title: Nelfinavir induces radiation sensitization in pituitary adenoma cells.
abstract: Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p < 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT-mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.forename: Alfred P
authors.initials: AP
authors.lastname: See
authors.forename: Khaled
authors.initials: K
authors.lastname: Aziz
authors.forename: Saravanan
authors.initials: S
authors.lastname: Thiyagarajan
authors.forename: Tarek
authors.initials: T
authors.lastname: Salih
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Gajula
authors.forename: Michael
authors.initials: M
authors.lastname: Armour
authors.forename: Jillian
authors.initials: J
authors.lastname: Phallen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Terezakis
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kleinberg
authors.forename: Kristen
authors.initials: K
authors.lastname: Redmond
authors.forename: Russell K
authors.initials: RK
authors.lastname: Hales
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvatori
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019888:Nelfinavir / Q000494:pharmacology*; D009374:Neoplasms, Experimental; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011388:Prolactin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017304:Annexin A5; D053148:Caspase 3; D019888:Nelfinavir; D019869:Phosphatidylinositol 3-Kinases; D011388:Prolactin; D051057:Proto-Oncogene Proteins c-akt; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse