Characteristic effect of an anticancer dinuclear platinum(II) complex on the higher-order structure of DNA |
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Authors: | Naoko Kida Yousuke Katsuda Yuko Yoshikawa Seiji Komeda Takaji Sato Yoshihiro Saito Masahiko Chikuma Mari Suzuki Tadayuki Imanaka Kenichi Yoshikawa |
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Institution: | (1) Laboratory of Bio-Analytical Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Japan;(2) Laboratory of Environmental Biotechnology, Research Organization of Science and Engineering, Ritsumeikan University, Kusatsu 525-8577, Japan;(3) Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Japan;(4) Department of Physics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan;(5) Spatio-Temporal Order Project, ICORP, JST, Kyoto 606-8502, Japan; |
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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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