DEKSRAZOKSANIN OLASI KARDİYOPROTEKTİF ETKİ MEKANİZMASI VE MUHTEMEL İNSAN TOPOİZOMERAZ IIΒ İNHİBİTÖRLERİ: İN SİLİCO ANALİZ

Year 2022, Volume: 46 Issue: 2, 474 - 486, 29.05.2022

Fuat Karakuş , Burak Kuzu

https://doi.org/10.33483/jfpau.1085504

Abstract

Amaç: Bu çalışmanın amacı deksrazoksanın kardiyoprotektif etkisinde hangi metabolitinin rol oynadığını belirlemek ve ayrıca deksrazoksanın klinik kullanımı sınırlı olduğu için deksrazoksana alternatif bileşikleri saptamaktı. Bu amaçla, deksrazoksan ve üç metabolitinin (B, C, ve ADR-925) ve ayrıca literatürde topoizomeraz VI (insan DNA topoizomeraz II beta’nın prototipi) için inhibitör olduğu bildirilen bileşiklerin insan DNA topoizomeraz II beta ile etkileşimleri moleküler kenetleme ile araştırıldı. Sonrasında tüm bu bileşiklerin teorik ADMET özellikleri belirlendi.

Gereç ve Yöntem: Moleküler yapılar Gaussview 05 ve Gaussian 03 paket programları ile optimize edildi. Moleküler kenetleme çalışmaları için AutoDock 4.2 yazılımı kullanıldı ve kenetleme kompleksleri Discovery Studio Client 4.1 programı kullanılarak 2D ve 3D olarak analiz edildi. Teorik ADMET parametrelerini hesaplamak için pkCSM çevrimiçi programı kullanıldı.

Sonuç ve Tartışma: Moleküler kenetleme çalışmaları sonucunda deksrazoksanın B metabolitinin, hem deksrazoksana hem de diğer metabolitlerine kıyasla insan DNA topoizomeraz II beta’ya daha fazla bağlanma potansiyeli olduğu belirlendi. Literatürde bildirilen diğer bileşiklerin de insan DNA topoizomeraz II beta’ya bağlanma potansiyelleri sırası ile radisikol>kinakrin>purpurin>9-Aminoakridin>heksilresorsinol şeklindeydi.

Sonuçlar, deksrazoksanın antrasiklin kardiyotoksisitesine karşı kardiyorprotektif etki mekanizmasında deksrazoksanın B metabolitinin önemli bir rol oynadığını göstermiştir. Bunun yanında, araştırılan diğer bileşiklerden purpurin dışındakilerin toksisite oluşturma potansiyelleri olduğu da belirlenmiştir. 

Keywords

Antrasiklin kardiyotoksisitesi, deksrazoksan, in siliko analiz, kardiyoprotektif ajanlar, topoizomeraz II inhibitörleri

Supporting Institution

Bu çalışma için herhangi bir kurumdan destek sağlanmamıştır

POSSIBLE CARDIOPROTECTIVE MECHANISM OF ACTION OF DEXRAZOXANE, AND PROBABLE HUMAN TOPOISOMERASE IIβ INHIBITORS: AN IN SILICO ANALYSIS

Abstract

Objective: The aim of this study was to determine which metabolite plays a role in the cardioprotective effect of dexrazoxane, and also to identify alternative compounds to dexrazoxane since clinical use of dexrazoxane is limited. For this purpose, the interactions of dexrazoxane and its three metabolites (B, C, and ADR-925), as well as the compounds, which reported to be inhibitors for topoisomerase VI (prototype of human DNA topoisomerase II beta), with human DNA topoisomerase II beta were investigated by molecular docking. Afterwards, the theoretical ADMET properties of all these compounds were determined

Material and Method: The molecular structures were optimized by Gaussview 05 and Gaussian 03 package programs. AutoDock 4.2 software was used for molecular docking studies and the docking complexes were analyzed in 2D and 3D using the Discovery Studio Client 4.1 program. The pkCSM online program was used to calculate the theoretical ADMET parameters.

