Abstract： Objective To investigate the radiosensitizing effect of 17AAG-cypate micelles on human non-small cell lung cancer A549 cells and its possible mechanism. Methods (1) A single-hit multi-target model formula was used to analyze the radiosensitizing effects of 17AAG-M and 17AAG-cypate-M.(2) The effects of 17AAG-cypate-M on the viability of A549 cells under laser and X-ray irradiation were analyzed by MTT assay.(3) The effect of the drugs on the cell senescence was observed by β-galactosidase staining assay.(4) The effects of different treatment conditions on DNA damage repair were analyzed by γ-H2AX immunofluorescence staining assay.(5) The expression of p-Erk1/2 and p-Akt was measured by Western blot. The paired t test was used for analyzing the differences between groups. Results Compared with the X-ray irradiation group, the X-ray+17AAG-cypate-M group had a lower mean lethal dose and a sensitization enhancement ratio greater than 1, indicating that 17AAG-cypate-M had a radiosensitizing effect. Compared with the 17AAG-M group, the 17AAG-cypate-M group showed significantly lower cell viability (P<0.01), a significantly higher percentage of aging cells (P<0.01), and significantly further delayed DNA damage repair (P<0.01). And the 17AAG-cypate-M group had lower expression of p-Erk1/2 and p-Akt than the 17AAG-M group. Conclusions Compared with 17AAG-M, 17AAG-cypate-M has a higher radiosensitizing effect on A549 cells. The mechanism might be inducing the cell senescence, delaying DNA damage repair, and inhibiting the expression of p-Erk1/2 and p-Akt.
[1] Noguchi M,Yu D,Hirayama R,et al. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamy-cin[J].Biochem Bioph Res Co,2006,351(3):658-663.DOI:10.1016/j.bbrc.2006.10.094. [2] Musha A,Yoshida Y,Takahashi T,et al. Synergistic effect of heat shock protein 90 inhibitor,17-allylamino-17-demethoxygeldanamycin and X-rays,but not carbon-ion beams,on lethality in human oral squamous cell carcinoma cells[J].J Radiat Res,2012,53(4):545-550.DOI:10.1093/jrr/rrs012. [3] Wang HY,Zhang XM,Wang P,et al. Characteristics of DNA-binding proteins determine the biological sensitivity to high-linear energy transfer radiation[J].Nucl Acids Res,2010,38(10):3245-3251.DOI:10.1093/nar/gkq069. [4] Barker CR,Hamlett J,Pennington SR,et al. The topoisomerase Ⅱ-Hsp90 complex:a new chemotherapeutic target?[J].Int J Cancer,2006,118(11):2685-2693.DOI:10.1002/ijc.21717. [5] Weng SH,Tseng SC,Huang YC,et al. Inhibition of thymidine phosphorylase expression by using an HSP90 inhibitor potentiates the cytotoxic effect of cisplatin in non-small-cell lung cancer cells[J].Biochem Pharmacol,2012,84(1):126-136.DOI:10.1016/j.bcp.2012.03.011. [6] Almutairi A,Guillaudeu SJ,Berezin MY,et al. Biodegradable pH-sensing dendritic nanoprobes for near-infrared fluorescence lifetime and intensity imaging[J].Am ChemSoc,2008,130(2):444-445.DOI:10.1021/ja078147e. [7] Yu J,Javier D,Yaseen MA,et al. Selfassembly synthesis,tumor cell targeting,and photothermal capabilities of antibody-coated indocyanine green nanocapsules[J].Am Chem Soc,2010,132(6):1929-1938.DOI:10.1021/ja908139y. [8] Hasenstein JR,Shin HC,Kasmerchak K,et al. Antitumor activity of Triolimus:a novel multidrug-loaded micelle containing Paclitaxel,Rapamycin,and 17-AAG[J].Mol Cancer Therap,2012,11(10):2233-2242.DOI:10.1158/1535-7163.MCT-11-0987. [9] Larson N,Greish K,Bauer H,et al. Synthesis and evaluation of poly (styrene-co-maleic acid) micellar nanocarriers for the delivery of tanespimycin[J].Int J Pharmaceut,2011,420(1):111-117.DOI:10.1016/j.ijpharm.2011.08.011. [10] Saxena V,Hussain MD.Formulation and in vitro evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG) loaded polymeric mixed micelles for glioblastoma multiforme[J].Colloid Surface B,2013,112:350-355.DOI:10.1016/j.colsurfb.2013.07.031. [11] Yang H,Mao HJ,Wan ZH,et al. Micelles assembled with carbocyanine dyes for theranostic near-infrared fluorescent cancer imaging and photothermal therapy[J].Biomaterials2013,34(36):9124-9133.DOI:10.1016/j.biomaterials.2013.08.022. [12] Li YL,Deng YB,Tian X,et al. Multipronged design of light-triggered nanoparticles to overcome cisplatin resistance for efficient ablation of resistant tumor[J].Acsnano,2015,10(9):9626-9637.DOI:10.1021/acsnano.5b05097. [13] Faried LS,Faried A,Kanuma T,et al. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin increases chemosensitivity of CaSki cells to paclitaxel[J].Eur J Cancer,2006,42(7):934-947.DOI:10.1016/j.ejca.2005.12.018. [14] Mondesire WH,Jian WG,Zhang HX,et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells[J].Clin Cancer Res,2004,10(20):7031-7042.DOI:10.1158/1078-0432.CCR-04-0361. [15] Kim DW,Kim SY,Kim HK,et al. Multicenter phase Ⅱ trial of Genexol-PM,a novel Cremophor-free,polymeric micelle formulation of paclitaxel,with cisplatin in patients with advanced non-small-cell lung cancer[J].Ann Oncol,2007,18(12):2009-2014.DOI:10.1093/annonc/mdm374.
2017, Vol. 26 
