title: Triazoloacridone C-1305 abrogates the restriction checkpoint in cells lacking functional p53 and promotes their accumulation in the G2/M phase of the cell cycle.
abstract: Triazoloacridone C-1305, a new topoisomerase II inhibitor, exhibits potent cytostatic activity toward various tumours under in vitro and in vivo conditions. Interestingly, mouse cells lacking poly(ADP-ribose) polymerase-1 are much more sensitive to C-1305 than their normal counterparts. In the present study we tested the hypothesis that the functional status of p53 in tumour cells might have an impact on the efficiency of C-1305 in experiments with both p53-deficient human HL-60 promyelocytic leukemia cells and human MCF-7 breast cancer cells harboring a functional p53 pathway. Exposure of both cancer cell lines to C-1305 reduced the number of viable cells in a time- and concentration-dependent manner. Remarkably, however, HL-60 cells were much more strongly affected than MCF-7 cells. Measurements of DNA concentrations in single cells revealed that C-1305 arrested the tested cancer cells at the G/M transition. Analysis of the cell cycle and apoptosis regulators revealed that C-1305 strongly elevated phosphorylation of CDK1 at the inhibitory sites (Thr14/Tyr15) in HL-60 cells. Furthermore, C-1305 increased phosphorylation of pRb protein and CDK2 at Thr160 in HL60 cells, but not in MCF-7 cells. These observations suggest that C-1305 abrogates the restriction checkpoint and promotes G1/S transition in cells lacking functional p53.
authors.affiliation: Cell Cycle Regulation Group, Institute of Cancer Research, Dept. of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Margarita
authors.initials: M
authors.lastname: Maurer
authors.forename: Oxana
authors.initials: O
authors.lastname: Komina
authors.forename: Andrzej
authors.initials: A
authors.lastname: Składanowski
authors.forename: Józefa
authors.initials: J
authors.lastname: Wesierska-Gadek
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects*; D018922:HL-60 Cells / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D000166:Acridines; C488734:C 1305; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2