地塞米松降低紫杉醇对肺癌细胞化疗作用的实验研究
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摘要
目的研究地塞米松(dexamethasone,Dex)降低紫杉醇对肺癌细胞的化疗作用。方法 MTT法考察不同浓度的紫杉醇,以及地塞米松(10μmol·L~(-1))与不同浓度的紫杉醇联用,对肺癌细胞A549、Calu-1存活率的影响;流式细胞仪检测细胞周期;Western blot检测地塞米松对糖皮质激素受体(GR)、P-糖蛋白(P-gP)、多药耐药蛋白1(MRP-1)表达的影响;裸鼠移植瘤实验考察地塞米松降低紫杉醇对肺癌细胞的化疗作用。结果与紫杉醇单独作用相比,地塞米松(10μmol·L~(-1))联合紫杉醇降低了紫杉醇对肺癌细胞A549、Calu-1的敏感性,使IC_(50)明显提高(A549细胞:IC_(50)由0.58μmol·L~(-1)提高到1.35μmol·L~(-1);Calu-1细胞:IC_(50)由1.10μmol·L~(-1)提高到2.10μmol·L~(-1));地塞米松使GR蛋白表达增高,同时使P-gP、MRP-1蛋白的表达明显升高;地塞米松联合紫杉醇明显降低紫杉醇对裸鼠移植瘤的抑瘤效果。结论地塞米松联合紫杉醇可能使肺癌细胞产生耐药性,降低紫杉醇的化疗效果。
Aim To investigate the effect of dexamethasone on paclitaxel chemotherapy, when given before chemotherapy. Methods MTT method was used to investigate the effects of paclitaxel at different concentrations and dexamethasone(10 μmol·L~(-1)) combined with paclitaxel at indicate dosages on the cell viability of lung cancer cells A549 and Calu-1. The cell cycle was detected by flow cytometry. The effect of dexamethasone on protein expression of glucocorticoid receptor(GR), P-glycoprotein(P-gP) and multidrug resistance protein-1(MRP-1) expression were detected by Western blot. The effect of dexamethasone on lung cancer resistance of paclitaxel xenografts in nude mice was studied as well. Results paclitaxel at indicate dosages with dexamethasone( 10 μmol·L-1) showed significantly increased IC50 value( A549: from 0.58 to1.35 μmol · L-1; Calu-1 from 1.10 to 2.10 μmol·L-1). Dexamethasone activated GR,increased GR expression,and up-regulated the expression of P-gP and MRP-1. Dexamethasone combined with paclitaxel significantly decreased the antitumor effect of paclitaxel on nude mice transplanted tumor. Conclusions Giving dexamethasone before chemotherapy may cause resistance to cancer cells and reduce the effect of paclitaxel chemotherapy.
Aim To investigate the effect of dexamethasone on paclitaxel chemotherapy, when given before chemotherapy. Methods MTT method was used to investigate the effects of paclitaxel at different concentrations and dexamethasone(10 μmol·L~(-1)) combined with paclitaxel at indicate dosages on the cell viability of lung cancer cells A549 and Calu-1. The cell cycle was detected by flow cytometry. The effect of dexamethasone on protein expression of glucocorticoid receptor(GR), P-glycoprotein(P-gP) and multidrug resistance protein-1(MRP-1) expression were detected by Western blot. The effect of dexamethasone on lung cancer resistance of paclitaxel xenografts in nude mice was studied as well. Results paclitaxel at indicate dosages with dexamethasone( 10 μmol·L-1) showed significantly increased IC50 value( A549: from 0.58 to1.35 μmol · L-1; Calu-1 from 1.10 to 2.10 μmol·L-1). Dexamethasone activated GR,increased GR expression,and up-regulated the expression of P-gP and MRP-1. Dexamethasone combined with paclitaxel significantly decreased the antitumor effect of paclitaxel on nude mice transplanted tumor. Conclusions Giving dexamethasone before chemotherapy may cause resistance to cancer cells and reduce the effect of paclitaxel chemotherapy.
引文
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[11] Veronika S, Martina T, Michaela D, et al. Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms[J]. Int J Oncol, 2016, 49(4): 1277-88.
[12] Chen Y X, Wang Y, Fu C C, et al. Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells[J]. Endocr Relat Cancer, 2010, 17(1): 39-50.
[13] Yang N, Zhang H, Si-Ma H, et al. Dexamethasone decreases hepatocellular carcinoma cell sensitivity to cisplatin-induced apoptosis[J]. Hepatogastroenterology, 2011, 58(15): 1730-5.
[14] Wang H, Li M, Rinehart J J, Zhang R. Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine[J]. Cancer Chemother Pharmaco, 2004, 53(6): 459-67.
[15] Henzi I, Walder B, Tramer M R. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review[J]. Anesth Analg, 2000, 90(1): 186-94.
[2] de Ruijter T C, Veeck J, de Hoon J P, et al. Characteristics of triple-negative breast cancer[J]. J Cancer Res Clin Oncol, 2011, 137(2):183-92.
[3] Bosch A, Eroles P, Zaragoza R, et al. Triplenegative breast cancer: molecular features, pathogenesis, treatment and current lines of research[J]. Cancer Treat Rev, 2010, 36(3):206-15.
[4] Clark O, Botrel T E, Paladini L, et al. Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis[J]. Core Evid, 2014, 9(2): 1-11.
[5] Narayanan S, Srinivas S, Feldman D. Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy[J]. Nat Rev Urol, 2016, 13(1): 47-60.
[6] Fujii Y, Nakayama M. Reduction of postoperative nausea and vomiting and analgesic requirement with dexamethasone in women undergoing general anesthesia for mastectomy[J]. Breast J, 2007, 13(6): 564-7.
[7] 赵素华,杨秀勤,朱伟 等. 水溶性紫杉醇前药的制备及抗肿瘤活性的研究[J]. 中国药理学通报, 2016 , 32(12) :1711-7.[7] Zhao S H, Yang X Q, Zhu W, et al. Preparation of anti-cancer water-soluble paclitaxel prodrug and its anti-cancer effect [J]. Chin Pharmacol Bull, 2016, 32(12): 1711-7.
[8] Mattern J, Büchler M W, Herr I. Cell cycle arrest by glucocorticoids may protect normal tissue and solid tumors from cancer therapy[J]. Cancer Biol Ther, 2007, 6(9):1345-54.
[9] Wang W, Li Y, Zhu J Y, et al. Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition[J]. Oncotarget, 2016 ,7(52):87232-87245.
[10] Ge H, Ni S, Wang X, et al. Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer[J]. PLoS One, 2012, 7(12): 1-14.
[11] Veronika S, Martina T, Michaela D, et al. Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms[J]. Int J Oncol, 2016, 49(4): 1277-88.
[12] Chen Y X, Wang Y, Fu C C, et al. Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells[J]. Endocr Relat Cancer, 2010, 17(1): 39-50.
[13] Yang N, Zhang H, Si-Ma H, et al. Dexamethasone decreases hepatocellular carcinoma cell sensitivity to cisplatin-induced apoptosis[J]. Hepatogastroenterology, 2011, 58(15): 1730-5.
[14] Wang H, Li M, Rinehart J J, Zhang R. Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine[J]. Cancer Chemother Pharmaco, 2004, 53(6): 459-67.
[15] Henzi I, Walder B, Tramer M R. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review[J]. Anesth Analg, 2000, 90(1): 186-94.