Skip to content
2000
Volume 19, Issue 3
  • ISSN: 2212-7968
  • E-ISSN: 1872-3136

Abstract

Background

Dysregulated metabolism, including lipid peroxidation, contributes to the various stages of breast cancer, including initiation and progression. However, 4-HNE mimetic as a new class of drugs of epigenetic enzymes is not explored.

Objective

The objective of this study was to explore the relevance of lipid peroxidation products in breast cancer and the design of mimetic 4-HNE as an inhibitor of SIRT2.

Methods

The metabolite profiling of 4-HNE was collected from the urine of breast cancer patients and healthy subjects by employing an in-house developed vertical tube gel electrophoresis (VTGE) tool and LC-HRMS. The determination of lipid peroxidation products MDA was estimated by thiobarbituric acid-reactive substance (TBARS) assay. Mimetic 4-HNE (4-HNEM) was designed and evaluated for their inhibitory binding affinity upon a potential target SIRT2 using molecular docking and molecular dynamics (MD) simulations.

Results

Metabolic profiling of 4-HNE indicated detectable levels in the urine of breast cancer patients over non-detectable levels in healthy subjects. Also, the level of TBARS MDA appeared to be reduced in the urine of breast cancer patients over healthy control. Computational tool-assisted molecular docking-based screening data predicted that 4-HNE has a good inhibitory binding affinity (-7.0 kcal/mol) upon SIRT2. Furthermore, the designed mimetic 4-HNEM projected an improved inhibitory binding affinity (-8.7 kcal/mol) against SIRT2. Furthermore, mimetic 4-HNEM exhibited equivalent strong binding affinity and specific interacting amino acid residues (ARG97, PHE119, ALA186, PHE234, PHE235) similar to a known SIRT2 inhibitor 8NO. ADMET profiles of 4-HNEM, including drug-induced liver injury and cytotoxicity, were found to be slightly better than a known SIRT2 inhibitor 8NO.

Conclusion

This study emphasizes the relevance of 4-HNE and MDA as biomarkers in breast cancer. A mimetic 4-HNEM is projected to be a novel small-molecule inhibitor of SIRT2 that could be explored as a potential combinatorial anticancer agent.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ccb/10.2174/0122127968367122250206065857
2025-02-17
2025-12-18

