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Characteristic effect of an anticancer dinuclear platinum(II) complex on the higher-order structure of DNA

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Abstract

It is known that a 1,2,3-triazolato-bridged dinuclear platinum(II) complex, [{cis-Pt(NH3)2}2(µ-OH)(µ-1,2,3-ta-N 1,N 2)](NO3)2 (AMTA), shows high in vitro cytotoxicity against several human tumor cell lines and circumvents cross-resistance to cisplatin. In the present study, we examined a dose- and time-dependent effect of AMTA on the higher-order structure of a large DNA, T4 phage DNA (166 kbp), by adapting single-molecule observation with fluorescence microscopy. It was found that AMTA induces the shrinking of DNA into a compact state with a much higher potency than cisplatin. From a quantitative analysis of the Brownian motion of individual DNA molecules in solution, it became clear that the density of a DNA segment in the compact state is about 2,000 times greater than that in the absence of AMTA. Circular dichroism spectra suggested that AMTA causes a transition from the B to the C form in the secondary structure of DNA, which is characterized by fast and slow processes. Electrophoretic measurements indicated that the binding of AMTA to supercoiled DNA induces unwinding of the double helix. Our results indicate that AMTA acts on DNA through both electrostatic interaction and coordination binding; the former causes a fast change in the secondary structure from the B to the C form, whereas the latter promotes shrinking in the higher-order structure as a relatively slow kinetic process. The shrinking effect of AMTA on DNA is attributable to the possible increase in the number of bridges along a DNA molecule. It is concluded that AMTA interacts with DNA in a manner markedly different from that of cisplatin.

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research (20034056, 18GS0421) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Laboratory of Bio-Analytical Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan

    Naoko Kida, Yousuke Katsuda, Takaji Sato, Yoshihiro Saito & Masahiko Chikuma

  2. Laboratory of Environmental Biotechnology, Research Organization of Science and Engineering, Ritsumeikan University, Kusatsu, 525-8577, Japan

    Yuko Yoshikawa & Tadayuki Imanaka

  3. Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, 513-8670, Japan

    Seiji Komeda

  4. Department of Physics, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan

    Mari Suzuki & Kenichi Yoshikawa

  5. Spatio-Temporal Order Project, ICORP, JST, Kyoto, 606-8502, Japan

    Mari Suzuki & Kenichi Yoshikawa

Authors
  1. Naoko Kida
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  2. Yousuke Katsuda
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  3. Yuko Yoshikawa
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  4. Seiji Komeda
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Correspondence to Yuko Yoshikawa.

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Kida, N., Katsuda, Y., Yoshikawa, Y. et al. Characteristic effect of an anticancer dinuclear platinum(II) complex on the higher-order structure of DNA. J Biol Inorg Chem 15, 701–707 (2010). https://doi.org/10.1007/s00775-010-0637-y

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  • DOI: https://doi.org/10.1007/s00775-010-0637-y

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