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The influence of an enamine usnic acid derivative (a tyrosyl-DNA phosphodiesterase 1 inhibitor) on the therapeutic effect of topotecan against transplanted tumors in vivo

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Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for 3′-end DNA lesions, predominantly stalled DNA–topoisomerase 1 (Top1) cleavage complexes. Tdp1 is a promising target for anticancer therapy based on DNA damage caused by Top1 poisoning. Earlier, we have reported about usnic acid enamine derivatives that are Tdp1 inhibitors sensitizing tumor cells to the action of Top1 poison (Zakharenko in J Nat Prod 79:2961−2967, 2016). In the present work, we showed a sensitizing effect of an enamine derivative of usnic acid (when administered intragastrically) on Lewis lung carcinoma in mice in combination with topotecan (TPT, Top1 poison used in the clinic). In the presence of the usnic acid derivative, both the volume of the primary tumor and the number of metastases significantly diminished. The absence of acute toxicity of this compound was demonstrated, as was the importance of the method of its administration for the manifestation of the sensitizing properties.

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Data availability

All data generated or analysed during this study are available on request from the authors.

Abbreviations

TPT:

Topotecan

UA:

Usnic acid

References

  1. Kiwerska K, Szyfter K (2019) DNA repair in cancer initiation, progression, and therapy-a double-edged sword. J Appl Genet 60:329–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Curtin NJ (2013) Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer. Br J Pharmacol 169:1745–1765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pouliot JJ, Yao KC, Robertson CA, Nash HA (1999) Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286:552–555

    Article  CAS  PubMed  Google Scholar 

  4. Beretta GL, Cossa G, Gatti L, Zunino F, Perego P (2010) Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin-based treatment. Curr Med Chem 17:1500–1508

    Article  CAS  PubMed  Google Scholar 

  5. Cuya SM, Comeaux EQ, Wanzeck K, Yoon KJ, van Waardenburg RC (2016) Dysregulated human tyrosyl-DNA phosphodiesterase I acts as cellular toxin. Oncotarget 7:86660–86674

    Article  PubMed  PubMed Central  Google Scholar 

  6. Katyal S, El-Khamisy SF, Russell HR, Li Y, Ju L, Caldecott KW, McKinnon PJ (2007) TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J 26:4720–4731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alagoz M, Wells OS, El-Khamisy SF (2014) TDP1 deficiency sensitizes human cells to base damage via distinct topoisomerase I and PARP mechanisms with potential applications for cancer therapy. Nucleic Acids Res 42:3089–3103

    Article  CAS  PubMed  Google Scholar 

  8. Huang HC, Liu J, Baglo Y, Rizvi I, Anbil S, Pigula M, Hasan T (2018) Mechanism-informed repurposing of minocycline overcomes resistance to topoisomerase inhibition for peritoneal carcinomatosis. Mol Cancer Ther 17:508–520

    Article  CAS  PubMed  Google Scholar 

  9. Nivens MC, Felder T, Galloway AH, Pena MM, Pouliot JJ, Spencer HT (2004) Engineered resistance to camptothecin and antifolates by retroviral coexpression of tyrosyl DNA phosphodiesterase-I and thymidylate synthase. Cancer Chemother Pharmacol 53:107–115

    Article  CAS  PubMed  Google Scholar 

  10. Barthelmes HU, Habermeyer M, Christensen MO, Mielke C, Interthal H, Pouliot JJ, Boege F, Marko D (2004) TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II. J Biol Chem 279:55618–55625

    Article  CAS  PubMed  Google Scholar 

  11. Meisenberg C, Gilbert DC, Chalmers A, Haley V, Gollins S, Ward SE, El-Khamisy SF (2015) Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. Mol Cancer Ther 14:575–585

    Article  CAS  PubMed  Google Scholar 

  12. Laev SS, Salakhutdinov NF, Lavrik OI (2016) Tyrosyl-DNA phosphodiesterase inhibitors: progress and potential. Bioorg Med Chem 24:5017–5027

    Article  CAS  PubMed  Google Scholar 

  13. Brettrager EJ, van Waardenburg RCAM (2019) Targeting tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts. Cancer Drug Resist 2:1153–1163