  • From This Site

    /content/journals/ccb/10.2174/0122127968367122250206065857
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. BrayF. LaversanneM. SungH. FerlayJ. SiegelR.L. SoerjomataramI. JemalA. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202474322926310.3322/caac.21834 38572751
     [Google Scholar]
  2. GuoS. GuanJ. ZhouS. Diffusing on two levels and optimizing for multiple properties: A novel approach to generating molecules with desirable properties. IEEE/ACM Trans.Comput. Biol. Bioinform.20242162050206310.1109/TCBB.2024.3434461
     [Google Scholar]
  3. LiJ. LiuY. FanW. WeiX-Y. LiuH. TangJ. LiQ. Empowering molecule discovery for molecule-caption translation with large language models: A chatgpt perspective.IEEE Trans. Knowl. Data Eng.202436116071608310.1109/TKDE.2024.3393356
     [Google Scholar]
  4. ZahraM.A. Al-TaherA. AlquhaidanM. HussainT. IsmailI. RayaI. KandeelM. The synergy of artificial intelligence and personalized medicine for the enhanced diagnosis, treatment, and prevention of disease.Drug Metab. Pers. Ther.2024392475810.1515/dmpt‑2024‑0003 38997240
     [Google Scholar]
  5. LuoX. ChengC. TanZ. LiN. TangM. YangL. CaoY. Emerging roles of lipid metabolism in cancer metastasis.Mol. Cancer20171617610.1186/s12943‑017‑0646‑3 28399876
     [Google Scholar]
  6. PashayanN. PharoahP.D.P. The challenge of early detection in cancer.Science2020368649158959010.1126/science.aaz2078 32381710
     [Google Scholar]
  7. StineZ.E. SchugZ.T. SalvinoJ.M. DangC.V. Targeting cancer metabolism in the era of precision oncology.Nat. Rev. Drug Discov.202221214116210.1038/s41573‑021‑00339‑6 34862480
     [Google Scholar]
  8. WangZ. WangY. LiZ. XueW. HuS. KongX. Lipid metabolism as a target for cancer drug resistance: Progress and prospects.Front. Pharmacol.202314127433510.3389/fphar.2023.1274335 37841917
     [Google Scholar]
  9. TerryA.R. HayN. Emerging targets in lipid metabolism for cancer therapy.Trends Pharmacol. Sci.202445653755110.1016/j.tips.2024.04.007 38762377
     [Google Scholar]
  10. CurrieE. SchulzeA. ZechnerR. WaltherT.C. FareseR.V.Jr Cellular fatty acid metabolism and cancer.Cell Metab.201318215316110.1016/j.cmet.2013.05.017 23791484
     [Google Scholar]
  11. IqbalM.J. KabeerA. AbbasZ. SiddiquiH.A. CalinaD. Sharifi-RadJ. ChoW.C. Interplay of oxidative stress, cellular communication and signaling pathways in cancer.Cell Commun. Signal.2024221710.1186/s12964‑023‑01398‑5 38167159
     [Google Scholar]
  12. LiK. DengZ. LeiC. DingX. LiJ. WangC. The role of oxidative stress in tumorigenesis and progression.Cells202413544110.3390/cells13050441 38474405
     [Google Scholar]
  13. GasparovicA.C. MilkovicL. SunjicS.B. ZarkovicN. Cancer growth regulation by 4-hydroxynonenal.Free Radic. Biol. Med.201711122623410.1016/j.freeradbiomed.2017.01.030 28131901
     [Google Scholar]
  14. SnaebjornssonM.T. Janaki-RamanS. SchulzeA. Greasing the wheels of the cancer machine: The role of lipid metabolism in cancer.Cell Metab.2020311627610.1016/j.cmet.2019.11.010 31813823
     [Google Scholar]
  15. JaganjacM. ZarkovicN. Lipid peroxidation linking diabetes and cancer: The importance of 4-hydroxynonenal.Antioxid. Redox Signal.20223716-181222123310.1089/ars.2022.0146 36242098
     [Google Scholar]
  16. JakovčevićA. ŽarkovićK. JakovčevićD. RakušićZ. PrgometD. WaegG. ŠunjićS.B. ŽarkovićN. The appearance of 4-hydroxy-2-nonenal (HNE) in squamous cell carcinoma of the oropharynx.Molecules202025486810.3390/molecules25040868 32079077
     [Google Scholar]
  17. EskelinenM. SaimanenI. KoskelaR. HolopainenA. SelanderT. EskelinenM. Plasma concentration of the lipid peroxidation (LP) biomarker 4-hydroxynonenal (4-HNE) in benign and cancer patients.In Vivo202236277377910.21873/invivo.12764 35241533
     [Google Scholar]
  18. GęgotekA. SkrzydlewskaE. Lipid peroxidation products’ role in autophagy regulation.Free Radic. Biol. Med.202421237538310.1016/j.freeradbiomed.2024.01.001 38182071
     [Google Scholar]
  19. AyalaA. MuñozM.F. ArgüellesS. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal.Oxid. Med. Cell. Longev.2014201413110.1155/2014/360438 24999379
     [Google Scholar]
