Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment.
Protection of p53 wild type cells from taxol by nutlin-3 in the combined lung cancer treatment.
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DOI：
10.1186/1471-2407-10-57
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发表时间：
2010-02-23
期刊：
影响因子：
3.8
通讯作者：
Abolmaali ND
中科院分区：
文献类型：
--
作者：
Tokalov SV;Abolmaali ND
肿瘤抑制因子TP53基因的突变是人类肿瘤中最常见的高频遗传改变之一，并已被证明与放化疗耐药性有关。癌细胞中缺乏野生型TP53基因可以利用两种拮抗药物的序列来获得治疗优势。本研究的目的是通过紫杉醇选择性地杀死p53缺陷细胞（FaDu和H1299），并通过事先给药nutlin-3来保护p53野生型细胞（A549），与某些已知的抗癌药物（5-氟尿嘧啶、喜树碱、罗司维汀）进行比较。用流式细胞术研究了5-氟尿嘧啶、喜树碱、玫瑰槐碱和胡桃素-3单独给药或与紫杉醇联合给药的细胞毒和细胞抑制作用。结果表明，nutlin-3对A549细胞具有抑制生长和保护作用。FaDu和H1299细胞对相同的处理有丝分裂阻滞和大量凋亡。与坚果素-3相比，其他化合物（5-氟尿嘧啶、喜树碱和罗斯科维汀）的选择性较弱，毒性较高。我们提出了一种利用nutlin-3在保护正常细胞免受紫杉醇侵害的同时选择性地增加p53缺陷细胞凋亡的治疗策略。
Mutations within the tumor suppressor TP53 gene are one of the most common genetic alterations present at high frequency in human tumors and have been shown to be associated with resistance to radio-chemotherapy. The lack of the wild type TP53 gene in cancer cells could be exploited for therapeutic advantage using a sequence of two antagonistic drugs. The aim of this study was to selectively kill p53 deficient cells (FaDu and H1299) by taxol and to protect p53 wild type cells (A549) by the prior administration of nutlin-3 in comparison to certain known anticancer drugs (5-fluorouracil, camptothecin, roscovitine). Cytotoxic and cytostatic properties of 5-fluorouracil, camptothecin, roscovitine and nutlin-3 administrating alone or in combination with taxol were investigated in vitro by flow cytometry. It was found that nutlin-3 induced growth arrest and protected A549 cells from taxol. FaDu and H1299 cells responded to the same treatments with mitotic arrest and massive apoptosis. Other compounds (5-fluorouracil, camptothecin and roscovitine) revealed weaker selectivity and elevated toxicity in comparison to nutlin-3. We propose a therapeutic strategy protecting normal cells from taxol while increasing apoptosis selectively in p53-deficient cells using nutlin-3.
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