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HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model

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Abstract

The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting epigenetic “readers”, i.e., bromodomains (BRD) and post-translational modifications of nucleosomal histone proteins regulate gene expression in both cancerous and healthy cells. In this study, the new epigenetic agent BRD inhibitor PLX51107 and histone deacetylase (HDAC) inhibitor SAHA’ s (Vorinostat) single/combined applications’ reflections were analyzed in case of cell proliferation, cytotoxicity, apoptosis, cell cycle arrest, and finally target gene expression regulation upon both AML and healthy B-lymphocyte cells; HL60 and NCIBL2171, respectively; in vitro. Since mono treatments of either Vorinostat or Plx51107 regulated cellular responses such as growth, proliferation, apoptosis, and cell cycle arrest of tumor cells; their combination treatments exerted accelerated results. We detected that combined treatment of Plx51107 and Vorinostat strengthened effects detected upon leukemic cells for gaining more sensitization to the agents, decreasing cell proliferation, dramatically inducing apoptosis, and cell cycle arrest; thus regulating target gene expressions. We have shown for the first time that the newly analyzed BRD inhibitor Plx51107 could be a promising therapeutic approach for hematological malignancies and its mono or combined usage might support a rapid transition to clinical trials.

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Data availability

The datasets generated analyzed during the current study are available from the corresponding author on reasonable request.

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Since this article does not include any studies with human participants or animals, an informed consent form is not required.

References

  1. Abedin SM, Boddy CS, Munshi HG. BET inhibitors in the treatment of hematologic malignancies: current insights and prospects. OncoTargets Ther. 2016. https://doi.org/10.2147/OTT.S100515.

    Article  Google Scholar 

  2. Attia SM, Al-Khalifa MK, Al-Hamamah MA, Alotaibi MR, Attia MSM, Ahmad SF, et al. Vorinostat is genotoxic and epigenotoxic in the mouse bone marrow cells at the human equivalent doses. Toxicology. 2020. https://doi.org/10.1016/j.tox.2020.152507.

    Article  PubMed  Google Scholar 

  3. Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res. 2015;21(7):1628–38.

    Article  PubMed  CAS  Google Scholar 

  4. Cengiz Seval G, Beksac M. A comparative safety review of histone deacetylase inhibitors for the treatment of myeloma. Expert Opin Drug Saf. 2019. https://doi.org/10.1080/14740338.2019.1615051.

    Article  PubMed  Google Scholar 

  5. Chen X, Burkhardt DB, Hartman AA, Hu X, Eastman AE, Sun C, et al. MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors. Nat Commun. 2019;10(1):1–15.

    Article  Google Scholar 

  6. Čokić VP, Mojsilović S, Jauković A, Kraguljac-Kurtović N, Mojsilović S, Šefer D, et al. Gene expression profile of circulating CD34+ cells and granulocytes in chronic myeloid leukemia. Blood Cells Mol Dis. 2015;55(4):373–81.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Coudé MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015;6(19):17698.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dalva K. Hematopoez. Türk Klinik Biyokimya Sempozyumu. Denizli. Erişim adresi (2018). http://tkb.dergisi.org/pdf/pdf_TKB_317.pdf

  9. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer J. 2016. https://doi.org/10.1038/bcj.2016.50.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fasouli ES, Katsantoni E. JAK-STAT in early hematopoiesis and leukemia. Front Cell Dev Biol. 2021;9: 669363. https://doi.org/10.3389/fcell.2021.669363.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fong CY, Gilan O, Lam EY, Rubin AF, Ftouni S, Tyler D, et al. BET inhibitor resistance emerges from leukemia stem cells. Nature. 2015;525(7570):538.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ge W, Liu Z, Sun Y, Wang T, Guo H, Chen X, et al. Design and synthesis of parthenolide-SAHA hybrids for the intervention of drug-resistant acute myeloid leukemia. Bioorg Chem. 2019;87:699–713. https://doi.org/10.1016/j.bioorg.2019.03.056.

    Article  PubMed  CAS  Google Scholar 

  13. Hassell. Histone deacetylases and their inhibitors in cancer epigenetics. Diseases. 2019;7(4):57. https://doi.org/10.3390/diseases7040057.

