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Gossypol Interferes with Both Type I and Type II Topoisomerase Activities Without Generating Strand Breaks

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Abstract

A considerable number of agents with chemotherapeutic potentials reported over the past years were shown to interfere with the reactions of DNA topoisomerases, the essential enzymes that regulate conformational changes in DNA topology. Gossypol, a naturally occurring bioactive phytochemical is a chemopreventive agent against various types of cancer cell growth with a reported activity on mammalian topoisomerase II. The compounds targeting topoisomerases vary in their mode of action; class I compounds act by stabilizing covalent topoisomerase-DNA complexes resulting in DNA strand breaks while class II compounds interfere with the catalytic function of topoisomerases without generating strand breaks. In this study, we report Gossypol as the interfering agent with type I topoisomerases as well. We also carried out an extensive set of assays to analyze the type of interference manifested by Gossypol on DNA topoisomerases. Our results strongly suggest that Gossypol is a potential class II inhibitor as it blocked DNA topoisomerase reactions with no consequently formed strand breaks.

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References

  1. Wang, Y. C., & Rao, P. N. (1984). Effect of gossypol on DNA synthesis and cell cycle progression of mammalian cells in vitro. Cancer Research, 44, 35–38.

    PubMed  CAS  Google Scholar 

  2. Moon, D. O., Choi, Y. H., Moon, S. K., Kim, W. J., & Kim, G. Y. (2011). Gossypol decreases tumor necrosis factor-α-induced intercellular adhesion molecule-1 expression via suppression of NF-κB activity. Food and Chemical Toxicology, 49, 999–1005.

    Article  PubMed  CAS  Google Scholar 

  3. Huang, Y. W., Wang, L. S., Chang, H. L., Ye, W., Sugimoto, Y., Dowd, M. K., et al. (2006). Effects of serum on (–)-gossypol-suppressed growth in human prostate cancer cells. Anticancer Research, 26, 3613–3620.

    PubMed  CAS  Google Scholar 

  4. Volate, S. R., Kawasaki, B. T., Hurt, E. M., Milner, J. A., Kim, Y. S., White, J., et al. (2010). Gossypol induces apoptosis by activating p53 in prostate cancer cells and prostate tumor-initiating cells. Molecular Cancer Therapeutics, 9, 461–470.

    Article  PubMed  CAS  Google Scholar 

  5. Olgiati, K. L., & Toscano, W. A., Jr. (1983). Kinetics of gossypol inhibition of bovine lactate dehydrogenase X. Biochemical and Biophysical Research Communications, 115, 180–185.

    Article  PubMed  CAS  Google Scholar 

  6. Baumgrass, R., Weiwad, M., Erdmann, F., Liu, J. O., Wunderlich, D., Grabley, S., et al. (2001). Reversible inhibition of calcineurin by the polyphenolic aldehyde gossypol. Journal of Biological Chemistry, 276, 47914–47921.

    PubMed  CAS  Google Scholar 

  7. Adlakha, R. C., Ashorn, C. L., Chan, D., & Zwelling, L. A. (1989). Modulation of 4′-(9-acridinylamino) metanesulfon-m-anisidide-induced, topoisomerase II-mediated DNA cleavage by gossypol. Cancer Research, 49, 2052–2058.

    PubMed  CAS  Google Scholar 

  8. Wang, J. C. (1996). DNA topoisomerases. Annual Review Biochemistry, 65, 635–692.

    Article  CAS  Google Scholar 

  9. Topcu, Z. (2001). DNA topoisomerases as targets for anticancer drugs. Journal of Clinical Pharmacy and Therapeutics, 26, 405–416.

    Article  PubMed  CAS  Google Scholar 

  10. Wang, J. C. (2002). Cellular roles of DNA topoisomerases: a molecular perspective. Nature Reviews, 3, 430–440.

    Article  PubMed  CAS  Google Scholar 

  11. D’Arpa, P., & Liu, L. F. (1989). Topoisomerase-targeting antitumor drugs. Biochimica et Biophysica Acta, 989, 163–177.

    PubMed  Google Scholar 

  12. Hsiang, Y. H., & Liu, L. F. (1988). Identification of mammalian topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Research, 26, 1722–1726.

