蟾毒灵对非小细胞肺癌顺铂化疗的增敏作用及机制

doi:10.6040/j.issn.1671-7554.0.2014.934

摘要/Abstract

摘要： 目的研究蟾毒灵对人非小细胞肺癌(NSCLC)A549细胞、H1975细胞的顺铂化疗增敏作用并探讨其可能的参与机制。方法以不同浓度蟾毒灵、顺铂及二者联合分别处理A549细胞、H1975细胞, 采用CCK-8法、流式细胞术等方法检测药物对细胞增殖和凋亡的影响;Western blotting技术检测药物作用后核因子-κB(NF-κB)、c-myc等的表达。结果蟾毒灵可显著抑制A549细胞、H1975细胞增殖并诱导细胞凋亡, 且具有一定的时间、浓度依赖性;低剂量蟾毒灵可明显增加A549细胞、H1975细胞对顺铂的化疗敏感性, 且此过程伴随NF-κB、c-myc的表达下调。结论蟾毒灵显著增加A549细胞、H1975细胞对顺铂的敏感性;抑制NF-κB的活化及其下游分子c-myc的表达是其可能的参与机制之一。

关键词: 蟾毒灵, 细胞凋亡, 顺铂, 核因子-κB/c-myc, 非小细胞肺癌, 增敏

Abstract: Objective To investigate the effect of bufalin on chemosensitivity to cisplatin in non-small cell lung cancer (NSCLC) A549 and H1975 cells and explore the underlying molecular mechanisms. Methods A549 and H1975 cells were treated with various concentrations of genistein, cisplatin and their combination respectively. CCK-8 assay and flow cytometric analysis were used to investigate their effect on cell proliferation and apoptosis; Western blotting analysis was used to investigate the expressions of nuclear factor-kappa B(NF-κB) and its downstream molecule c-myc. Results Bufalin significantly inhibited the proliferation and induced apoptosis of A549 and H1975 cells in a time-and dose-dependent manner. Low concentration of bufalin significantly increased chemosensitivity to cisplatin in A549 and H1975 cells, accompanied by down-regulation of NF-κB and its downstream molecule c-myc. Conclusion Bufalin significantly increased chemosensitivity to cisplatin in A549 and H1975 cells, which is partly through inhibiting the activation of NF-κB and down-regulating its downstream molecular c-myc.

Key words: Chemosensitivity, Non-small cell lung cancer, Nuclear factor-kappa B/c-myc, Bufalin, Cell apoptosis, Cisplatin

中图分类号:

R734.2

杨璐, 刘延国, 李际盛, 王秀问. 蟾毒灵对非小细胞肺癌顺铂化疗的增敏作用及机制[J]. 山东大学学报（医学版）, 2015, 53(3): 6-11.

YANG Lu, LIU Yanguo, LI Jisheng, WANG Xiuwen. Effect of bufalin on chemosensitivity to cisplatin in non-small cell lung cancer and the underlying mechanisms[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2015, 53(3): 6-11.