Result and Discussion: As a result of molecular docking studies, it was determined that the B metabolite of dexrazoxane has a higher binding potential to human DNA topoisomerase II beta compared to both dexrazoxane and its other metabolites. The binding potentials of other compounds reported in the literature to human DNA topoisomerase II beta were radicicol>quinacrine>purpurin>9-Aminoacridine>hexylresorcinol, respectively.

The results showed that the B metabolite of dexrazoxane plays an important role in the cardioprotective mechanism of action of dexrazoxane against anthracycline cardiotoxicity. In addition, it has been determined that other compounds, except purpurin, have the potential to cause toxicity.

Keywords

Anthracycline cardiotoxicity, cardioprotective agents, dexrazoxane, in silico analysis, topoisomerase II inhibitors

References

• 1. Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological reviews, 56(2), 185–229. [Crossref]
• 2. Lefrak, E. A., Pitha, J., Rosenheim, S., & Gottlieb, J. A. (1973). A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer, 32(2), 302–314. [Crossref]
• 3. Gerber, M. A., Gilbert, E. M., & Chung, K. J. (1975). Adriamycin cardiotoxicity in a child with Wilms tumor. Report of a case and review of the literature. The Journal of pediatrics, 87(4), 629–632. [Crossref]
• 4. McGowan, J. V., Chung, R., Maulik, A., Piotrowska, I., Walker, J. M., & Yellon, D. M. (2017). Anthracycline Chemotherapy and Cardiotoxicity. Cardiovascular drugs and therapy, 31(1), 63–75. [Crossref]
• 5. Von Hoff, D. D., Layard, M. W., Basa, P., Davis, H. L., Jr, Von Hoff, A. L., Rozencweig, M., & Muggia, F. M. (1979). Risk factors for doxorubicin-induced congestive heart failure. Annals of internal medicine, 91(5), 710–717. [Crossref]
• 6. Wouters, K. A., Kremer, L. C., Miller, T. L., Herman, E. H., & Lipshultz, S. E. (2005). Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. British journal of haematology, 131(5), 561–578. [Crossref]
• 7. Hasinoff B. B. (2006). Dexrazoxane use in the prevention of anthracycline extravasation injury. Future oncology (London, England), 2(1), 15–20. [Crossref]
• 8. Speyer, J. L., Green, M. D., Kramer, E., Rey, M., Sanger, J., Ward, C., Dubin, N., Ferrans, V., Stecy, P., & Zeleniuch-Jacquotte, A. (1988). Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. The New England journal of medicine, 319(12), 745–752. [Crossref]
• 9. Spalato Ceruso, M., Napolitano, A., Silletta, M., Mazzocca, A., Valeri, S., Improta, L., Santini, D., Tonini, G., Badalamenti, G., & Vincenzi, B. (2019). Use of Cardioprotective Dexrazoxane Is Associated with Increased Myelotoxicity in Anthracycline-Treated Soft-Tissue Sarcoma Patients. Chemotherapy, 64(2), 105–109. [Crossref]
• 10. Vrooman, L. M., Neuberg, D. S., Stevenson, K. E., Asselin, B. L., Athale, U. H., Clavell, L., Cole, P. D., Kelly, K. M., Larsen, E. C., Laverdière, C., Michon, B., Schorin, M., Schwartz, C. L., Cohen, H. J., Lipshultz, S. E., Silverman, L. B., & Sallan, S. E. (2011). The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. European journal of cancer, 47(9), 1373–1379. [Crossref]
• 11. Walker, D. M., Fisher, B. T., Seif, A. E., Huang, Y. S., Torp, K., Li, Y., & Aplenc, R. (2013). Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the Pediatric Health Information Systems database. Pediatric blood & cancer, 60(4), 616–620. [Crossref]
