title: Different roles of p53 in the regulation of DNA damage caused by 1,2-heteroannelated anthraquinones and doxorubicin.
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.
authors.affiliation: Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan, ROC.
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chang
authors.forename: Hwei-Jen
authors.initials: HJ
authors.lastname: Lee
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Liu
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Lin
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.forename: Tsai-Yuan
authors.initials: TY
authors.lastname: Hsieh
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
mesh_terms: D000375:Aging; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II