    Article  PubMed Central  CAS  Google Scholar 

  14. Huang CS, Tan M, Zhang XM, Luo X, Tian RM, Su Q, et al. Expression and clinical significance of STAT3 genes in patients with acute myeloid leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019;27(1):45–51.

    PubMed  Google Scholar 

  15. Iacobucci I. GATA-related hematologic disorders. Exp Hematol. 2016;44(8):696–705.

    Article  Google Scholar 

  16. Ivanov M, Barragan I, Ingelman-Sundberg M. Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol Sci. 2014. https://doi.org/10.1016/j.tips.2014.05.004.

    Article  PubMed  Google Scholar 

  17. José-Enériz ES, Gimenez-Camino N, Agirre X, Prosper F. HDAC inhibitors in acute myeloid leukemia. Cancers. 2019. https://doi.org/10.3390/cancers11111794.

    Article  Google Scholar 

  18. Jostes S, Nettersheim D, Schorle H. Epigenetic drugs and their molecular targets in testicular germ cell tumors. Nat Rev Urol. 2019;16(4):245–59.

    Article  PubMed  Google Scholar 

  19. Kayser S, Levis MJ. Advances in targeted therapy for acute myeloid leukemia. Br J Hematol. 2018;180(4):484–500.

    Article  Google Scholar 

  20. Khangura RK, Bali A, Jaggi AS, Singh N. Histone acetylation and histone deacetylation in neuropathic pain: an unresolved puzzle? Eur J Pharmacol. 2017. https://doi.org/10.1016/j.ejphar.2016.12.001.

    Article  PubMed  Google Scholar 

  21. Krönke J, Kuchenbauer F, Kull M, Teleanu V, Bullinger L, Bunjes D, et al. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM). Leukemia. 2017;31(6):1363–7.

    Article  PubMed  Google Scholar 

  22. Liu S, Li F, Pan L, Yang Z, Shu Y, Lv W, et al. BRD4 inhibitor and histone deacetylase inhibitor synergistically inhibit the proliferation of gallbladder cancer in vitro and in vivo. Cancer Sci. 2019;110(8):2493–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Mao J, Li S, Zhao H, Zhu Y, Hong M, Zhu H, et al. Effects of chidamide and its combination with decitabine on proliferation and apoptosis of leukemia cell lines. Am J Transl Res. 2018;10(8):2567–78.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA. 2011;108(40):16669–74. https://doi.org/10.1073/pnas.1108190108.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013. https://doi.org/10.1038/npp.2012.112.

    Article  PubMed  Google Scholar 

  26. Nikbakht N, Tiago M, Erkes DA, Chervoneva I, Aplin AE. BET inhibition modifies melanoma infiltrating T cells and enhances response to PD-L1 blockade. J Investig Dermatol. 2019;139(7):1612.

    Article  PubMed  CAS  Google Scholar 

  27. Orkin SH. Transcription factors and hematopoietic development. J Biol Chem. 1995;270(10):4955–8.

    Article  PubMed  CAS  Google Scholar 

  28. Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: from structures to applications. Epigenetics. 2017;12(5):323–39. https://doi.org/10.1080/15592294.2016.1265710.

    Article  PubMed  Google Scholar 

  29. Pericole FV, Lazarini M, De Paiva LB, Duarte ADSS, Vieira Ferro KP, Niemann FS, et al. BRD4 inhibition enhances azacitidine efficacy in acute myeloid leukemia and myelodysplastic syndromes. Front Oncol. 2019;9:16.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ramadoss M, Mahadevan V. Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors. Drug Discov Today. 2018. https://doi.org/10.1016/j.drudis.2017.09.011.

    Article  PubMed  Google Scholar 

  31. Sarnik J, Popławski T, Tokarz P. BET proteins as attractive targets for cancer therapeutics. Int J Mol Sci. 2021;22(20):11102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Silva G, Cardoso BA, Belo H, Almeida AM. Vorinostat induces apoptosis and differentiation in myeloid malignancies: genetic and molecular mechanisms. PLoS ONE. 2013;8(1): e53766.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev. 2019;36:70–87.