• 12. Hellmann, K, Rhomberg, W. Razoxane and Dexrazoxane – Two Multifunctional Agents: Experimental and Clinical Results, Springer, London, (2010).
• 13. Hasinoff B. B. (1989). The interaction of the cardioprotective agent ICRF-187 [+)-1,2-bis(3,5-dioxopiperazinyl-1-yL)propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin. Agents and actions, 26(3-4), 378–385. [Crossref]
• 14. Hasinoff, B. B., Venkataram, S., Singh, M., & Kuschak, T. I. (1994). Metabolism of the cardioprotective agents dexrazoxane (ICRF-187) and levrazoxane (ICRF-186) by the isolated hepatocyte. Xenobiotica; the fate of foreign compounds in biological systems, 24(10), 977–987. [Crossref]
• 15. Jirkovský, E., Jirkovská, A., Bureš, J., Chládek, J., Lenčová, O., Stariat, J., Pokorná, Z., Karabanovich, G., Roh, J., Brázdová, P., Šimůnek, T., Kovaříková, P., & Štěrba, M. (2018). Pharmacokinetics of the Cardioprotective Drug Dexrazoxane and Its Active Metabolite ADR-925 with Focus on Cardiomyocytes and the Heart. The Journal of pharmacology and experimental therapeutics, 364(3), 433–446. [Crossref]
• 16. BB, H., Hellmann, K., Hermanl, E. H., & Ferransi, V. J. (1998). Chemical, biological and clinical aspects of dexrazoxane and other bisdioxopiperazines. Current medicinal chemistry, 5(1), 1-28.
• 17. Simůnek, T., Klimtová, I., Kaplanová, J., Sterba, M., Mazurová, Y., Adamcová, M., Hrdina, R., Gersl, V., & Ponka, P. (2005). Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits. Pharmacological research, 51(3), 223–231. [Crossref]
• 18. Sterba, M., Popelová, O., Simunek, T., Mazurová, Y., Potácová, A., Adamcová, M., Kaiserová, H., Ponka, P., & Gersl, V. (2006). Cardioprotective effects of a novel iron chelator, pyridoxal 2-chlorobenzoyl hydrazone, in the rabbit model of daunorubicin-induced cardiotoxicity. The Journal of pharmacology and experimental therapeutics, 319(3), 1336–1347. [Crossref]
• 19. Lyu, Y. L., Kerrigan, J. E., Lin, C. P., Azarova, A. M., Tsai, Y. C., Ban, Y., & Liu, L. F. (2007). Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer research, 67(18), 8839–8846. [Crossref]
• 20. Deng, S., Yan, T., Jendrny, C., Nemecek, A., Vincetic, M., Gödtel-Armbrust, U., & Wojnowski, L. (2014). Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms. BMC cancer, 14, 842. [Crossref]
• 21. Vejpongsa, P., & Yeh, E. T. (2014). Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clinical pharmacology and therapeutics, 95(1), 45–52. [Crossref]
• 22. Hasinoff, B. B., Patel, D., & Wu, X. (2020). The Role of Topoisomerase IIβ in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane. Cardiovascular toxicology, 20(3), 312–320. [Crossref]
• 23. Hasinoff, B. B., Patel, D., & Wu, X. (2020). A QSAR study that compares the ability of bisdioxopiperazine analogs of the doxorubicin cardioprotective agent dexrazoxane (ICRF-187) to protect myocytes with DNA topoisomerase II inhibition. Toxicology and applied pharmacology, 399, 115038. [Crossref]
• 24. Jirkovský, E., Jirkovská, A., Bavlovič-Piskáčková, H., Skalická, V., Pokorná, Z., Karabanovich, G., Kollárová-Brázdová, P., Kubeš, J., Lenčová-Popelová, O., Mazurová, Y., Adamcová, M., Lyon, A. R., Roh, J., Šimůnek, T., Štěrbová-Kovaříková, P., & Štěrba, M. (2021). Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation. Circulation. Heart failure, 14(11), e008209. [Crossref]