    Google Scholar 

  13. Sordet, O., Khan, Q. A., & Pommier, Y. (2004). Apoptotic topoisomerase I-DNA complexes induced by oxygen radicals and mitochondrial dysfunction. Cell Cycle, 3, 1095–1097.

    Article  PubMed  CAS  Google Scholar 

  14. Galvez, M., Martín-Cordero, C., & Ayuso, M. J. (2005). Iridoids as DNA topoisomerase I poisons. Journal of Enzyme Inhibition and Medicinal Chemistry, 20, 389–392.

    Article  PubMed  CAS  Google Scholar 

  15. Ishar, M. P., Singh, G., Singh, S., Sreenivasan, K. K., & Singh, G. (2006). Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents. Bioorganic & Medicinal Chemistry Letters, 16, 1366–1370.

    Article  CAS  Google Scholar 

  16. Kucukoglu, O., Ozturk, B., Kamataki, T., & Topcu, Z. (2006). Inhibitory activities of Helichrysum taxa on mammalian type I DNA topoisomerase. Pharmaceutical Biology, 44, 189–193.

    Article  Google Scholar 

  17. Alpan, S., Gunes, S., & Topcu, Z. (2007). 1H-Benzimidazole derivatives as mammalian DNA topoisomerase I inhibitors. Acta Biochimica Polonica, 54, 561–565.

    PubMed  CAS  Google Scholar 

  18. Canturk, P., Kucukoglu, K., Topcu, Z., Gul, M., & Gul, H. I. (2008). Effect of some bis-Mannich bases and corresponding piperidinols on DNA topoisomerase I. Arzneimittel Forschung, 58, 686–691.

    PubMed  CAS  Google Scholar 

  19. Topcu, Z., Ozturk, B., Kucukoglu, O., & Kilinc, E. (2008). Flavonoids in Helichrysum pamphylicum inhibit mammalian type I DNA topoisomerase. Zeitschrift für Naturforschung C, 63, 69–74.

    CAS  Google Scholar 

  20. Coban, G., Zencir, S., Zupkó, I., Réthy, B., Gunes, H. S., & Topcu, Z. (2009). Synthesis and biological activity evaluation of 1H-benzimidazoles via mammalian DNA topoisomerase I and cytostaticity assays. European Journal of Medicinal Chemistry, 44, 2280–2285.

    Article  PubMed  CAS  Google Scholar 

  21. Sarikaya, D., Bilgen, C., Kamataki, T., & Topcu, Z. (2006). Comparative cytochrome P450–1A1, −2A6, −2B6, −2C, −2D6, −2E1, −3A5 and −4B1 expressions in human larynx tissue analysed at mRNA level. Biopharmaceutics & Drug Disposition, 27, 353–359.

    Article  CAS  Google Scholar 

  22. Mete, E., Gul, H. I., Canturk, P., & Topcu, Z. (2010). Biological activity of 1-aryl-3-phenethylamino-1-propanone hydrochlorides and 3-aroyl-4-aryl-1-phenethyl-4-piperidinols on PC-3 cells and DNA topoisomerase I enzyme. Zeitschrift für Naturforschung C, 65, 647–652.

    CAS  Google Scholar 

  23. Marini, J. C., Miller, K. G., & Englund, P. T. (1980). Decatenation of kinetoplast DNA by topoisomerases. Journal of Biological Chemistry, 255, 4976–4979.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK) (Grant no. TBAG108T548 to ZT).

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Authors and Affiliations

  1. Department of Biotechnology, Graduate School of Natural and Applied Sciences, Ege University, Izmir, Turkey

    Muge Senarisoy & Pakize Canturk

  2. Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey

    Sevil Zencir

  3. Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey

    Yusuf Baran

  4. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Izmir, 35100, Turkey

    Zeki Topcu

Authors
  1. Muge Senarisoy
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  2. Pakize Canturk
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  3. Sevil Zencir
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  4. Yusuf Baran
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  5. Zeki Topcu
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Correspondence to Zeki Topcu.

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Senarisoy, M., Canturk, P., Zencir, S. et al. Gossypol Interferes with Both Type I and Type II Topoisomerase Activities Without Generating Strand Breaks. Cell Biochem Biophys 66, 199–204 (2013). https://doi.org/10.1007/s12013-012-9468-5

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  • DOI: https://doi.org/10.1007/s12013-012-9468-5

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