TY - JOUR
T1 - Nelfinavir induces radiation sensitization in pituitary adenoma cells
AU - Zeng, Jing
AU - See, Alfred P.
AU - Aziz, Khaled
AU - Thiyagarajan, Saravanan
AU - Salih, Tarek
AU - Gajula, Rajendra P.
AU - Armour, Michael
AU - Phallen, Jillian
AU - Terezakis, Stephanie
AU - Kleinberg, Lawrence
AU - Redmond, Kristen
AU - Hales, Russell K.
AU - Salvatori, Roberto
AU - Quinones-Hinojosa, Alfredo
AU - Tran, Phuoc T.
AU - Lim, Michael
N1 - Funding Information:
using the Mouse/Rat Prolactin ELISA kit from Calbiotech T.S. was supported by the Johns Hopkins Post-baccalaureate (PR063F100) as described by the manufacturer with GH3 Research Education Program. P.T.T. was supported by the Parker cells plated into 96 well plates. All experiments were done in B. Francis Fellowship and the ASTRO Junior Faculty Career duplicates. Research Training Award.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - 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 d, 17 d with nelfinavir treatment, 27 d with radiation 6 Gy, and 41 d with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on protein gel 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.
AB - 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 d, 17 d with nelfinavir treatment, 27 d with radiation 6 Gy, and 41 d with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on protein gel 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.
KW - Nelfinavir
KW - PI3K-AKT-mTOR
KW - Pituitary adenomas
KW - Radiosensitizer
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U2 - 10.4161/cbt.12.7.17172
DO - 10.4161/cbt.12.7.17172
M3 - Article
C2 - 21811091
AN - SCOPUS:80053391859
SN - 1538-4047
VL - 12
SP - 657
EP - 663
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 7
ER -