Effects of DNA Threading Bis(9-aminoacridine-4-carboxamides) on Global Gene Expression

摘要

The capacity of series of DNA-threading bis(9-aminoacridine-4-carboxamides) comprising ethylmorpholino, ethylpiperidine and N-methylpiperidin-4-yl sidechains joined by different linkers, to modulate gene expression in human leukaemia cells was investigated. The chosen compounds provided the opportunity for probing the relationships between the structure ligand structure and the drug effects on transcription, information that might lead to a greater understanding of their potential as antitumour agents. As revealed by DNA microarray analysis of 6000 genes, at equitoxic doses, 5?—IC50 values for growth inhibition, all of the drugs perturb transcription, resulting in both up- and down-regulation of many hundreds of genes, 24 h after drug exposure. Under these conditions, the capacity to inhibit transcription decreases in the order C3NC3 morpholino C2pipC2 morpholino C8 piperidine C8NMP C2pipC2 piperidine. Cluster analysis segregated the examined agents into two groups: the first included C2pipC2 morpholino and C3NC3 morpholino and the second C2pipC2 piperidine, C8 piperidine and C8NMP. This classification agreed with the ontological analysis for the markedly up-regulated genes that showed a relatively specific profile for each group. Interestingly, the general up-regulation responses for the first group (C3NC3 morpholino and C2pipC2 morpholino) indicated marked up-regulation amongst the transcription gene set, which suggests that the transcription machinery is the main target for the members of this group. While in the second group (C2pipC2 piperidine, C8 piperidine, C8NMP), the general up-regulation responses for the three agents are dominated by the protein modification process ontological class, implying at least involvement of topoisomerase poisoning in their mode of action.