  20. BoseC. HindleA. LeeJ. KopelJ. TonkS. PaladeP.T. SinghalS.S. AwasthiS. SinghS.P. Anticancer activity of ω-6 fatty acids through increased 4-HNE in breast cancer cells.Cancers20211324637710.3390/cancers13246377 34944997
     [Google Scholar]
  21. VasanN. BaselgaJ. HymanD.M. A view on drug resistance in cancer.Nature2019575778229930910.1038/s41586‑019‑1730‑1 31723286
     [Google Scholar]
  22. SadidaH.Q. AbdullaA. MarzooqiS.A. HashemS. MachaM.A. AkilA.S.A.S. BhatA.A. Epigenetic modifications: Key players in cancer heterogeneity and drug resistance.Transl. Oncol.20243910182110.1016/j.tranon.2023.101821 37931371
     [Google Scholar]
  23. ZhangL. KimS. RenX. The clinical significance of SIRT2 in malignancies: A tumor suppressor or an oncogene?Front. Oncol.202010172110.3389/fonc.2020.01721 33014852
     [Google Scholar]
  24. RussoC. MaugeriA. De LucaL. GittoR. LombardoG.E. MusumeciL. De SarroG. CirmiS. NavarraM. The SIRT2 pathway is involved in the antiproliferative effect of flavanones in human leukemia monocytic THP-1 cells.Biomedicines20221010238310.3390/biomedicines10102383 36289647
     [Google Scholar]
  25. YuL. LiY. SongS. ZhangY. WangY. WangH. YangZ. WangY. The dual role of sirtuins in cancer: Biological functions and implications.Front. Oncol.202414138492810.3389/fonc.2024.1384928 38947884
     [Google Scholar]
  26. RumpfT. SchiedelM. KaramanB. RoesslerC. NorthB.J. LehotzkyA. OláhJ. LadweinK.I. SchmidtkunzK. GajerM. PannekM. SteegbornC. SinclairD.A. GerhardtS. OvádiJ. SchutkowskiM. SipplW. EinsleO. JungM. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.Nat. Commun.201561626310.1038/ncomms7263 25672491
     [Google Scholar]
  27. KudoN. Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalyzed by SIRT2.Philos. Trans. R. Soc. Lond. B Biol. Sci.2018373174820170070
     [Google Scholar]
  28. ZhangM. DuW. AcklinS. JinS. XiaF. SIRT2 protects peripheral neurons from cisplatin-induced injury by enhancing nucleotide excision repair.J. Clin. Invest.202013062953296510.1172/JCI123159 32134743
     [Google Scholar]
  29. BadranM.M. AbbasS.H. TateishiH. MaemotoY. TomaT. ItoA. FujitaM. OtsukaM. Abdel-AzizM. RadwanM.O. Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy.Eur. J. Med. Chem.202426911630210.1016/j.ejmech.2024.116302 38484678
     [Google Scholar]
  30. MitrukaM. GoreC.R. KumarA. SarodeS.C. SharmaN.K. Undetectable free aromatic amino acids in nails of breast carcinoma: Biomarker discovery by a novel metabolite purification VTGE system.Front. Oncol.20201090810.3389/fonc.2020.00908 32695662
     [Google Scholar]
  31. KumarA. PatelS. BhatkarD. SarodeS.C. SharmaN.K. A novel method to detect intracellular metabolite alterations in MCF-7 cells by doxorubicin induced cell death.Metabolomics2021171310.1007/s11306‑020‑01755‑2 33389242
     [Google Scholar]
  32. MorrisG.M. GoodsellD.S. HallidayR.S. HueyR. HartW.E. BelewR.K. OlsonA.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function.J. Comput. Chem.199819141639166210.1002/(SICI)1096‑987X(19981115)19:14<1639::AID‑JCC10>3.0.CO;2‑B
     [Google Scholar]
  33. TrottO. OlsonA.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.21334 19499576
     [Google Scholar]
  34. Discovery Studio Visualizer v3.0, Accelrys Software Inc; ,2010
     [Google Scholar]
  35. ReleaseS. 2019-4: Desmond Molecular Dynamics System.New York, NYD. E. Shaw Research2019
     [Google Scholar]
  36. SchymanP. LiuR. DesaiV. WallqvistA. vNN web server for ADMET predictions.Front. Pharmacol.2017888910.3389/fphar.2017.00889 29255418
     [Google Scholar]
/content/journals/ccb/10.2174/0122127968367122250206065857
Loading
Modulation of Urinary Lipid Peroxidation Products in Breast Cancer and Design of Mimetic 4-HNE (4-HNEM) as SIRT2 Inhibitor
Curr Chem Biol 19, 189 (2025); https://doi.org/10.2174/0122127968367122250206065857
/content/journals/ccb/10.2174/0122127968367122250206065857
/content/journals/ccb/10.2174/0122127968367122250206065857
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 4-hne; epigenome; lipid peroxidation; metabolic reprogramming; microenvironment; Neoplasms; sirt2

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test