Research Article
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Investigation of the Enyzmatic Interactions Between Roxithromycin and DNA Topoisomerase I and II

Year 2025, Volume: 46 Issue: 3, 512 - 516, 30.09.2025
https://doi.org/10.17776/csj.1691571

Abstract

drugs. The reasons underlying this unique priority are that topoisomerase enzymes are indispensable for the cell's own life dynamics, in the synthesis of RNA and proteins in the cell, or more importantly, for the preservation of genetic material. These enzymes are similar in terms of structure and functionality in many living groups, and by having relatively similar activities, they enable the creation of controlled DNA breaks and the reunification of DNA fragments in the cell. In fact, they are a kind of problem solver regarding the use of narrow spaces with their activities that enable the separation of long DNA molecules, which can be considered as gigantic in size, depending on the cell area in which they are located. In our study, the anticancer activity of Roxithromycin has been evaluated by topoisomerase enzyme assay analyses. Given the growing body of evidence supporting the anticancer properties of certain antibiotics, we evaluated whether Roxithromycin has different targets than those known through its potential anticancer effects and interactions with topoisomerase enzymes. Our findings revealed that roxithromycin selectively inhibited topoisomerase II activity, but did not show any inhibitory effect on topoisomerase I.

Supporting Institution

Scientific Research Project Fund of Sivas Cumhuriyet University

Project Number

ECZ 2022-087

References

  • Pommier Y., Sun Y.,. Huang S.Y. N, and Nitiss J.L., Roles of eukaryotic topoisomerases in transcription, replication and genomic stability, Nat Rev Mol Cell Biol., 11 (2016) 703-721.
  • Wang, J.C., Cellular roles of DNA topoisomerases: A molecular perspective, Nat Rev Mol Cell Biol., (6) (2002) 430-440.
  • Pommier Y., Leo E., Zhang H., and Marchand C., DNA topoisomerases and their poisoning by anticancer and antibacterial drugs, Chem Biol., 17 (5) (2010) 421-433.
  • Nadelmann J., Francis J.H., Brodie S.E., Muca E., and Abramson D.H., Is intravitreal topotecan toxic to retinal function?, Br J Ophthalmol., 105 (7) (2021) 1016-1018.
  • Sen M., Rao R., Mulay K., Reddy V.A.P., and Honavar S.G., Intravitreal Topotecan for Vitreous Seeds in Retinoblastoma, Ophthalmology, 131 (10) (2024) 1215-1224.
  • Moreno L, Weston R, Owens C, Valteau-Couanet D, Gambart M, Castel V, Zwaan CM, Nysom K, Gerber N, Castellano A, Laureys G, Ladenstein R, Rössler J, Makin G, Murphy D, Morland B, Vaidya S, Thebaud E, van Eijkelenburg N, Tweddle DA, Barone G, Tandonnet J, Corradini N, Chastagner P, Paillard C, Bautista FJ, Gallego Melcon S, De Wilde B, Marshall L, Gray J, Burchill SA, Schleiermacher G, Chesler L, Peet A, Leach MO, McHugh K, Hayes R, Jerome N, Caron H, Laidler J, Fenwick N, Holt G, Moroz V, Kearns P, Gates S, Pearson ADJ, Wheatley K., Innovative Therapies for Children with Cancer (ITCC) and European Association for Neuroblastoma Research (SIOPEN). Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial, J Clin Oncol., 42 ( 10) (2024) 1135-1145.
  • Upadhyayula P.S., Spinazzi E.F., Argenziano M. G., Canoll P., and Bruce J.N., Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience, Pharmaceutics, 13 (1) (2020) 39.