参考文献

[1] Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014[J]. CA Cancer J Clin, 2014, 64(1):9-29.
[2] Ramalingam S, Pawlish K, Gadgeel S, et al. Lung cancer in young patients:analysis of a Surveillance, Epidemiology, and End Results database[J]. J Clin Oncol, 1998, 16(2):651-657.
[3] Miller YE. Pathogenesis of lung cancer:100 year report[J]. Am J Respir Cell Mol Biol, 2005, 33(3):216-223.
[4] Ettinger DS, Akerley W, Borghaei H, et al. Non-small cell lung cancer, version 2. 2013[J]. J Natl Compr Canc Netw, 2013, 11(6):645-653
[5] Li M, Yu X, Guo H, et al. Bufalin exerts antitumor effects by inducing cell cycle arrest and triggering apoptosis in pancreatic cancer cells[J]. Tumour Biol, 2014, 35(3):2461-2471.
[6] Gu W, Liu L, Fang FF, et al. Reversal effect of bufalin on multidrug resistance in human hepatocellular carcinoma BEL-7402/5-FU cells[J]. Oncol Rep, 2014, 31(1):216-222.
[7] Bian X, McAllister-Lucas LM, Shao F, et al. NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells[J]. J Biol Chem, 2001, 276(52):48921-48929.
[8] Chuang SE, Yeh PY, Lu YS, et al. Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells[J]. Biochem Pharmacol, 2002, 63(9):1709-1716.
[9] Yeh PY, Chuang SE, Yeh KH, et al. Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation[J]. Biochem Pharmacol, 2002, 63(8):1423-1430.
[10] Shen DY, Zhang W, Zeng X, et al. Inhibition of Wnt/beta-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma[J]. Cancer Sci, 2013, 104(10):1303-1308.
[11] Biroccio A, Benassi B, Amodei S, et al. C-Myc down-regulation increases susceptibility to cisplatin through reactive oxygen species-mediated apoptosis in M14 human melanoma cells[J]. Mol Pharmacol, 2001, 60(1):174-182.
[12] 田甜,李际盛,王亚伟,等. 染料木黄酮在小细胞肺癌H446细胞中通过抑制FoxM1通路发挥抗肿瘤作用[J]. 山东大学学报:医学版, 2013, 51(6):45-48. TIAN Tian, LI Jisheng, WANG Yawei, et al. Genistein exerts antitumor effects in small cell lung cancer H446 cells via suppressing the activity of FoxM1 pathway[J]. Journal of Shandong University:Health Science, 2013, 51(6):45-48.
[13] Huang C, Chen A, Guo M, et al. Membrane dielectric responses of bufalin-induced apoptosis in HL-60 cells detected by an electrorotation chip[J]. Biotechnol Lett, 2007, 29(9):1307-1313.
[14] Takai N, Ueda T, Nishida M, et al. Bufalin induces growth inhibition, cell cycle arrest and apoptosis in human endometrial and ovarian cancer cells[J]. Int J Mol Med, 2008, 21(5):637-643.
[15] 朱志图,王锴,郁云龙.蟾蜍灵联合奥沙利铂对胃癌MGC803细胞增殖抑制及凋亡的影响[J].中国老年学杂志, 2011, 31(17):3303-3306. ZHU Zhitu, WANG Kai, YU Yunlong. Bufalin and oxaliplatin inhibiting proliferation and induced apoptosis of gastric cancer cell line MGC-803[J]. Chinese Journal of Gerontology, 2011, 31(17):3303-3306.
[16] Colon-Otero G, Niedringhaus RD, Hillman SH, et al. A phase II trial of edatrexate, vinblastine, adriamycin, cisplastin, and filgrastim (EVAC/G-CSF) in patients with non-small-cell carcinoma of the lungs:a North Central Cancer Treatment Group Trial[J]. Am J Clin Oncol, 2001, 24(6):551-555.
[17] Yun HS, Baek JH, Yim JH, et al. Knockdown of hepatoma-derived growth factor-related protein-3 induces apoptosis of H1299 cells via ROS-dependent and p53-independent NF-kappaB activation[J]. Biochem Biophys Res Commun, 2014, 449(4):471-476.
[18] 王伟霞, 刘晓晴, 刘广贤, 等.多药耐药细胞株A549/Gem的建立及其生物学特性研究[J]. 中国肺癌杂志, 2008,11(1):55-61. WANG Weixia, LIU Xiaoqing, LIU Guangxian, et al. Establishment and biological characteristics of a multi-drug resistant cell line A549/Gem[J]. Zhongguo Fei Ai Za Zhi, 2008, 11(1):55-61.
[19] 潘泳岐,高原,都凤霞,等. C-myc参与β-catenin介导的肺腺癌A549/DDP细胞的化疗耐药的实验研究[J]. 中华临床医师杂志:电子版, 2013, 7(12):5408-5414. PAN Yongqi, GAO Yuan, DU Fengxia, et al. C-myc participates in β-catenin mediated lung adenocarcinoma cell A549/DDP drug resistance[J]. Chin J Clinicians:Electronic Edition, 2013, 7(12):5408-5414.
[20] Bang S, Jeon TJ, Kim MH, et al. Phase II study of cisplatin combined with weekly gemcitabine in the treatment of patients with metastatic pancreatic carcinoma[J]. Pancreatology, 2006, 6(6):635-641.
[21] Cascinu S, Gasparini G, Catalano V, et al. A phase I-II study of gemcitabine and docetaxel in advanced pancreatic cancer:a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)[J]. Ann Oncol, 1999, 10(11):1377-1379.

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