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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

DNA damage by 5-H-Y is repaired primarily by different pathways from ICL repair.(A) Sensitivity assay to the 5-H-Y or cisplatin in wtDT40 cells and FUNCD2-KO cells using a colony formation assay. Mean ± SD of three independent experiments is shown. See also Fig. S7. (B) Cell proliferation assay of cisplatin-resistant HCC1428 cells upon 5-H-Y or cisplatin treatment. HCC1428 cells were treated with the indicated concentrations of 5-H-Y or cisplatin, and cell numbers were monitored. 5-H-Y was effective even in this cisplatin-resistant cell line. (C) A model figure. This study demonstrated that 5-H-Y inhibited DNA replication, and arrests the treated cells in S/G2 phase. 5-H-Y binds tightly to chromatin DNA and induces chromatin folding.
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f6: DNA damage by 5-H-Y is repaired primarily by different pathways from ICL repair.(A) Sensitivity assay to the 5-H-Y or cisplatin in wtDT40 cells and FUNCD2-KO cells using a colony formation assay. Mean ± SD of three independent experiments is shown. See also Fig. S7. (B) Cell proliferation assay of cisplatin-resistant HCC1428 cells upon 5-H-Y or cisplatin treatment. HCC1428 cells were treated with the indicated concentrations of 5-H-Y or cisplatin, and cell numbers were monitored. 5-H-Y was effective even in this cisplatin-resistant cell line. (C) A model figure. This study demonstrated that 5-H-Y inhibited DNA replication, and arrests the treated cells in S/G2 phase. 5-H-Y binds tightly to chromatin DNA and induces chromatin folding.

Mentions: 5-H-Y and cisplatin inhibited wild-type DT40 cell growth in a similar manner (Fig. S1B). Then we examined the cell viability of DT40 cells lacking one of the FANC genes, FANCD2, by colony formation assays in the presence of 5-H-Y or cisplatin39. FANCD2-KO cells showed no hypersensitivity to 5-H-Y while just 2 μM cisplatin was enough to completely inhibit colony formation (Fig. 6A). A similar tendency was also observed using the FANCC- and FANCJ-KO DT40 cells although they seem to be more sick and more sensitive to any perturbations than FANCD2-KO cells4041 (Fig. S7). Taken together with the in vitro data, our results demonstrated that 5-H-Y has a different cytotoxic mechanism than cisplatin: DNA damage by 5-H-Y is repaired by different pathways from ICL repair.


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)

DNA damage by 5-H-Y is repaired primarily by different pathways from ICL repair.(A) Sensitivity assay to the 5-H-Y or cisplatin in wtDT40 cells and FUNCD2-KO cells using a colony formation assay. Mean ± SD of three independent experiments is shown. See also Fig. S7. (B) Cell proliferation assay of cisplatin-resistant HCC1428 cells upon 5-H-Y or cisplatin treatment. HCC1428 cells were treated with the indicated concentrations of 5-H-Y or cisplatin, and cell numbers were monitored. 5-H-Y was effective even in this cisplatin-resistant cell line. (C) A model figure. This study demonstrated that 5-H-Y inhibited DNA replication, and arrests the treated cells in S/G2 phase. 5-H-Y binds tightly to chromatin DNA and induces chromatin folding.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: DNA damage by 5-H-Y is repaired primarily by different pathways from ICL repair.(A) Sensitivity assay to the 5-H-Y or cisplatin in wtDT40 cells and FUNCD2-KO cells using a colony formation assay. Mean ± SD of three independent experiments is shown. See also Fig. S7. (B) Cell proliferation assay of cisplatin-resistant HCC1428 cells upon 5-H-Y or cisplatin treatment. HCC1428 cells were treated with the indicated concentrations of 5-H-Y or cisplatin, and cell numbers were monitored. 5-H-Y was effective even in this cisplatin-resistant cell line. (C) A model figure. This study demonstrated that 5-H-Y inhibited DNA replication, and arrests the treated cells in S/G2 phase. 5-H-Y binds tightly to chromatin DNA and induces chromatin folding.
Mentions: 5-H-Y and cisplatin inhibited wild-type DT40 cell growth in a similar manner (Fig. S1B). Then we examined the cell viability of DT40 cells lacking one of the FANC genes, FANCD2, by colony formation assays in the presence of 5-H-Y or cisplatin39. FANCD2-KO cells showed no hypersensitivity to 5-H-Y while just 2 μM cisplatin was enough to completely inhibit colony formation (Fig. 6A). A similar tendency was also observed using the FANCC- and FANCJ-KO DT40 cells although they seem to be more sick and more sensitive to any perturbations than FANCD2-KO cells4041 (Fig. S7). Taken together with the in vitro data, our results demonstrated that 5-H-Y has a different cytotoxic mechanism than cisplatin: DNA damage by 5-H-Y is repaired by different pathways from ICL repair.

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