Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer.
Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer.
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DOI：
10.1371/journal.pone.0051821
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bai C
中科院分区：
文献类型：
--
作者：
Ge H;Ni S;Wang X;Xu N;Liu Y;Wang X;Wang L;Song D;Song Y;Bai C
地塞米松（DEX）联合治疗已被证明对NSCLC患者有益，通过减少化疗后的副作用改善临床症状。然而，最近的研究表明，DEX可以使癌细胞对细胞毒性药物治疗更不敏感，但不知道DEX联合治疗是否会影响治疗诱导的衰老（TIS），也不知道它是以p53依赖还是p53非依赖的方式。我们在不同的人NSCLC细胞系中进行了检查，并在存在或不存在DEX的情况下检测了顺铂（DDP）治疗后的细胞衰老。通过使用在裸鼠中作为异种移植瘤生长的人肺癌细胞系的肿瘤生长实验来评估DEX和DDP组合的体内作用。与DDP组相比，化疗期间DEX联合治疗NSCLC可增加肿瘤细胞活力并抑制TIS。DEX共处理组细胞DNA损伤信号通路蛋白表达减少，p53和p21 CIP 1表达降低，细胞分泌程序降低，NF-κB及其信号级联反应下调。DEX还显著降低体内DDP敏感性。我们的研究结果强调DEX通过钝化NSCLC化疗后治疗诱导的细胞衰老来降低化疗敏感性，这可能至少部分地以p53依赖的方式。因此，这些数据引起了人们对糖皮质激素（GC）与抗肿瘤药物在癌症患者临床管理中广泛联合使用的担忧。
Dexamethasone (DEX) co-treatment has proved beneficial in NSCLC patients, improving clinical symptoms by the reduction of side effects after chemotherapy. However, recent studies have shown that DEX could render cancer cells more insensitive to cytotoxic drug therapy, but it is not known whether DEX co-treatment could influence therapy-induced senescence (TIS), and unknown whether it is in a p53-dependent or p53-independent manner. We examined in different human NSCLC cell lines and detected cellular senescence after cisplatin (DDP) treatment in the presence or absence of DEX. The in vivo effect of the combination of DEX and DDP was assessed by tumor growth experiments using human lung cancer cell lines growing as xenograft tumors in nude mice. Co-treatment with DEX during chemotherapy in NSCLC resulted in increased tumor cell viability and inhibition of TIS compared with DDP treated group. DEX co-treatment cells exhibited the decrease of DNA damage signaling pathway proteins, the lower expression of p53 and p21CIP1, the lower cellular secretory program and down-regulation of NF-κB and its signaling cascade. DEX also significantly reduced DDP sensitivity in vivo. Our results underscore that DEX reduces chemotherapy sensitivity by blunting therapy induced cellular senescence after chemotherapy in NSCLC, which may, at least in part, in a p53-dependent manner. These data therefore raise concerns about the widespread combined use of gluocorticoids (GCs) with antineoplastic drugs in the clinical management of cancer patients.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1158/1078-0432.ccr-10-3349
发表时间：
2011-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Raabe EH;Lim KS;Kim JM;Meeker A;Mao XG;Nikkhah G;Maciaczyk J;Kahlert U;Jain D;Bar E;Cohen KJ;Eberhart CG
通讯作者：
Eberhart CG
DOI：
10.1158/1078-0432.ccr-10-0513
发表时间：
2010-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rossetto D;Truman AW;Kron SJ;Côté J
通讯作者：
Côté J
影响因子：
4.8
作者：
King, Elizabeth M.;Holden, Neil S.;Newton, Robert
通讯作者：
Newton, Robert
影响因子：
4.8
作者：
Ak, Prashanth;Levine, Arnold J.
通讯作者：
Levine, Arnold J.