  • Baize N, Monnet I, Greillier L, Geier M, Lena H, Janicot H, Vergnenegre A, Crequit J, Lamy R, Auliac JB, Letreut J, Le Caer H, Gervais R, Dansin E, Madroszyk A, Renault PA, Le Garff G, Falchero L, Berard H, Schott R, Saulnier P, Chouaid C; Groupe Français de Pneumo-Cancérologie 01–13 investigators, Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial, Lancet Oncol., 21 (9) (2020) 1224-1233.
  • Singh V., Afshan T., Tyagi P., Varadwaj P.K., and Sahoo A.K., Recent development of multi-targeted inhibitors of human topoisomerase II enzyme as potent cancer therapeutics, Int J Biol Macromol., 226, (2023) 473-484.
  • Kciuk M., Gielecińska A., Mujwar S., Kołat D., Kałuzińska-Kołat Ż., Celik I., Kontek R., Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity, Cells, 12 (4) (2023) 659.
  • Matias-Barrios V.M. and Dong X., The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy, Pharmaceuticals, 16 (1) (2023) 94.
  • Avendaño C. and Menéndez J.C., DNA Intercalators and Topoisomerase Inhibitors, in Medicinal Chemistry of Anticancer Drugs, (2008), 199-228.
  • [Nitiss J.L., Investigating the biological functions of DNA topoisomerases in eukaryotic cells, Biochim Biophys Acta., 1400 (1-3) (1998) 63-81.
  • Champoux J.J., DNA Topoisomerases: Structure, Function, and Mechanism, Annu Rev Biochem., 70 (2001) 369-413.
  • Yadav V. and Talwar P., Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth, Biomed Pharmacother., 111 (2019) 934-946.
  • Elik A., Gokce G., Bostanci E., and Kiziloluk D., Development of Electrochemical DNA Sensor for The Determination of Anaplasma Phagocytophilum, Cumhuriyet Sci. J., 38 (3) (2017) 525-534.
  • Farouk F, Elmaaty AA, Elkamhawy A, Tawfik HO, Alnajjar R, Abourehab MAS, Saleh MA, Eldehna WM, Al-Karmalawy AA., Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies, J Enzyme Inhib Med Chem., 38 (1) (2023) 2171029.
  • Shinoda M., Macrolides as Immunomodulatory Agents Springer, in Progress in Inflammation Research 1st ed. Bruce K. Rubin, Masaharu Shinkai (Eds). (2024) 223-254.
  • Yatsunami J., Tsuruta N., Fukuno Y., Kawashima M., Taniguchi S., and Hayashi S., Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis of mouse B16 melanoma cells, Clin Exp Metastasis., 17 (2) (1999) 119-124.
  • Ueno S, Aoki D, Kubo F, Hiwatashi K, Matsushita K, Oyama T, Maruyama I, Aikou T., Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma, Clin Cancer Res., 11 (15) (2005) 5645-5650.
  • Gentry L.O., Roxithromycin, a new macrolide antibiotic, in the treatment of infections in the lower respiratory tract: an overview, J Antimicrob Chemother., 20, (1987) 145-152.
  • Young R.A., Gonzalez J.P., Sorkin E.M., Roxithromycin. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy, Drugs, 37 (1) (1989) 8-41.
  • Nitiss J.L., Topoisomerase Assays, Curr Protoc Pharmacol., 1, (1998) 3:Unit3.3.
  • Hicyilmaz A.M., Nergiz K., Canturk P., Berisha A., Kaya S., Evaluation of the interactions of the Sunitinib malate with topoisomerase enzymes by in vitro enzyme and molecular docking analyses, Maghr. J. Pure & Appl. Sci., 1, (2023) 13-22.
  • Gok E., Unal N., Gungor B., Karakus G., Kaya S., Canturk P., Katin K.P., Evaluation of the Anticancer and Biological Activities of Istaroxime via Ex Vivo Analyses, Molecular Docking and Conceptual Density Functional Theory Computations, Molecules, 28 (22) (2023)
  • Senkardeş S., Bolat I,, Şahinbey H,, Karakus S,, Erdoğan O,, Canturk P., Yözgüven S.Y., Çevik O., Design, synthesis and molecular modeling studies of thiosemicarbazide & thiazolyl-hydrazone derivatives as potential anticancer agents and topoisomerase inhibitors, J Mol Struct., 1302, (2024) 137488.

