Radio sensitizing effect of double PI3K/mTOR inhibitor NVPBEZ235 on Hela cells of cervical cancer

doi:10.12092/j.issn.1009-2501.2018.01.004

Abstract

Abstract:

AIM: To investigate the effect that external irradiation of dual PI3K/mTOR inhibitors NVPBEZ235 on cervical cancer Hela cells. METHODS: Cervical cancer Hela cells treated with different concentrations of NVPBEZ235 and the radiotherapy (irradiation, IR) were examined for cell viability using MTT assay and colony forming ability. The cycle arrest of cervical cancer cells combined drug with IR was analyzed by using the flow cytometry. RESULTS: Compared with the control group, NVPBEZ235 can inhibit human cervical carcinoma cell in vitro (P<0.05). The combined use of NVPBEZ235 significantly enhanced the inhibitory effect of IR (P<0.05) in Hela cells. In vitro, NVPBEZ235 and IR, which had synergistic effect, can block cell cycle to G2/M period by the combined effect which was significantly greater than the effect of one single drug (P<0.05). CONCLUSION: 20% IC50 NVPBEZ235 can promote the cell's radiation sensitivity, inhibit the proliferation of cells, and thereby, increase its radio sensitivity to cervical cancer cells.

Key words: dual PI3K/mTOR inhibitor, NVPBEZ235, Hela, radio sensitization

CLC Number:

R965.2

ZHENG Yingao, LI Shengze, ZHANG Lei, GUO Xiangrui, BAO Jiaqian, WU Tao, LIU Jian. Radio sensitizing effect of double PI3K/mTOR inhibitor NVPBEZ235 on Hela cells of cervical cancer[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(1): 18-23.

References

［1］Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008［J］.Int J Cancer,2010,127(12):2893-2917.
［2］Wieringa HW,van der Zee AG,de Vries EG,et al. Breaking the DNA damage response to improve cervical cancer treatment［J］.Cancer Treat Rev,2016,42(3):30-40.
［3］Asimomytis A, Karanikou M, Rodolakis A, et al. mTOR downstream effectors, 4EBP1 and eIF4E, are over expressed and associated with HPV status in precancerous lesions and carcinomas of the uterine cervix ［J］.Oncol Lett,2016,12(5):3234-3240.
［4］Tangjitgamol S, Katanyoo K, Laopaiboon M, et al. Adjuvant chemotherapy after concurrent chemoradiation for locally advanced cervical cancer ［J］.Cochrane Database Syst Rev,2014,3(12):CD010401.
［5］Dizon DS, Mackay HJ, Thomas GM, et al. State of the science in cervical cancer: where we are Today and where we need to go ［J］.Cancer,2014,120(15): 2282-2288.
［6］Musa F,Alard A,David-West G,et al.Dual mTORC1/2 inhibition as a novel strategy for the resensitization and treatment of platinum-resistant ovarian cancer［J］.Mol Cancer Ther,2016,15(7):1557-1567.
［7］Rebecca VW,Massaro RR,Fedorenko IV,et al.Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma,Pigment［J］.Pigment Cell Melanoma Res,2014,27(3):465-478.
［8］Djuzenova CS, Fiedler V, Katzer A, et al. Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radio sensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiatio schedule ［J］.Oncotarget,2016,7(25):38191-38209.
［9］Kuger S,Graus D,Brendtke R,et al.Radio sensitization of glioblastoma cell lines by the dual PI3K and mTOR inhibitor NVP-BEZ235 depends on drug-irradiation schedule［J］.Transl Oncol,2013,6(2):169-179.
［10］Liu YN,Wan RZ,Liu ZP，et al.Recent developments of small molecule PI3K/mTOR dual inhibitors［J］.Mini Rev Med Chem,2013,13(14):2047-2059.
［11］Li YC，He SM，He ZX，et al．Plumbagin induces apoptotic and autophagic cell death through inhibition of the PI3K / Akt / m TOR pathway in human non-small cell lung cancer cells ［J］. Cancer Lett, 2014, 344(2):239-259．
［12］Feng T, Zheng L, Liu F, et al. Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway［J］.Oncotarget, 2016, 7(36):58381-58395.
［13］Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity［J］. Mol Cancer Ther, 2008, 7(7):1851-1863.
［14］Xie G, Wang Z, Chen Y, et al. Dual blocking of PI3K and mTOR signaling by NVP-BEZ235 inhibits proliferation in cervical carcinoma cells and enhances therapeutic response［J］. Cancer Lett, 2017, 1(388):12-20.
［15］Zhao B，Li L，Liu J，et al．Exposure to perfluorooctane sulfonate in utero reduces testosterone production in rat fetal Leydig cells［J］.PLoS One, 2014, 9(1):e78888.
［16］Wang WJ，Long LM，Yang N，et al．NVP-BEZ235，a novel dual PI3K / m TOR inhibitor， enhances the radiosensitivity of human glioma stem cells in vitro［J］. Acta Pharmacol Sin, 2013, 34(5):681-690.

[1]	ZHANG Zhe, LYU Yu, HUANG Panhao. Forsythiaside B inhibits the proliferation activity of HeLa cells though transcription factor NF-κB [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(4): 387-392.
[2]	YANG Jing-ya, WANG Xiao-ji, ZHANG Jian. Antitumor effect of combination of carboxymethyl-chitosan and Adriamycin in vitro [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2009, 14(11): 1253-1257.
[3]	ZHAO Ling-wu, WAN Fu-sheng. Apoptosis-induced effect of solanum lyratum thunb extract on human cervical cancer hela cells [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(8): 883-887.
[4]	MA Run-Di, YU Li-Jian, SU Wei-Ming, SHAO Hai-Yan, LIAO Ming-Neng, HE Dong-Mei, HUANG Lai-Zhen. Induction of cell cycle arrest and apoptosis by tubeimoside I isolated from Bolbostemma paniculatum in HeLa cells [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(3): 261-269.
[5]	ZHANG Jing, YANG Jing, WU Ji-Liang, ZHANG Lin, ZHAN Chun. Preparation of isoliquiritigenin liposome and its inhibitive effects on prolif-eration of human cervical cancer cells in vitro [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(11): 1268-1272.
[6]	HUO Guan-Hua, LU Yao-Feng, ZHANG Jin-Feng, GAO Hong -Qiu. Cytotoxicity induced by a combination ofγ-radiation with menadione sodium bisulfates on HeLa cells [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2003, 8(5): 530-533.