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Oncotarget:合成性植物激素促癌细胞死亡

来源:生物谷 2016-02-18 15:23

图片来源:medicalxpress.com

2016年2月18日 讯 /生物谷BIOON/ --发表于国际杂志Oncotarget上的一项最新研究中,来自乔治敦大学等处的科学家通过研究发现,两种模拟植物激素的药物可以有效促进DNA损伤并且关闭主要的DNA修复机制,这或许会为开发潜在的抗癌疗法提供思路。这两种药物MEB55和ST362是一种合成形式的独脚金内酯(strigolactones),而独脚金内酯是植物根部产生的一种激素,其可以调节植物地上部分及根部的发育。

研究人员首次调查发现这种植物激素具有抗癌特性,自从2009年以来,就有一系列研究发现合成性的独脚金内酯可以抑制乳腺癌、结直肠癌等其它多种癌症细胞的生长;而本文研究则揭示了独脚金内酯的作用机制,当其结合另外一种抗癌药物时就会对人类前列腺癌细胞带来致死性的杀伤作用。

Ronit Yarden博士说道,MEB55和ST362都是非常潜在的因子,我们的研究发现,当利用抗癌药物PARP抑制剂时,这种药物组合就可以有效杀灭癌细胞,同时并不伤害正常细胞;本文中研究者首次合成了MEB55和ST362,利用一种重新编程的技术,研究者们就可以在患者的前列腺癌细胞中对这种药物制剂进行研究。

当MEB55和ST362其中一种结合PARP抑制剂进行作用时,癌细胞就会被杀死;合成性的植物激素可以在细胞DNA复制后且细胞分裂之前抑制细胞的DNA修复过程;PARP抑制剂可以关闭第二种修复通路,从而使得癌细胞没有备选通路来进行细胞修复,这样一来癌细胞唯有死亡之路。在细胞中DNA复制的错误非常普遍,因此没有DNA修复的机制,癌细胞最终将会被摧毁。

研究者使用PARP抑制剂源于其该抑制剂在治疗乳腺癌和卵巢癌中的良好表现,这两种癌症通常是由于BRCA1/2基因突变而产生,BRCA基因在正常情况下会控制DNA的修复通路,但当其突变时就不能够修复基因,而合成性的激素也可以提供相同的效应。(生物谷Bioon.com)

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Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair

Michael P. Croglio1,*, Jefferson M. Haake1,*, Colin P. Ryan1, Victor S. Wang1, Jennifer Lapier1, Jamie P. Schlarbaum1, Yaron Dayani1, Emma Artuso3, Cristina Prandi3, Hinanit Koltai4, Keli Agama5, Yves Pommier5, Yu Chen6, Lucas Tricoli2, Jeannine R. LaRocque1, Christopher Albanese2,7 and Ronit I. Yarden1,2

Strigolactones are a novel class of plant hormones produced in roots that regulate shoot and root development. We previously reported that strigolactone analogs (SLs) induce G2/M cell cycle arrest and apoptosis in a variety of human cancer cells and inhibit tumor growth of human breast cancer xenografts in mice. SLs had no significant influences on non-transformed cells. Here we report for the first time that SLs induce DNA damage in the form of DNA double-strand breaks (DSBs) and activate the DNA damage response signaling by inducing phosphorylation of ATM, ATR and DNA-PKcs and co-localization of the DNA damage signaling protein, 53BP1, with γH2AX nuclear foci. We further report that in addition to DSBs induction, SLs simultaneously impair DSBs repair, mostly homology-directed repair (HDR) and to a lesser extent non-homologous end joining (NHEJ). In response to SLs, RAD51, the homologous DSB repair protein, is ubiquitinated and targeted for proteasomal degradation and it fails to co-localize with γH2AX foci. Interestingly, SLs synergize with DNA damaging agents-based therapeutics. The combination of PARP inhibitors and SLs showed an especially potent synergy, but only in BRCA1-proficient cells. No synergy was observed between SLs and PARP inhibitors in BRCA1-deficient cells, supporting a role for SLs in HDR impairment. Together, our data suggest that SLs increase genome instability and cell death by a unique mechanism of inducing DNA damage and inhibiting DNA repair./P>

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