Tumor cell death mediated by peptides that recognize branched intermediates of DNA replication and repair.
Tumor cell death mediated by peptides that recognize branched intermediates of DNA replication and repair.
复制标题
DOI：
10.1371/journal.pone.0078751
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Segall AM
中科院分区：
文献类型：
--
作者：
Dey M;Patra S;Su LY;Segall AM
仍然需要有效的癌症治疗方法，无论是对当前治疗方法反应不佳的癌症还是对现有治疗方法产生耐药性的癌症。在本文中，我们研究了结构选择性d-氨基酸肽wrwycr的作用，该肽在体外结合复制叉模拟物和同源重组（HR）的霍利迪连接（HJ）中间体，并抑制它们通过HJ加工酶的分解。我们预测用HJ结合化合物处理细胞将导致DNA损伤的积累。随着细胞修复内源性或外源性DNA损伤，塌陷的复制叉和HJ中间体将积累并作为HJ结合肽的靶标。抑制连接分辨率将导致DNA断裂的进一步积累，最终导致损伤的放大并导致细胞死亡。肽wrwycr和相关的wrwyrggrywrw都进入癌细胞，并以剂量和时间依赖的方式降低细胞存活率。DNA损伤的早期标志物γ H2 AX灶和53 BP 1灶随着暴露于肽的剂量和/或时间而增加。DNA断裂持续至少48小时，检查点蛋白Chk 1和Chk 2都被激活。即使在72 h后，细胞从S到G2/M的传代也被阻断。然而，在HeLa或PC 3细胞中没有诱导凋亡。基于集落形成测定，约35%的肽诱导的细胞毒性是不可逆的。最后，亚致死剂量的肽wrwycr（50-100 µM）与亚致死剂量的几种DNA损伤剂（依托泊苷、阿霉素和HU）联合使用，至少可以相加，有时还可以协同降低细胞存活率。总之，结果表明，肽值得进一步研究，作为一类新的抗癌治疗方法的原理证明分子，特别是与其他DNA损伤疗法的组合。
Effective treatments for cancer are still needed, both for cancers that do not respond well to current therapeutics and for cancers that become resistant to available treatments. Herein we investigated the effect of a structure-selective d-amino acid peptide wrwycr that binds replication fork mimics and Holliday Junction (HJs) intermediates of homologous recombination (HR) in vitro, and inhibits their resolution by HJ-processing enzymes. We predicted that treating cells with HJ-binding compounds would lead to accumulation of DNA damage. As cells repair endogenous or exogenous DNA damage, collapsed replication forks and HJ intermediates will accumulate and serve as targets for the HJ-binding peptides. Inhibiting junction resolution will lead to further accumulation of DNA breaks, eventually resulting in amplification of the damage and causing cell death. Both peptide wrwycr and the related wrwyrggrywrw entered cancer cells and reduced cell survival in a dose- and time-dependent manner. Early markers for DNA damage, γH2AX foci and 53BP1 foci, increased with dose and/or time exposure to the peptides. DNA breaks persisted at least 48 h, and both checkpoint proteins Chk1 and Chk2 were activated. The passage of the cells from S to G2/M was blocked even after 72 h. Apoptosis, however, was not induced in either HeLa or PC3 cells. Based on colony-forming assays, about 35% peptide-induced cytotoxicity was irreversible. Finally, sublethal doses of peptide wrwycr (50–100 µM) in conjunction with sublethal doses of several DNA damaging agents (etoposide, doxorubicin, and HU) reduced cell survival at least additively and sometimes synergistically. Taken together, the results suggest that the peptides merit further investigation as proof-of-principle molecules for a new class of anti-cancer therapeutics, in particular in combination with other DNA damaging therapies.
登录
查看更多内容
DOI：
10.1093/jnci/djp235
发表时间：
2009-09-02
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Cardoso F;Bedard PL;Winer EP;Pagani O;Senkus-Konefka E;Fallowfield LJ;Kyriakides S;Costa A;Cufer T;Albain KS;ESO-MBC Task Force
通讯作者：
ESO-MBC Task Force
影响因子：
11.4
作者：
Aylon, Y;Liefshitz, B;Kupiec, M
通讯作者：
Kupiec, M
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
6.6
作者：
GINGRICH, JR;TUCKER, JA;WEBB, KS
通讯作者：
WEBB, KS
影响因子：
7.8
作者：
Goldstein, JC;Rodier, F;Campisi, J
通讯作者：
Campisi, J