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Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

Imai R, Komeda S, Shimura M, Tamura S, Matsuyama S, Nishimura K, Rogge R, Matsunaga A, Hiratani I, Takata H, Uemura M, Iida Y, Yoshikawa Y, Hansen JC, Yamauchi K, Kanemaki MT, Maeshima K - Sci Rep (2016)

Bottom Line: Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy.The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity.Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.

ABSTRACT
Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective against cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers.

No MeSH data available.


Related in: MedlinePlus

Much lower interstrand crosslinking (ICL) activity of 5-H-Y.(A) Covalent binding of cisplatin (blue square) and 5-H-Y (red square) to calf-thymus DNA (n = 4). The rb value is defined as the molar ratio of platinum complex bound per nucleotide. (B) Interstrand crosslinking of drug-treated plasmid DNA. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h (upper) or 48 h (lower). The treated plasmid DNAs were electrophoresed on alkaline agarose gels. The gels with EtBr staining are shown. The positions of dsDNA, representing interstrand crosslinks, and ssDNA, including no crosslinks and intrastrand crosslinks, are shown. Values below the gels indicate intensities of dsDNA normalized by that of cisplatin. Note that there is much more dsDNA in cisplatin-treated DNA than in 5-H-Y-treated DNA. The two DNA templates, pUC19 and pBSII, produced similar results. (C) Experimental scheme of PCR amplification. DNA templates were treated with cisplatin or 5-H-Y. If inter-strand (middle) or intrastrand (bottom) crosslinks occur in the template DNA, DNA amplification by PCR is inhibited. (D) PCR results. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were used as PCR templates. They were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h or 48 h. The PCR products (marked with arrow) on the agarose gel after electrophoresis are shown. Values below the gel indicate the fluorescent intensities of the PCR product normalized by that of control. In the “Cisplatin + Control” lanes, PCR was performed using mixed templates of cisplatin-treated and no-treated plasmids. Note that PCR using cisplatin-treated template produced much less product.
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f4: Much lower interstrand crosslinking (ICL) activity of 5-H-Y.(A) Covalent binding of cisplatin (blue square) and 5-H-Y (red square) to calf-thymus DNA (n = 4). The rb value is defined as the molar ratio of platinum complex bound per nucleotide. (B) Interstrand crosslinking of drug-treated plasmid DNA. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h (upper) or 48 h (lower). The treated plasmid DNAs were electrophoresed on alkaline agarose gels. The gels with EtBr staining are shown. The positions of dsDNA, representing interstrand crosslinks, and ssDNA, including no crosslinks and intrastrand crosslinks, are shown. Values below the gels indicate intensities of dsDNA normalized by that of cisplatin. Note that there is much more dsDNA in cisplatin-treated DNA than in 5-H-Y-treated DNA. The two DNA templates, pUC19 and pBSII, produced similar results. (C) Experimental scheme of PCR amplification. DNA templates were treated with cisplatin or 5-H-Y. If inter-strand (middle) or intrastrand (bottom) crosslinks occur in the template DNA, DNA amplification by PCR is inhibited. (D) PCR results. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were used as PCR templates. They were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h or 48 h. The PCR products (marked with arrow) on the agarose gel after electrophoresis are shown. Values below the gel indicate the fluorescent intensities of the PCR product normalized by that of control. In the “Cisplatin + Control” lanes, PCR was performed using mixed templates of cisplatin-treated and no-treated plasmids. Note that PCR using cisplatin-treated template produced much less product.

Mentions: To investigate the DNA crosslinking ability of 5-H-Y, DNA purified from calf thymus was incubated with 5-H-Y or cisplatin for various periods of time. Quantification analysis showed that ~5-fold less 5-H-Y than cisplatin was bound covalently to DNA (Fig. 4A).


Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex.

