DNA interactions of 2-pyrrolinodoxorubicin, a distinctively more potent daunosamine-modified analogue of doxorubicin
DNA interactions of 2-pyrrolinodoxorubicin, a distinctively more potent daunosamine-modified analogue of doxorubicin
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DOI：
10.1016/j.bcp.2011.04.010
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发表时间：
2011-08-01
影响因子：
5.8
通讯作者：
Brabec, Viktor
中科院分区：
文献类型：
--
作者：
Stepankova, Jana;Studenovsky, Martin;Brabec, Viktor
早期显示，2-吡咯啉多柔比星在体外对人和小鼠癌细胞的活性比亲本多柔比星高500-1000倍。然而，在分子水平上，导致多柔比星和2-吡咯啉多柔比星之间效力如此大的差异的生化因素尚不清楚。为了提供这些信息，我们已经调查了在无细胞培养基中的生物化学和生物物理方法的相互作用的蒽环类药物与DNA，这些相互作用对人类拓扑异构酶II，人类布卢姆氏综合征解旋酶和原核T7 RNA聚合酶的活性的影响，以及这些药物的能力，形成DNA链间交联在无甲醛介质。旨在了解在多柔比星和2-pyrrolinodoxorubicin存在下的双螺旋DNA的性质的实验揭示了这些蒽环类药物的DNA修饰和导致的DNA构象改变的微小差异。类似地，2-吡咯啉多柔比星修饰DNA抑制拓扑异构酶II催化活性的能力与多柔比星没有显著差异。另一方面，我们证明了一个重要的因素，负责显着更高的抗增殖效力的DNA修饰2-吡咯啉阿霉素是这些修改的能力，以抑制下游的细胞过程，处理DNA损伤的这种药物，并涉及分离的互补链的DNA，如DNA解旋酶或RNA聚合酶。此外，结果也与以下假设一致，即特别是2-吡咯啉多柔比星容易形成DNA链间交联的能力是抑制用该多柔比星类似物处理的细胞中这些过程的原因。(C)2011 Elsevier Inc. All rights reserved.
It was shown earlier that 2-pyrrolinodoxorubicin was 500-1000 times more active towards human and mouse cancer cells in vitro than parental doxorubicin. However, the biochemical factors responsible for such a large difference in potency between doxorubicin and 2-pyrrolinodoxorubicin are not clear at the molecular level. To provide this information, we have investigated in cell-free media by biochemical and biophysical methods interactions of both anthracyclines with DNA, effects of these interactions on activity of human topoisomerase II, human Bloom's syndrome helicase and prokaryotic T7 RNA polymerase, and the capability of these drugs to form DNA interstrand cross-links in formaldehyde-free medium. Experiments aimed at understanding the properties of double-helical DNA in the presence of doxorubicin and 2-pyrrolinodoxorubicin revealed only small differences in DNA modifications by these anthracyclines and resulting conformational alterations in DNA. Similarly, the ability of 2-pyrrolinodoxorubicin modifications of DNA to inhibit catalytic activity of topoisomerase II does not differ significantly from that of doxorubicin. On the other hand, we demonstrate that an important factor responsible for the markedly higher antiproliferative potency of DNA modifications by 2-pyrrolinodoxorubicin is capability of these modifications to inhibit downstream cellular processes which process DNA damaged by this drug and involve separation of complementary strands of DNA, such as DNA unwinding by helicases or RNA polymerases. In addition, the results are also consistent with the hypothesis that in particular the capability of 2-pyrrolinodoxorubicin to readily form DNA interstrand cross-links is responsible for inhibition of these processes in the cells treated with this analogue of doxorubicin. (C) 2011 Elsevier Inc. All rights reserved.