Limits...
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

5-H-Y inhibits cell proliferation and is incorporated into cell nuclei.(A) Chemical structures of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y) (left) and cis-diamminedichloridoplatinum(II) (cisplatin) (right). (B) Cell proliferation assays with 5-H-Y or cisplatin treatment. Four human cell lines (PC9, HeLa, U2OS, and TIG-1) were treated with the indicated concentrations of 5-H-Y or cisplatin, and the cell numbers were monitored from 0 to 96 h for human cells (for TIG-1, see also Fig. S1A). (C) Schematic view of scanning X-ray fluorescence microscopy. The X-ray beam, highly focused by a set of mirrors (KB-mirror) was focused on the cells refs 54 and 55. Then X-ray fluorescence was detected by the silicon drift detector (SDD). (D) SXFM analysis after drug treatment. Cell morphologies obtained by Nomarski (DIC). Brighter colors indicate a higher signal intensity of each element. Representative results are shown. Results are shown for 5-H-Y (top) and cisplatin (middle), untreated control PC9 cells (bottom). Note the high intensity of Pt in 5-H-Y treated cells. Pt, platinum signal, P, phosphorus, S, sulfur, Zn, zinc. Color bars indicate elemental content, expressed in fg/μm2. The phosphorus- and zinc -rich regions in the cells seem to be nuclei. Bars show 10 μm. (E) Amounts of platinum in PC9 whole cells, nuclei, and DNA fractions of 5-H-Y- and cisplatin-treated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4837362&req=5

f1: 5-H-Y inhibits cell proliferation and is incorporated into cell nuclei.(A) Chemical structures of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y) (left) and cis-diamminedichloridoplatinum(II) (cisplatin) (right). (B) Cell proliferation assays with 5-H-Y or cisplatin treatment. Four human cell lines (PC9, HeLa, U2OS, and TIG-1) were treated with the indicated concentrations of 5-H-Y or cisplatin, and the cell numbers were monitored from 0 to 96 h for human cells (for TIG-1, see also Fig. S1A). (C) Schematic view of scanning X-ray fluorescence microscopy. The X-ray beam, highly focused by a set of mirrors (KB-mirror) was focused on the cells refs 54 and 55. Then X-ray fluorescence was detected by the silicon drift detector (SDD). (D) SXFM analysis after drug treatment. Cell morphologies obtained by Nomarski (DIC). Brighter colors indicate a higher signal intensity of each element. Representative results are shown. Results are shown for 5-H-Y (top) and cisplatin (middle), untreated control PC9 cells (bottom). Note the high intensity of Pt in 5-H-Y treated cells. Pt, platinum signal, P, phosphorus, S, sulfur, Zn, zinc. Color bars indicate elemental content, expressed in fg/μm2. The phosphorus- and zinc -rich regions in the cells seem to be nuclei. Bars show 10 μm. (E) Amounts of platinum in PC9 whole cells, nuclei, and DNA fractions of 5-H-Y- and cisplatin-treated cells.

Mentions: Platinum-based drugs are the most commonly used anticancer agents, especially for the treatment of testicular, ovarian, and colorectal cancers. Cis-diamminedichloridoplatinum(II) (cisplatin, Fig. 1A)34 is a platinum-based DNA crosslinking agent that first proved the importance of platinum-DNA interactions5. Cisplatin and the other platinum-based drugs, such as carboplatin and oxaliplatin6, are considered to work in a similar fashion7. The platinum–DNA interactions make both inter- and intrastrand crosslinks in DNA, suppressing DNA replication7 and also RNA transcription8. For DNA replication process, intra-strand DNA crosslinks can be bypassed by some translesion synthesis (TLS) polymerases7. To deal with interstrand DNA crosslinks (ICLs), mammalian cells have evolved the Fanconi anemia (FA)/BRCA pathway, which is coupled with DNA replication9. FA is a rare genetic disorder characterized by progressive bone marrow failure and a highly elevated risk of hematological and squamous cancers10. To date, 19 FANC genes have been identified from FA patients, whose cells are highly sensitive to ICL-inducing agents, including cisplatin. Although the precise mechanism of ICL repair by the FA/BRCA pathway is not yet fully understood, it is clear that complex actions of FA proteins, nucleases, TLS polymerases, and homologous recombination proteins are involved. Importantly, loss of any protein involved in the FA/BRCA pathway ultimately leads to hypersensitivity to cisplatin.


