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

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1720-1728
Number of pages9
JournalInternational Journal of Biochemistry and Cell Biology
Volume43
Issue number12
DOIs
Publication statusPublished - Dec 2011
Externally publishedYes

Fingerprint

Anthraquinones
Doxorubicin
DNA Damage
DNA
National Cancer Institute (U.S.)
Drug Design
Telomerase
Autophagy
Proteasome Endopeptidase Complex
Cytotoxicity
HeLa Cells
Pharmaceutical Preparations
Proteolysis
Assays
Cell Cycle
Cells
Apoptosis
Anti-Bacterial Agents
Degradation
Proteins

Keywords

  • Apoptosis
  • Autophagy
  • DNA damage
  • Doxorubicin
  • Senescence

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

Different roles of p53 in the regulation of DNA damage caused by 1,2-heteroannelated anthraquinones and doxorubicin. / Chang, Yung Lung; Lee, Hwei Jen; Liu, Shu Ting; Lin, Yu Sheng; Chen, Tsung Chih; Hsieh, Tsai Yuan; Huang, Hsu Shan; Huang, Shih Ming.

In: International Journal of Biochemistry and Cell Biology, Vol. 43, No. 12, 12.2011, p. 1720-1728.

Research output: Contribution to journalArticle

Chang, Yung Lung ; Lee, Hwei Jen ; Liu, Shu Ting ; Lin, Yu Sheng ; Chen, Tsung Chih ; Hsieh, Tsai Yuan ; Huang, Hsu Shan ; Huang, Shih Ming. / Different roles of p53 in the regulation of DNA damage caused by 1,2-heteroannelated anthraquinones and doxorubicin. In: International Journal of Biochemistry and Cell Biology. 2011 ; Vol. 43, No. 12. pp. 1720-1728.
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