    PubMed  PubMed Central  Google Scholar 

  14. Zakharenko A, Dyrkheeva N, Lavrik O (2019) Dual DNA topoisomerase 1 and tyrosyl-DNA phosphodiesterase 1 inhibition for improved anticancer activity. Med Res Rev 39:1427–1441

    Article  CAS  PubMed  Google Scholar 

  15. Zakharenko AL, Luzina OA, Sokolov DN, Zakharova OD, Rakhmanova ME, Chepanova AA, Dyrkheeva NS, Lavrik OI, Salakhutdinov NF (2017) Usnic acid derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1. Russ J Bioorg Chem 43:84–90

    Article  CAS  Google Scholar 

  16. Dyrkheeva N, Luzina O, Filimonov A, Zakharova O, Ilina E, Zakharenko A, Kuprushkin M, Nilov D, Gushchina I, Švedas V, Salakhutdinov N, Lavrik O (2018) Inhibitory effect of new semisynthetic usnic acid derivatives on human tyrosyl-DNA phosphodiesterase 1. Planta Med 85:103–111

    PubMed  Google Scholar 

  17. Li-Zhulanov NS, Zakharenko AL, Chepanova AA, Patel J, Zafar A, Volcho KP, Salakhutdinov NF, Reynisson J, Leung IKH, Lavrik OI (2018) A novel class of tyrosyl-DNA phosphodiesterase 1 inhibitors that contains the octahydro-2H-chromen-4-ol scaffold. Molecules 23:2468

    Article  PubMed Central  CAS  Google Scholar 

  18. Komarova AO, Drenichev MS, Dyrkheeva NS, Kulikova IV, Oslovsky VE, Zakharova OD, Zakharenko AL, Mikhailov SN, Lavrik OI (2018) Novel group of tyrosyl-DNA-phosphodiesterase 1 inhibitors based on disaccharide nucleosides as drug prototypes for anti-cancer therapy. J Enzyme Inhib Med Chem 33:1415–1429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang XR, Wang HW, Tang WL, Zhang Y, Yang H, Hu DX, Ravji A, Marchand C, Kiselev E, Ofori-Atta K, Agama K, Pommier Y, An LK (2018) Discovery, synthesis, and evaluation of oxynitidine derivatives as dual inhibitors of DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), and potential antitumor agents. J Med Chem 61:9908–9930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zakharenko AL, Luzina OA, Sokolov DN, Kaledin VI, Nikolin VP, Popova NA, Patel J, Zakharova OD, Chepanova AA, Zafar A, Reynisson J, Leung E, Leung IKH, Volcho KP, Salakhutdinov NF, Lavrik OI (2019) Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topotecan on in vivo tumor models. Eur J Med Chem 161:581–593

    Article  CAS  PubMed  Google Scholar 

  21. Mamontova EM, Zakharenko AL, Zakharova OD, Dyrkheeva NS, Volcho KP, Reynisson J, Arabshahi HJ, Salakhutdinov NF, Lavrik OI (2020) Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening. Bioorg Med Chem 28:115234

    Article  CAS  PubMed  Google Scholar 

  22. Khomenko TM, Zakharenko AL, Chepanova AA, Ilina ES, Zakharova OD, Kaledin VI, Nikolin VP, Popova NA, Korchagina DV, Reynisson J, Chand R, Ayine-Tora DM, Patel J, Leung IKH, Volcho KP, Salakhutdinov NF, Lavrik OI (2019) Promising new inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 4-arylcoumarin and monoterpenoid moieties as components of complex antitumor therapy. Int J Mol Sci 21:126

    Article  PubMed Central  CAS  Google Scholar 

  23. Filimonov AS, Chepanova AA, Luzina OA, Zakharenko AL, Zakharova OD, Ilina ES, Dyrkheeva NS, Kuprushkin MS, Kolotaev AV, Khachatryan DS, Patel J, Leung IKH, Chand R, Ayine-Tora DM, Reynisson J, Volcho KP, Salakhutdinov NF, Lavrik OI (2019) New hydrazinothiazole derivatives of usnic acid as potent Tdp1 inhibitors. Molecules 24:E3711

