Pifithrin-α, an inhibitor of p53, enhances the genetic instability induced by etoposide (VP16) in human lymphoblastoid cells treated in vitro
Pifithrin-α, an inhibitor of p53, enhances the genetic instability induced by etoposide (VP16) in human lymphoblastoid cells treated in vitro
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DOI：
10.1016/s0027-5107(01)00273-1
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发表时间：
2002-02-20
影响因子：
2.3
通讯作者：
Palitti, F
中科院分区：
文献类型：
--
作者：
Bassi, L;Carloni, M;Palitti, F
最近的研究表明，在化疗和放疗期间，正常组织中诱导的p53依赖性细胞凋亡可能导致严重的副作用，限制了抗癌治疗的效率。本研究的目的是进一步表征p53在维持基因组稳定性中的作用，并验证氟虫腈- α (pft - α)对正常细胞中p53功能的抑制是否有助于减少癌症治疗的副作用。来自同一供体的两种人类淋巴母细胞样细胞系，TK6 （p53野生型）和WTK1 （p53突变型），用抗肿瘤药物依托泊苷（VP16）治疗，在p53抑制剂pft - α存在或不存在的情况下，依托泊苷是DNA拓扑异构酶11的抑制剂。用VP16处理TK6和WTK1后，我们观察到WTK1 （p53突变）染色体畸变和TK6 （p53野生型）细胞凋亡的诱导程度更高。pft - α对VP16处理的TK6细胞的p53抑制产生了染色体畸变的增加和凋亡的减少。因此，通过pft - α暂时抑制p53的功能，增加正常细胞的存活，可能是减少癌症治疗副作用的一种有希望的方法，但重要的是要考虑到存活的细胞可能被基因修饰，因此继发性肿瘤的风险可能会增加。(C) 2002 Elsevier Science B.V.版权所有
Recent studies indicate that p53-dependent apoptosis induced in normal tissues during chemo- and radiotherapy can cause severe side effects of anti-cancer treatments that limit their efficiency.The aim of the present work was to further characterise the role of p53 in maintaining genomic stability and to verify whether the inhibition of p53 function in normal cells by pifithrin-alpha (PFT-alpha) may contribute in reducing the side effects of cancer therapy.Two human lymphoblastoid cell lines, derived from the same donor, TK6 (p53 wild type) and WTK1 (p53 mutated) have been treated with an anti-neoplastic drug, the etoposide (VP16), an inhibitor of DNA topoisomerase 11 in presence or in absence of the p53 inhibitor PFT-alpha.Following treatments with VP16 on TK6 and WTK1, we observed a higher induction of chromosome aberrations in WTK1 (p53 mutated) and of apoptosis in TK6 (p53 wild-type) cells. The p53 inhibition by PFT-alpha in VP16 treated TK6 cells produced an increase of chromosomal aberrations and a reduction of apoptosis. Therefore, the temporary suppression of the function of p53 by PFT-alpha, increasing the survival of the normal cells, could be a promising approach to reduce the side-effects of cancer therapy but it is important to consider that the surviving cells could be genetically modified and consequently the risk of secondary tumours could be increased. (C) 2002 Elsevier Science B.V. All rights reserved.