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)

5-H-Y inhibits cell proliferation and is incorporated into cell nuclei.(A) Chemical structures of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y) (left) and cis-diamminedichloridoplatinum(II) (cisplatin) (right). (B) Cell proliferation assays with 5-H-Y or cisplatin treatment. Four human cell lines (PC9, HeLa, U2OS, and TIG-1) were treated with the indicated concentrations of 5-H-Y or cisplatin, and the cell numbers were monitored from 0 to 96 h for human cells (for TIG-1, see also Fig. S1A). (C) Schematic view of scanning X-ray fluorescence microscopy. The X-ray beam, highly focused by a set of mirrors (KB-mirror) was focused on the cells refs 54 and 55. Then X-ray fluorescence was detected by the silicon drift detector (SDD). (D) SXFM analysis after drug treatment. Cell morphologies obtained by Nomarski (DIC). Brighter colors indicate a higher signal intensity of each element. Representative results are shown. Results are shown for 5-H-Y (top) and cisplatin (middle), untreated control PC9 cells (bottom). Note the high intensity of Pt in 5-H-Y treated cells. Pt, platinum signal, P, phosphorus, S, sulfur, Zn, zinc. Color bars indicate elemental content, expressed in fg/μm2. The phosphorus- and zinc -rich regions in the cells seem to be nuclei. Bars show 10 μm. (E) Amounts of platinum in PC9 whole cells, nuclei, and DNA fractions of 5-H-Y- and cisplatin-treated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: 5-H-Y inhibits cell proliferation and is incorporated into cell nuclei.(A) Chemical structures of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y) (left) and cis-diamminedichloridoplatinum(II) (cisplatin) (right). (B) Cell proliferation assays with 5-H-Y or cisplatin treatment. Four human cell lines (PC9, HeLa, U2OS, and TIG-1) were treated with the indicated concentrations of 5-H-Y or cisplatin, and the cell numbers were monitored from 0 to 96 h for human cells (for TIG-1, see also Fig. S1A). (C) Schematic view of scanning X-ray fluorescence microscopy. The X-ray beam, highly focused by a set of mirrors (KB-mirror) was focused on the cells refs 54 and 55. Then X-ray fluorescence was detected by the silicon drift detector (SDD). (D) SXFM analysis after drug treatment. Cell morphologies obtained by Nomarski (DIC). Brighter colors indicate a higher signal intensity of each element. Representative results are shown. Results are shown for 5-H-Y (top) and cisplatin (middle), untreated control PC9 cells (bottom). Note the high intensity of Pt in 5-H-Y treated cells. Pt, platinum signal, P, phosphorus, S, sulfur, Zn, zinc. Color bars indicate elemental content, expressed in fg/μm2. The phosphorus- and zinc -rich regions in the cells seem to be nuclei. Bars show 10 μm. (E) Amounts of platinum in PC9 whole cells, nuclei, and DNA fractions of 5-H-Y- and cisplatin-treated cells.
Mentions: Platinum-based drugs are the most commonly used anticancer agents, especially for the treatment of testicular, ovarian, and colorectal cancers. Cis-diamminedichloridoplatinum(II) (cisplatin, Fig. 1A)34 is a platinum-based DNA crosslinking agent that first proved the importance of platinum-DNA interactions5. Cisplatin and the other platinum-based drugs, such as carboplatin and oxaliplatin6, are considered to work in a similar fashion7. The platinum–DNA interactions make both inter- and intrastrand crosslinks in DNA, suppressing DNA replication7 and also RNA transcription8. For DNA replication process, intra-strand DNA crosslinks can be bypassed by some translesion synthesis (TLS) polymerases7. To deal with interstrand DNA crosslinks (ICLs), mammalian cells have evolved the Fanconi anemia (FA)/BRCA pathway, which is coupled with DNA replication9. FA is a rare genetic disorder characterized by progressive bone marrow failure and a highly elevated risk of hematological and squamous cancers10. To date, 19 FANC genes have been identified from FA patients, whose cells are highly sensitive to ICL-inducing agents, including cisplatin. Although the precise mechanism of ICL repair by the FA/BRCA pathway is not yet fully understood, it is clear that complex actions of FA proteins, nucleases, TLS polymerases, and homologous recombination proteins are involved. Importantly, loss of any protein involved in the FA/BRCA pathway ultimately leads to hypersensitivity to cisplatin.

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