    Article  PubMed  CAS  Google Scholar 

  24. Kovaleva K, Oleshko O, Mamontova E, Yarovaya O, Zakharova O, Zakharenko A, Kononova A, Dyrkheeva N, Cheresiz S, Pokrovsky A, Lavrik O, Salakhutdinov N (2019) Dehydroabietylamine ureas and thioureas as tyrosyl-DNA phosphodiesterase 1 inhibitors that enhance the antitumor effect of temozolomide on glioblastoma cells. J Nat Prod 82:2443–2450

    Article  CAS  PubMed  Google Scholar 

  25. Chepanova AA, Li-Zhulanov NS, Sukhikh AS, Zafar A, Reynisson J, Zakharenko AL, Zakharova OD, Korchagina DV, Volcho KP, Salakhutdinov NF, Lavrik OI (2020) Effective inhibitors of tyrosyl-DNA phosphodiesterase 1 based on monoterpenoids as potential agents for antitumor therapy. Rus J Bioorg Chem 45:647–655

    Article  Google Scholar 

  26. Gladkova ED, Nechepurenko IV, Bredikhin RA, Chepanova AA, Zakharenko AL, Luzina OA, Ilina ES, Dyrkheeva NS, Mamontova EM, Anarbaev RO, Reynisson J, Volcho KP, Salakhutdinov NF, Lavrik OI (2020) The first berberine-based inhibitors of tyrosyl-DNA phosphodiesterase 1 (Tdp1), an important DNA repair enzyme. Int J Mol Sci 21:7162

    Article  CAS  PubMed Central  Google Scholar 

  27. Wang P, Elsayed MSA, Plescia CB, Ravji A, Redon CE, Kiselev E, Marchand C, Zeleznik O, Agama K, Pommier Y, Cushman M (2017) Synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1, tyrosyl-DNA phosphodiesterase 1 (Tdp1), and tyrosyl-DNA phosphodiesterase 2 (Tdp2). J Med Chem 60:3275–3288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nguyen TX, Morrell A, Conda-Sheridan M, Marchand C, Agama K, Bermingham A, Stephen AG, Chergui A, Naumova A, Fisher R, O’Keefe BR, Pommier Y, Cushman M (2012) Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors. J Med Chem 55:4457–4478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nguyen TX, Abdelmalak M, Marchand C, Agama K, Pommier Y, Cushman M (2015) Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (Top1)−tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. J Med Chem 58:3188–3208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Conda-Sheridan M, Reddy PVN, Morrell A, Cobb BT, Marchand C, Agama K, Chergui A, Renaud A, Stephen AG, Bindu LK, Pommier Y, Cushman M (2013) Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA-phosphodiesterase I (Tdp1) and topoisomerase I (Top1). J Med Chem 56:182–200

    Article  CAS  PubMed  Google Scholar 

  31. Lv PC, Agama K, Marchand C, Pommier Y, Cushman M (2014) Design, synthesis, and biological evaluation of O-2-modified indenoisoquinolines as dual topoisomerase I−tyrosyl-DNA phosphodiesterase I inhibitors. J Med Chem 57:4324–4336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Beck DE, Lv W, Abdelmalak M, Plescia CB, Agama K, Marchand C, Pommier Y, Cushman M (2016) Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons. Bioorg Med Chem 24:1469–1479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Elsayed MSA, Su Y, Wang P, Sethi T, Agama K, Ravji A, Redon CE, Kiselev E, Horzmann KA, Freeman JL, Pommier Y, Cushman M (2017) Design and synthesis of chlorinated and fluorinated 7-azaindenoisoquinolines as potent cytotoxic anticancer agents that inhibit topoisomerase I. J Med Chem 60:5364–5376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luzina OA, Salakhutdinov NF (2018) Usnic acid and its derivatives for pharmaceutical use: a patent review (2000–2017). Exp Opin Ther Patents 28:477–491