• 25. Gadelle, D., Bocs, C., Graille, M., & Forterre, P. (2005). Inhibition of archaeal growth and DNA topoisomerase VI activities by the Hsp90 inhibitor radicicol. Nucleic acids research, 33(7), 2310–2317. [Crossref]
• 26. Taylor, J. A., Mitchenall, L. A., Rejzek, M., Field, R. A., & Maxwell, A. (2013). Application of a novel microtitre plate-based assay for the discovery of new inhibitors of DNA gyrase and DNA topoisomerase VI. PloS one, 8(2), e58010. [Crossref]
• 27. Bergerat, A., Gadelle, D., & Forterre, P. (1994). Purification of a DNA topoisomerase II from the hyperthermophilic archaeon Sulfolobus shibatae. A thermostable enzyme with both bacterial and eucaryal features. The Journal of biological chemistry, 269(44), 27663–27669. [Crossref]
• 28. Sugimoto-Shirasu, K., Stacey, N. J., Corsar, J., Roberts, K., & McCann, M. C. (2002). DNA topoisomerase VI is essential for endoreduplication in Arabidopsis. Current biology : CB, 12(20), 1782–1786. [Crossref]
• 29. Wei, H., Ruthenburg, A. J., Bechis, S. K., & Verdine, G. L. (2005). Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. The Journal of biological chemistry, 280(44), 37041–37047. [Crossref]
• 30. Wu, C. C., Li, T. K., Farh, L., Lin, L. Y., Lin, T. S., Yu, Y. J., Yen, T. J., Chiang, C. W., & Chan, N. L. (2011). Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science (New York, N.Y.), 333(6041), 459–462. [Crossref]
• 31. Pires, D. E., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of medicinal chemistry, 58(9), 4066–4072. [Crossref]
• 32. Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews, 46(1-3), 3–26. [Crossref]
• 33. Sanguinetti, M. C., & Tristani-Firouzi, M. (2006). hERG potassium channels and cardiac arrhythmia. Nature, 440(7083), 463–469. [Crossref]
• 34. Gadelle, D., Graille, M., & Forterre, P. (2006). The HSP90 and DNA topoisomerase VI inhibitor radicicol also inhibits human type II DNA topoisomerase. Biochemical pharmacology, 72(10), 1207–1216. [Crossref]
• 35. Gibb, W., Isenberg, D. A., & Snaith, M. L. (1985). Mepacrine induced hepatitis. Annals of the rheumatic diseases, 44(12), 861–862. [Crossref]
• 36. Scoazec, J. Y., Krolak-Salmon, P., Casez, O., Besson, G., Thobois, S., Kopp, N., Perret-Liaudet, A., & Streichenberger, N. (2003). Quinacrine-induced cytolytic hepatitis in sporadic Creutzfeldt-Jakob disease. Annals of neurology, 53(4), 546–547. [Crossref]
• 37. Conte, T. C., Franco, D. V., Baptista, I. L., Bueno, C. R., Jr, Selistre-de-Araújo, H. S., Brum, P. C., Moriscot, A. S., & Miyabara, E. H. (2008). Radicicol improves regeneration of skeletal muscle previously damaged by crotoxin in mice. Toxicon : official journal of the International Society on Toxinology, 52(1), 146–155. [Crossref]
• 38. Nascimento, T. L., Conte, T. C., Rissato, T. S., Luna, M. S., Soares, A. G., Moriscot, A. S., Yamanouye, N., & Miyabara, E. H. (2019). Radicicol enhances the regeneration of skeletal muscle injured by crotoxin via decrease of NF-kB activation. Toxicon: official journal of the International Society on Toxinology, 167, 6–9. [Crossref]
• 39. Singh, J., Hussain, Y., Luqman, S., & Meena, A. (2020). Purpurin: A natural anthraquinone with multifaceted pharmacological activities. Phytotherapy research : PTR, 10.1002/ptr.6965. Advance online publication. [Crossref]
• 40. Burrows, D., & Irvine, J. (1982). Contact dermatitis to hexylresorcinol. Contact dermatitis, 8(1), 71. [Crossref]