Year 2025, Volume: 46 Issue: 3, 512 - 516, 30.09.2025
https://doi.org/10.17776/csj.1691571

Abstract

Project Number

ECZ 2022-087

References

  • Pommier Y., Sun Y.,. Huang S.Y. N, and Nitiss J.L., Roles of eukaryotic topoisomerases in transcription, replication and genomic stability, Nat Rev Mol Cell Biol., 11 (2016) 703-721.
  • Wang, J.C., Cellular roles of DNA topoisomerases: A molecular perspective, Nat Rev Mol Cell Biol., (6) (2002) 430-440.
  • Pommier Y., Leo E., Zhang H., and Marchand C., DNA topoisomerases and their poisoning by anticancer and antibacterial drugs, Chem Biol., 17 (5) (2010) 421-433.
  • Nadelmann J., Francis J.H., Brodie S.E., Muca E., and Abramson D.H., Is intravitreal topotecan toxic to retinal function?, Br J Ophthalmol., 105 (7) (2021) 1016-1018.
  • Sen M., Rao R., Mulay K., Reddy V.A.P., and Honavar S.G., Intravitreal Topotecan for Vitreous Seeds in Retinoblastoma, Ophthalmology, 131 (10) (2024) 1215-1224.
  • Moreno L, Weston R, Owens C, Valteau-Couanet D, Gambart M, Castel V, Zwaan CM, Nysom K, Gerber N, Castellano A, Laureys G, Ladenstein R, Rössler J, Makin G, Murphy D, Morland B, Vaidya S, Thebaud E, van Eijkelenburg N, Tweddle DA, Barone G, Tandonnet J, Corradini N, Chastagner P, Paillard C, Bautista FJ, Gallego Melcon S, De Wilde B, Marshall L, Gray J, Burchill SA, Schleiermacher G, Chesler L, Peet A, Leach MO, McHugh K, Hayes R, Jerome N, Caron H, Laidler J, Fenwick N, Holt G, Moroz V, Kearns P, Gates S, Pearson ADJ, Wheatley K., Innovative Therapies for Children with Cancer (ITCC) and European Association for Neuroblastoma Research (SIOPEN). Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial, J Clin Oncol., 42 ( 10) (2024) 1135-1145.
  • Upadhyayula P.S., Spinazzi E.F., Argenziano M. G., Canoll P., and Bruce J.N., Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience, Pharmaceutics, 13 (1) (2020) 39.
  • Baize N, Monnet I, Greillier L, Geier M, Lena H, Janicot H, Vergnenegre A, Crequit J, Lamy R, Auliac JB, Letreut J, Le Caer H, Gervais R, Dansin E, Madroszyk A, Renault PA, Le Garff G, Falchero L, Berard H, Schott R, Saulnier P, Chouaid C; Groupe Français de Pneumo-Cancérologie 01–13 investigators, Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial, Lancet Oncol., 21 (9) (2020) 1224-1233.
  • Singh V., Afshan T., Tyagi P., Varadwaj P.K., and Sahoo A.K., Recent development of multi-targeted inhibitors of human topoisomerase II enzyme as potent cancer therapeutics, Int J Biol Macromol., 226, (2023) 473-484.
  • Kciuk M., Gielecińska A., Mujwar S., Kołat D., Kałuzińska-Kołat Ż., Celik I., Kontek R., Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity, Cells, 12 (4) (2023) 659.
  • Matias-Barrios V.M. and Dong X., The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy, Pharmaceuticals, 16 (1) (2023) 94.
  • Avendaño C. and Menéndez J.C., DNA Intercalators and Topoisomerase Inhibitors, in Medicinal Chemistry of Anticancer Drugs, (2008), 199-228.
  • [Nitiss J.L., Investigating the biological functions of DNA topoisomerases in eukaryotic cells, Biochim Biophys Acta., 1400 (1-3) (1998) 63-81.