    Article  CAS  Google Scholar 

  35. Zakharenko A, Sokolov D, Luzina O, Sukhanova M, Khodyreva S, Zakharova O, Salakhutdinov N, Lavrik O (2012) Influence of usnic acid and its derivatives on the activity of mammalian poly(ADP-ribose)polymerase 1 and DNA polymerase β. Med Chem 8:883–893

    Article  CAS  PubMed  Google Scholar 

  36. Zakharenko A, Luzina O, Koval O, Nilov D, Gushchina I, Dyrkheeva N, Švedas V, Salakhutdinov N, Lavrik O (2016) Tyrosyl-DNA phosphodiesterase 1 inhibitors: usnic acid enamines enhance the cytotoxic effect of camptothecin. J Nat Prod 79:2961–2967

    Article  CAS  PubMed  Google Scholar 

  37. Koldysheva EV, Men’shchikova AP, Lushnikova EL, Popova NA, Kaledin VI, Nikolin VP, Zakharenko AL, Luzina OA, Salakhutdinov NF, Lavrik OI (2019) Antimetastatic activity of combined topotecan and tyrosyl-DNA phosphodiesterase-1 inhibitor on modeled lewis lung carcinoma. Bull Exp Biol Med 166:661–666

    Article  CAS  PubMed  Google Scholar 

  38. Bertram JS, Janik P (1980) Establishment of a cloned line of Lewis lung carcinoma cells adapted to cell culture. Cancer Lett 11:63–73

    Article  CAS  PubMed  Google Scholar 

  39. Zhu H, Kauffman ME, Trush MA, Jia ZQ, Li YR (2018) A simple bioluminescence imaging method for studying cancer cell growth and metastasis after subcutaneous injection of Lewis lung carcinoma cells in syngeneic C57BL/6 mice. React Oxyg Species (Apex) 5:118–125

    CAS  Google Scholar 

  40. Ma XM, Yu MW, Zhang GL, Yu J, Cao KX, Sun X, Yang GW, Wang XM (2017) Comparison of mouse models of Lewis lung carcinoma subcutaneously transplanted at different sites. Acta Lab Anim Sci Sin 25:386–390

    CAS  Google Scholar 

  41. Klein G, Klein E (1951) The transformation of a solid transplantable mouse carcinoma into an “ascites tumor.” Cancer Res 11:466–469

    CAS  PubMed  Google Scholar 

  42. Patt HM, Blackford ME (1954) Quantitative studies of the growth response of the Krebs ascites tumor. Cancer Res 14:391–396

    CAS  PubMed  Google Scholar 

  43. Yushok WD, Mallalieu LJ, Batt WG (1956) Properties of Krebs 2 ascites carcinoma cells: weight, size, specific gravity, and protein content. J Frankl Inst 262:507–509

    Article  CAS  Google Scholar 

  44. Parsons DF, Marko M, Braun SJ, Wansor KJ (1982) Ascites tumor invasion of mouse peritoneum studied by high-voltage electron microscope stereoscopy. Cancer Res 42:4574–4583

    CAS  PubMed  Google Scholar 

  45. Lin TC, Liao YC, Chang WT, Yang CH, Cheng LH, Cheng M, Cheng HC (2018) The establishment of a lung colonization assay for circulating tumor cell visualization in lung tissues. J Vis Exp 136:56761

    Google Scholar 

  46. Shtro AA, Zarubaev VV, Luzina OA, Sokolov DN, Salakhutdinov NF (2015) Derivatives of usnic acid inhibit broad range of influenza viruses and protect mice from lethal influenza infection. Antivir Chem Chemother 24:92–98

    Article  CAS  PubMed  Google Scholar 

  47. Luzina O, Zakharenko A, Sokolov D, Salakhutdinov N, Lavrik O, Khazanov V (2017) 2-Acetyl-6-(2-(2-(4-brombenzylidene) Hydrazinyl)thiazol-4-yl)-3,7,9-trihydroxy-8,9b-dimethyldiobenzo[b,d]furan-1(9bh)-oh, with Inhibiting Action on Human Tyrosyl-DNA-phosphodiesterase 1. Patent RU2627764

