Prev. Article Next Article Table of Contents

Article

Effects of Polyamines on the DNA-Reactive Properties of Dimeric Mithramycin Complexed with Cobalt(II): Implications for Anticancer Therapy

Your current credentials do not allow retrieval of the full text.

Purchase the full-text

PDF/HTML,
figures/images,
references and tables,
(where available)

Ming-Hon Hou*, Wen-Je Lu, Chun-Yu Huang, Ruey-Jane Fan and Jeu-Ming P. Yuann

^‡ Biotechnology Center

^§ Institute of Genomics and Bioinformatics

Department of Life Science

National Chung Hsing University, Taichung, 402 Taiwan

Department of Biotechnology, Ming Chuan University, Taoyuan County, 333 Taiwan

Biochemistry, 2009, 48 (22), pp 4691–4698

DOI: 10.1021/bi900092w

Publication Date (Web): April 15, 2009

*To whom the correspondence should be addressed at the Institute of Genomics and Bioinformatics, National Chung Hsing University. Tel: 886-4-22840450 ext 6131. Fax: 886-4-22861905. E-mail: mhho@dragon.nchu.edu.tw.

Section:

Pharmacology

Abstract

Few studies have examined the effects of polyamines on the action of DNA-binding anticancer drugs. Here, a Co(II)-mediated dimeric mithramycin (Mith) complex, (Mith)₂−Co(II), was shown to be resistant to polyamine competition toward the divalent metal ion when compared to the Fe(II)-mediated drug complexes. Surface plasmon resonance experiments demonstrated that polyamines interfered with the binding capacity and association rates of (Mith)₂−Co(II) binding to DNA duplexes, while the dissociation rates were not affected. Although (Mith)₂−Co(II) exhibited the highest oxidative activity under physiological conditions (pH 7.3 and 37 °C), polyamines (spermine in particular) inhibited the DNA cleavage activity of the (Mith)₂−Co(II) in a concentration-dependent manner. Depletion of intracellular polyamines by methylglyoxal bis(guanylhydrazone) (MGBG) enhanced the sensitivity of A549 lung cancer cells to (Mith)₂−Co(II), most likely due to the decreased intracellular effect of polyamines on the action of (Mith)₂−Co(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links