  • Champoux J.J., DNA Topoisomerases: Structure, Function, and Mechanism, Annu Rev Biochem., 70 (2001) 369-413.
  • Yadav V. and Talwar P., Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth, Biomed Pharmacother., 111 (2019) 934-946.
  • Elik A., Gokce G., Bostanci E., and Kiziloluk D., Development of Electrochemical DNA Sensor for The Determination of Anaplasma Phagocytophilum, Cumhuriyet Sci. J., 38 (3) (2017) 525-534.
  • Farouk F, Elmaaty AA, Elkamhawy A, Tawfik HO, Alnajjar R, Abourehab MAS, Saleh MA, Eldehna WM, Al-Karmalawy AA., Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies, J Enzyme Inhib Med Chem., 38 (1) (2023) 2171029.
  • Shinoda M., Macrolides as Immunomodulatory Agents Springer, in Progress in Inflammation Research 1st ed. Bruce K. Rubin, Masaharu Shinkai (Eds). (2024) 223-254.
  • Yatsunami J., Tsuruta N., Fukuno Y., Kawashima M., Taniguchi S., and Hayashi S., Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis of mouse B16 melanoma cells, Clin Exp Metastasis., 17 (2) (1999) 119-124.
  • Ueno S, Aoki D, Kubo F, Hiwatashi K, Matsushita K, Oyama T, Maruyama I, Aikou T., Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma, Clin Cancer Res., 11 (15) (2005) 5645-5650.
  • Gentry L.O., Roxithromycin, a new macrolide antibiotic, in the treatment of infections in the lower respiratory tract: an overview, J Antimicrob Chemother., 20, (1987) 145-152.
  • Young R.A., Gonzalez J.P., Sorkin E.M., Roxithromycin. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy, Drugs, 37 (1) (1989) 8-41.
  • Nitiss J.L., Topoisomerase Assays, Curr Protoc Pharmacol., 1, (1998) 3:Unit3.3.
  • Hicyilmaz A.M., Nergiz K., Canturk P., Berisha A., Kaya S., Evaluation of the interactions of the Sunitinib malate with topoisomerase enzymes by in vitro enzyme and molecular docking analyses, Maghr. J. Pure & Appl. Sci., 1, (2023) 13-22.
  • Gok E., Unal N., Gungor B., Karakus G., Kaya S., Canturk P., Katin K.P., Evaluation of the Anticancer and Biological Activities of Istaroxime via Ex Vivo Analyses, Molecular Docking and Conceptual Density Functional Theory Computations, Molecules, 28 (22) (2023)
  • Senkardeş S., Bolat I,, Şahinbey H,, Karakus S,, Erdoğan O,, Canturk P., Yözgüven S.Y., Çevik O., Design, synthesis and molecular modeling studies of thiosemicarbazide & thiazolyl-hydrazone derivatives as potential anticancer agents and topoisomerase inhibitors, J Mol Struct., 1302, (2024) 137488.
There are 26 citations in total.

Details

Primary Language English
Subjects Cancer Biology, Pharmaceutical Analytical Chemistry, Pharmacology and Pharmaceutical Sciences (Other), Electroanalytical Chemistry
Journal Section Natural Sciences
Authors

Esra Koca 0009-0004-1327-6556

Pakize Cantürk 0000-0001-8623-784X

Gültekin Gökçe 0009-0002-4100-3788

Project Number ECZ 2022-087
Publication Date September 30, 2025
Submission Date May 5, 2025
Acceptance Date September 18, 2025
Published in Issue Year 2025 Volume: 46 Issue: 3

Cite

APA Koca, E., Cantürk, P., & Gökçe, G. (2025). Investigation of the Enyzmatic Interactions Between Roxithromycin and DNA Topoisomerase I and II. Cumhuriyet Science Journal, 46(3), 512-516. https://doi.org/10.17776/csj.1691571