title: Mithramycin forms a stable dimeric complex by chelating with Fe(II): DNA-interacting characteristics, cellular permeation and cytotoxicity.
abstract: Mith (mithramycin) forms a 2:1 stoichiometry drug-metal complex through the chelation with Fe(II) ion as studied using circular dichroism spectroscopy. The binding affinity between Mith and Fe(II) is much greater than other divalent metal ions, including Mg(II), Zn(II), Co(II), Ni(II) and Mn(II). The [(Mith)2-Fe(II)] complex binds to DNA and induces a conformational change of DNA. Kinetic analysis of surface plasmon resonance studies revealed that the [(Mith)2-Fe(II)] complex binds to DNA duplex with higher affinity compared with the [(Mith)2-Mg(II)] complex. A molecular model of the Mith-DNA-Metal(II) complex is presented. DNA-break assay showed that the [(Mith)2-Fe(II)] complex was capable of promoting the one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide. Intracellular Fe(II) assays and fluorescence microscopy studies using K562 indicated that this dimer complex maintains its structural integrity and permeates into the inside of K562 cells, respectively. The [(Mith)2-Fe(II)] complex exhibited higher cytotoxicity than the drug alone in some cancer cell lines, probably related to its higher DNA-binding and cleavage activity. Evidences obtained in this study suggest that the biological effects caused by the [(Mith)2-Fe(II)] complex may be further explored in the future.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica Taipei, 115 Taiwan.
authors.forename: Ming-Hon
authors.initials: MH
authors.lastname: Hou
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D001483:Base Sequence; D002413:Cations, Divalent / Q000737:chemistry; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry; D020014:K562 Cells; D008670:Metals / Q000737:chemistry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D020349:Surface Plasmon Resonance
chemical_list: D000903:Antibiotics, Antineoplastic; D002413:Cations, Divalent; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D008670:Metals; C497846:bis(mithromycin)iron(II); D004247:DNA; D008926:Plicamycin
references.citation: Blood. 2002 Jul 15;100(2):666-76
references.pmid: 12091363
references.citation: Blood. 1998 Aug 15;92(4):1384-9
references.pmid: 9694727
references.citation: Biochemistry. 1993 Jul 6;32(26):6588-604
references.pmid: 8329387
references.citation: Adv Pharmacol Chemother. 1975;12(0):1-30
references.pmid: 125531
references.citation: Nucleic Acids Res. 1985 Dec 20;13(24):8695-714
references.pmid: 2934687
references.citation: J Med Chem. 1999 Jul 29;42(15):2844-51
references.pmid: 10425093
references.citation: Blood. 1999 Sep 15;94(6):2128-34
references.pmid: 10477743
references.citation: J Neurosci. 2004 Nov 17;24(46):10335-42
references.pmid: 15548647
references.citation: J Mol Biol. 1993 Jun 5;231(3):753-67
references.pmid: 8515449
references.citation: Med Res Rev. 2003 Nov;23(6):697-762
references.pmid: 12939790
references.citation: Nucleic Acids Res. 2002 Nov 15;30(22):4910-7
references.pmid: 12433994
references.citation: J Mol Biol. 1995 Sep 1;251(5):674-89
references.pmid: 7666419
references.citation: Biochemistry. 1997 Feb 25;36(8):2291-9
references.pmid: 9047331
references.citation: Am J Physiol. 1995 Jun;268(6 Pt 1):C1354-61
references.pmid: 7611353
references.citation: Nucleic Acids Res. 2004;32(6):2000-7
references.pmid: 15064359
references.citation: J Am Chem Soc. 2003 May 14;125(19):5745-53
references.pmid: 12733914
references.citation: J Bone Joint Surg Am. 1972 Dec;54(8):1730-6
references.pmid: 4265871
references.citation: Oncogene. 1995 Jun 15;10(12):2323-30
references.pmid: 7784080
references.citation: Nucleic Acids Res. 2001 Dec 15;29(24):5121-8
references.pmid: 11812845
references.citation: Biopolymers. 2000 Aug;54(2):104-14
references.pmid: 10861371
references.citation: J Urol. 1972 Mar;107(3):429-32
references.pmid: 4258726
references.citation: Nucleic Acids Res. 2004;32(7):2214-22
references.pmid: 15107489
references.citation: Biopolymers. 1990 Feb 15;29(3):481-9
references.pmid: 2110008
references.citation: J Biol Chem. 1995 Oct 13;270(41):24209-15
references.pmid: 7592626
references.citation: Oncology. 1973;28(2):147-63
references.pmid: 4270380
references.citation: Free Radic Biol Med. 2002 Oct 15;33(8):1037-46
references.pmid: 12374615
references.citation: Anal Biochem. 1996 Jan 15;233(2):221-7
references.pmid: 8789722
references.citation: Biochemistry. 1995 Jan 31;34(4):1376-85
references.pmid: 7827085
references.citation: Blood. 2003 Aug 15;102(4):1276-81
references.pmid: 12738678
references.citation: Blood. 2001 Aug 1;98(3):842-50
references.pmid: 11468187
references.citation: Biochem Biophys Res Commun. 1989 Apr 28;160(2):517-24
references.pmid: 2524195
references.citation: Biochimie. 1995;77(9):729-38
references.pmid: 8789464
references.citation: Biochemistry. 2003 Oct 14;42(40):11751-61
references.pmid: 14529286
references.citation: Pharmacol Ther. 1999 Sep;83(3):181-215
references.pmid: 10576292
references.citation: J Med Chem. 2003 Apr 24;46(9):1683-9
references.pmid: 12699386
references.citation: Eur J Biochem. 1991 Jun 1;198(2):333-8
references.pmid: 1828228
references.citation: FEBS Lett. 1990 May 7;264(1):100-4
references.pmid: 2140099
references.citation: Biochem Biophys Res Commun. 1990 Dec 14;173(2):689-96
references.pmid: 2148084
references.citation: Annu Rev Biochem. 1971;40:775-810
references.pmid: 4107711
references.citation: Acta Crystallogr D Biol Crystallogr. 1996 Jan 1;52(Pt 1):57-64
references.pmid: 15299726
references.citation: Biochemistry. 1983 May 10;22(10):2373-7
references.pmid: 6222762