Different roles of p53 in the regulation of DNA damage caused by 1,2-heteroannelated anthraquinones and doxorubicin

Yung Lung Chang, Hwei Jen Lee, Shu Ting Liu, Yu Sheng Lin, Tsung Chih Chen, Tsai Yuan Hsieh, Hsu Shan Huang, Shih Ming Huang

研究成果: 雜誌貢獻文章同行評審

27 引文 斯高帕斯(Scopus)

摘要

The anthracyclin antibiotic agent doxorubicin (DXR) has been widely used as a chemotherapeutic drug for more than 40 years, but its clinical use has been limited by its cardiotoxicity. The mechanism of action of DXR remains uncertain and controversial. A series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione compounds were synthesized and their cytotoxicity profiles were analyzed using the National Cancer Institute 60 (NCI 60) platform and human telomerase inhibition assays. In the current study, three of the 1,2-heteroannelated anthraquinones, NSC745795, NSC745885 and NSC745887, were found to differ from each other with respect to their effects on cell cycle regulation, apoptosis, autophagy, senescence and their abilities to induce DNA damage. The differences depended on the presence or absence of a heterocyclic moiety, which suggested that the differences were due, at least in part, to differential effects on specific cellular targets, such as p53. In contrast to DXR, which induced p53 expression, treatment with NSC745885 resulted in the degradation of several proteins, including p53, via proteasome-dependent and -independent pathways in HeLa cells. These results provide insights into the molecular mechanisms governing cell inhibition by 1,2-heteroannelated anthraquinone derivatives and suggest that these mechanisms could serve as the basis for new structure-based drug designs.
原文英語
頁(從 - 到)1720-1728
頁數9
期刊International Journal of Biochemistry and Cell Biology
43
發行號12
DOIs
出版狀態已發佈 - 12月 2011
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 細胞生物學

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