Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 1)

One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. Here, we compare three members of this class - the antracyclines doxorubicin and aclarubicin, and a chemically unrelated compound, etoposide. Aclarubicin does not induce DNA breaks. We define a new activity for the antracyclines: unsupported histone eviction from ´open´ or loosely packed chromosomal areas reflecting exon and promoter regions. As a result, the epigenome and the transcriptome are strongly affected. Tissue culture cells were treated with doxorubicin, aclarubicin or etoposide for 2 hours. Then drugs were removed by extensive washing. cells were further cultured for indicated days before total RNA were extracted and compared to un-treated control.

一类主流的抗癌药物通过靶向拓扑异构酶II（topoisomerase II），诱导DNA双链断裂并杀伤快速增殖的细胞。本研究对该类药物的三种成员开展了对比分析：蒽环类（antracyclines）药物多柔比星（doxorubicin）、阿克拉霉素（aclarubicin），以及化学结构无关的化合物依托泊苷（etoposide）。其中阿克拉霉素不会诱导DNA双链断裂。我们为蒽环类药物揭示了一种全新的活性：无需辅助因子介导的组蛋白移除，该过程作用于‘开放’或松散包装的染色体区域——这类区域对应外显子与启动子区域。此过程会显著影响表观基因组（epigenome）与转录组（transcriptome）。研究人员将体外培养的细胞分别用多柔比星、阿克拉霉素及依托泊苷处理2小时，随后通过彻底冲洗移除药物，继续将细胞培养至指定天数，再提取总RNA并与未处理的对照组进行比对分析。