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. 2018 Oct 4;8:14827. doi: 10.1038/s41598-018-33139-x

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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MST-312 inhibits DNA topoisomerase II. (A) COMPARE analysis of MST-312 with anticancer compounds. Similarities between chemical fingerprints of MST-312 and anticancer compounds in the JFCR39 cancer cell line panel were evaluated. (B) Correlation between sensitivities to MST-312 and DNA topoisomerase II (Topo II) inhibitors ICRF-193 (blue, R² = 0.2101), ICRF-154 (dark blue, R² = 0.24561), NC-190 (orange, R² = 0.22231) and TAS-103 (purple, R² = 0.17742). (C) In vitro Topo II enzyme assay. Kinetoplast DNA was incubated with Topo II in the presence of the indicated concentrations of the compounds and subjected to agarose gel electrophoresis. Decatenated DNA is a marker of Topo II reaction. Border of two different gels, which were derived from the same experiment and processed in parallel, was indicated by a dotted line. (D) Spotting assay of 10-fold serial dilution of the yeast parental strain YFK30 and top2 K414N mutant. The 10-fold dilutions of log-phase cells were spotted onto YPD plates containing the indicated concentrations of MST-312 or the positive control doxorubicin and then cells were cultivated at 30 °C. In the right panel, border of two different parts of the same plate was indicated by a dotted line. (E) Telomere immuno-FISH analysis. NCI-H522 cells were treated with 5 μM MST-312 or Topo II inhibitors (150 μM ICRF-193, 0.2 μM TAS-103 or 8.5 μM etoposide) for 48 h and then subjected to telomere immuno-FISH analysis. Left: representative photos. Red: telomere DNA; green: phospho-ATM (p1981); blue: DAPI stain of DNA. Right: quantitative graphs of phospho-ATM (p1981) and TIF-positive cells. Cells with more than four foci were counted as positive. (F) Effect of MST-295 on Topo II enzyme activity. (G) TIF induced by MST-295 in NCI-H522 cells. Cells were treated with 5 μM MST-295 or MST-312 for 48 h and then subjected to telomere immuno-FISH. Numbers of TIF and enlarged TIF were quantitated. (H) Effect of MST-295 on DNA double strand breaks in DMS114 cells. Cells were treated as in (G) and metaphase spreads of chromosomes were analysed for DNA double strand breaks. Error bar indicates standard deviation. Asterisk indicates statistical significance (Tukey-Kramer test).