  48. Krishna DR, Venkataramana D (1992) Pharmacokinetics of D(+)-usnic acid in rabbits after intravenous and oral administration. Drug Metab Dispos 20:909–911

    CAS  PubMed  Google Scholar 

  49. Turner PV, Brabb T, Pekow C, Vasbinder MA (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 50:600–613

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lukas G, Brindle SD, Greengard P (1971) The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 178:562–566

    CAS  PubMed  Google Scholar 

  51. Einarsdóttir E, Groeneweg J, Bjórnsdóttir GG, Harardóttir G, Omarsdóttir S, Ingólfsdóttir K, Ögmundsdóttir HM (2010) Cellular mechanisms of the anticancer effects of the lichen compound usnic acid. Planta Med 76:969–974

    Article  PubMed  CAS  Google Scholar 

  52. Bakorová M, Jendelovsky R, Kello M, Bakor M, Mikeš J, Fedoroko P (2012) Lichen secondary metabolites are responsible for induction of apoptosis in HT-29 and A2780 human cancer cell lines. Toxicol In Vitro 26:462–468

    Article  CAS  Google Scholar 

  53. Rabelo TK, Zeidán-Chuliá F, Vasques LM, dos Santos JPA, da Rocha RF, de Bittencourt Pasquali MA, Rybarczyk Filho JL, Araujo AAS, Moreira JCF, Gelain DP (2012) Redox characterization of usnic acid and its cytotoxic effect on human neuron-like cells (SH-SY5Y). Toxicol In Vitro 26:304–314

    Article  CAS  PubMed  Google Scholar 

  54. Sahu SC, O’Donnell MW, Sprando RL (2012) Effects of usnic acid exposure on human hepatoblastoma HepG2 cells in culture. J Appl Toxicol 32:739–749

    Article  CAS  PubMed  Google Scholar 

  55. Luzina OA, Salakhutdinov NF (2016) Biological activity of usnic acid and its derivatives: part 2. Effects on higher organisms. molecular and physicochemical aspects. Russ J Bioorg Chem 42:249–268

    Article  CAS  Google Scholar 

  56. Kawale AS, Povirk LF (2018) Tyrosyl-DNA phosphodiesterases: rescuing the genome from the risks of relaxation. Nucleic Acids Res 46:520–537

    Article  CAS  PubMed  Google Scholar 

  57. Dyrkheeva NS, Zakharenko AL, Novoselova ES, Chepanova AA, Popova NA, Nikolin VP, Luzina OA, Salakhutdinov NF, Ryabchikova EI, Lavrik OI (2021) Antitumor activity of the combination of topotecan and tyrosyl-DNA-phosphodiesterase 1 inhibitor on model Krebs-2 mouse ascite carcinoma. Mol Biol (Mosk) 55:312–317

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by a Grant from the Ministry of Science and Higher Education Russian Federation (Agreement No. 075-15-2020-773).

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Authors and Affiliations

  1. Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

    V. P. Nikolin, N. A. Popova & V. I. Kaledin

  2. N. N. Vorozhtsov Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 9 Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

    O. A. Luzina & N. F. Salakhutdinov

  3. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 8 Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

    A. L. Zakharenko & O. I. Lavrik

  4. Novosibirsk State University, 1 Pirogova Str., Novosibirsk, Russian Federation, 630090

    N. A. Popova, N. F. Salakhutdinov & O. I. Lavrik

  5. Altai State University, 61 Lenina Ave., Barnaul, Russian Federation, 656049

    O. I. Lavrik

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  1. V. P. Nikolin
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  2. N. A. Popova
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  3. V. I. Kaledin
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  4. O. A. Luzina
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  5. A. L. Zakharenko
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  6. N. F. Salakhutdinov
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V. I. Kaledin—deceased.

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Nikolin, V.P., Popova, N.A., Kaledin, V.I. et al. The influence of an enamine usnic acid derivative (a tyrosyl-DNA phosphodiesterase 1 inhibitor) on the therapeutic effect of topotecan against transplanted tumors in vivo. Clin Exp Metastasis 38, 431–440 (2021). https://doi.org/10.1007/s10585-021-10113-y

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