Imai R, Komeda S, Shimura M, Tamura S, Matsuyama S, Nishimura K, Rogge R, Matsunaga A, Hiratani I, Takata H, Uemura M, Iida Y, Yoshikawa Y, Hansen JC, Yamauchi K, Kanemaki MT, Maeshima K - Sci Rep (2016)

Much lower interstrand crosslinking (ICL) activity of 5-H-Y.(A) Covalent binding of cisplatin (blue square) and 5-H-Y (red square) to calf-thymus DNA (n = 4). The rb value is defined as the molar ratio of platinum complex bound per nucleotide. (B) Interstrand crosslinking of drug-treated plasmid DNA. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h (upper) or 48 h (lower). The treated plasmid DNAs were electrophoresed on alkaline agarose gels. The gels with EtBr staining are shown. The positions of dsDNA, representing interstrand crosslinks, and ssDNA, including no crosslinks and intrastrand crosslinks, are shown. Values below the gels indicate intensities of dsDNA normalized by that of cisplatin. Note that there is much more dsDNA in cisplatin-treated DNA than in 5-H-Y-treated DNA. The two DNA templates, pUC19 and pBSII, produced similar results. (C) Experimental scheme of PCR amplification. DNA templates were treated with cisplatin or 5-H-Y. If inter-strand (middle) or intrastrand (bottom) crosslinks occur in the template DNA, DNA amplification by PCR is inhibited. (D) PCR results. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were used as PCR templates. They were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h or 48 h. The PCR products (marked with arrow) on the agarose gel after electrophoresis are shown. Values below the gel indicate the fluorescent intensities of the PCR product normalized by that of control. In the “Cisplatin + Control” lanes, PCR was performed using mixed templates of cisplatin-treated and no-treated plasmids. Note that PCR using cisplatin-treated template produced much less product.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837362&req=5

f4: Much lower interstrand crosslinking (ICL) activity of 5-H-Y.(A) Covalent binding of cisplatin (blue square) and 5-H-Y (red square) to calf-thymus DNA (n = 4). The rb value is defined as the molar ratio of platinum complex bound per nucleotide. (B) Interstrand crosslinking of drug-treated plasmid DNA. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h (upper) or 48 h (lower). The treated plasmid DNAs were electrophoresed on alkaline agarose gels. The gels with EtBr staining are shown. The positions of dsDNA, representing interstrand crosslinks, and ssDNA, including no crosslinks and intrastrand crosslinks, are shown. Values below the gels indicate intensities of dsDNA normalized by that of cisplatin. Note that there is much more dsDNA in cisplatin-treated DNA than in 5-H-Y-treated DNA. The two DNA templates, pUC19 and pBSII, produced similar results. (C) Experimental scheme of PCR amplification. DNA templates were treated with cisplatin or 5-H-Y. If inter-strand (middle) or intrastrand (bottom) crosslinks occur in the template DNA, DNA amplification by PCR is inhibited. (D) PCR results. Two types of plasmid DNAs, pUC19 (left) and pBluescript II (pBSII) (right), were used as PCR templates. They were treated with no drug (Control), cisplatin, or 5-H-Y for 24 h or 48 h. The PCR products (marked with arrow) on the agarose gel after electrophoresis are shown. Values below the gel indicate the fluorescent intensities of the PCR product normalized by that of control. In the “Cisplatin + Control” lanes, PCR was performed using mixed templates of cisplatin-treated and no-treated plasmids. Note that PCR using cisplatin-treated template produced much less product.
Mentions: To investigate the DNA crosslinking ability of 5-H-Y, DNA purified from calf thymus was incubated with 5-H-Y or cisplatin for various periods of time. Quantification analysis showed that ~5-fold less 5-H-Y than cisplatin was bound covalently to DNA (Fig. 4A).

Bottom Line: Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy.The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity.Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Biological Macromolecules Laboratory, Structural Biology Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.

ABSTRACT
Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug-DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective against cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers.

No MeSH data available.


Related in: MedlinePlus