    Article  PubMed  Google Scholar 

  34. Shimizu R, Yamamoto M. GATA-related hematologic disorders. Exp Hematol. 2016;44(8):696–705. https://doi.org/10.1016/j.exphem.2016.05.010 (Epub 25 May 2016).

  35. Stewart HJS, Horne GA, Bastow S, Chevassut TJT. BRD4 associates with p53 in DNMT3A-mutated leukemia cells and is implicated in apoptosis by the bromodomain inhibitor JQ1. Cancer Med. 2013;2:826–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Stewart HJS, Shalit E, Halliday L, Morey D, Chevassut TJ. Acute myeloid leukemia cells exhibit selective down-regulation of DNMT3A isoform 2. Leuk Lymphoma. 2015. https://doi.org/10.3109/10428194.2015.1032965.

    Article  PubMed  Google Scholar 

  37. Strauss J, Figg WD. Using epigenetic therapy to overcome chemotherapy resistance. Anticancer Res Int Inst Anticancer Res. 2016;36(1):1–4.

    CAS  Google Scholar 

  38. Sun CC, Li SJ, Chen ZL, Li G, Zhang Q, Li DJ. Expression and prognosis analyses of runt-related transcription factor family in human leukemia. Mol Ther Oncolytics. 2019;12:103–11. https://doi.org/10.1016/j.omto.2018.12.008.

    Article  PubMed  CAS  Google Scholar 

  39. Sun Y, Wang H, Luo C. miR-100 regulates cell viability and apoptosis by targeting ATM in pediatric acute myeloid leukemia. Biochem Biophys Res Commun. 2019. https://doi.org/10.1016/j.bbrc.2019.11.156.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Taniguchi Y. The bromodomain and extra-terminal domain (BET) family: functional anatomy of BET paralogous proteins. Int J Mol Sci. 2016. https://doi.org/10.3390/ijms17111849.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wen JC, Jiang T, Bao Y, Lin XJ, Wang WQ, Liu D, Zhao LX. Synthesis and antitumor activity of S-hexyl (heptyl) substituted ethanethioate derivatives. Yao xue xue bao = Acta Pharm Sin. 2014;49(3):352–8.

    CAS  Google Scholar 

  42. Young CS, Clarke KM, Kettyle LM, Thompson A, Mills KI. Decitabine-Vorinostat combination treatment in acute myeloid leukemia activates pathways with potential for novel triple therapy. Oncotarget. 2017;8(31):51429.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zhao X, Liu H, Wang L, Yang L, Liu X. Current and emerging molecular and epigenetic disease entities in acute myeloid leukemia and a critical assessment of their therapeutic modalities. Semin Cancer Biol. 2020. https://doi.org/10.1016/j.semcancer.2020.11.010.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was supported by Ege University Scientific Research Projects Coordinatorship referred to as TGA-2019-20763. All of the experimental studies were carried out in Ege University Medical Biology Department Laboratories.

Funding

This study was funded by Ege University Scientific Research Projects Coordinatorship referred to as TGA-2019-20763.

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Authors and Affiliations

  1. Medical Biology Department, Ege University Medical School, Izmir, Turkey

    İlayda Alcitepe, İlknur Karatekin & Burcin Tezcanli Kaymaz

  2. Basic Oncology Department, Ege University Health Science Institute, Izmir, Turkey

    Hilal Salcin

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  1. İlayda Alcitepe
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Contributions

HS and IA performed cell culture and follow-up. HS, IA, and IK performed cytotoxicity and apoptosis analysis of the agents on leukemia and non- leukemia cells. BTK determined gene expression changes by qRT-PCR and performed statistical analysis. IA and BTK has written the paper; BTK as the supervisor.

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Correspondence to Burcin Tezcanli Kaymaz.

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This article does not contain any studies with human participants or animals performed by the author IA and BTK.

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Alcitepe, İ., Salcin, H., Karatekin, İ. et al. HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model. Med Oncol 39, 257 (2022). https://doi.org/10.1007/s12032-022-01858-x

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