title: The crucial role of divalent metal ions in the DNA-acting efficacy and inhibition of the transcription of dimeric chromomycin A3.
abstract: Chromomycin A3 (Chro) is capable of forming a stable dimeric complex via chelation with Ni(II), Fe(II) and Co(II). According to the circular dichroism study, the dimer conformations are significantly different among the Fe(II)-, Co(II)-, and Ni(II)-containing dimeric Chro complexes; however, the dimer conformations were preserved at high temperatures. Furthermore, we conducted a systematic study to determine the effects of these divalent metal ions on the DNA-acting efficacy of dimeric Chro, including its DNA-binding affinity, DNA stabilization capacity, DNA cleavage activity, and the inhibition of transcription both in vitro and within cells. Kinetic analyses using surface plasmon resonance (SPR) showed that Ni(II)(Chro)(2) exhibited the highest K(a) with a value of 1.26 × 10(7) M(-1), which is approximately 1.6- and 3.7-fold higher than the K(a) values obtained for Co(II)(Chro)(2) and Fe(II)(Chro)(2), respectively. The T(m) and ΔG values for the DNA duplex increased after the addition of drug complexes in the following order: Ni(II)(Chro)(2)>Co(II)(Chro)(2)>Fe(II)(Chro)(2). In the DNA integrity assays, the DNA cleavage rate of Co(II)(Chro)(2) (1.2 × 10(-3) s(-1)) is higher than those of Fe(II)(Chro)(2) and Ni(II)(Chro)(2), which were calculated to be 1 × 10(-4) and 3.1 × 10(-4) s(-1), respectively. Consistent with the SPR and UV melting results, Ni(II)(Chro)(2) possesses the highest inhibitory effect on in vitro transcription and c-myc transcription within cells compared to Co(II)(Chro)(2) and Fe(II)(Chro)(2). By comparing the cytotoxicity among Co(II)(Chro)(2), Fe(II)(Chro)(2), and Ni(II)(Chro)(2) to several cancer cell lines, our studies concluded that Ni(II)(Chro)(2) displayed more potential antitumor activities than Co(II)(Chro)(2) and Fe(II)(Chro)(2) did due to its higher DNA-acting efficacy. Changes to the divalent metal ions in the dimeric Chro complexes have been correlated with improved anticancer profiles. The availability of new metal derivatives of Chro may introduce new possibilities for exploiting the unique properties of this class of compounds for therapeutic applications.
authors.affiliation: Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Show-Mei
authors.initials: SM
authors.lastname: Chuang
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Wu
authors.forename: Ming-Hon
authors.initials: MH
authors.lastname: Hou
mesh_terms: D002413:Cations, Divalent / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D014128:Chromomycin A3 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D008670:Metals / Q000494:pharmacology*; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009692:Nucleic Acid Heteroduplexes / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D011487:Protein Conformation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D020349:Surface Plasmon Resonance; D014158:Transcription, Genetic / Q000187:drug effects*; D044366:Transition Temperature / Q000187:drug effects
chemical_list: D002413:Cations, Divalent; D008670:Metals; D009692:Nucleic Acid Heteroduplexes; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA; D014128:Chromomycin A3