma
authors: Bing
authors: B
authors: Xing
authors: Wei
authors: W
authors: Lian
authors: Jianqi
authors: J
authors: Xiao
authors: Feng
authors: F
authors: Cai
authors: Hongbin
authors: H
authors: Zhang
authors: Renzhi
authors: R
authors: Wang
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011388:Prolactin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D019382:Human Growth Hormone; D003606:Dacarbazine; D011388:Prolactin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide