Skip to content
2000
image of Network Pharmacology Reveals Luteolin From Vitex Negundo Novel Targets CDK1/Cyclin B In ER+ Breast Cancer Stem Cells

Abstract

Introduction

Breast cancer remains a leading cause of cancer-related mortality in women, primarily due to Breast Cancer Stem Cells (BCSCs), which contribute to tumor progression, metastasis, and resistance to conventional therapies. Linn. (VN), a medicinal plant abundant in polyphenolic flavonoids such as luteolin (LT), has previously demonstrated anticancer potential. This study investigates the active metabolite profiling of VN targeting BCSCs and evaluates LT’s therapeutic potential through and approaches.

Methods

An integrated network pharmacology and computational approach identified VN metabolites targeting BCSCs, including CDK1, cyclin B1/B2, TOP1, GSK-3β, and PARP1. Mutational analysis in MCF-7 cells followed by luteolin (LT) treatment assessed its impact on stemness, gene expression, ROS generation, cell cycle, and apoptosis. Molecular docking and dynamics confirmed LT’s strong binding to CDK1/Cyclin B.

Results

LT significantly reduced the properties of BCSCs by inhibiting the CDK1/Cyclin B complex and downregulating associated genes. It induced ROS-mediated apoptosis and altered cell cycle distribution, notably increasing G1 and S phase populations. Molecular modeling confirmed strong binding of LT to CDK1/Cyclin B, suggesting disruption of cell cycle regulation and self-renewal.

Discussion

LT binds strongly to CDK1 and Cyclin B proteins, suppressing their activity in MCF-7 cells. This disrupts gene expression linked to BCSC self-renewal, induces apoptosis, and causes cell cycle arrest. LT targeting CDK1/Cyclin B complexes offers promising therapeutic potential for future clinical development against BCSCs.

Conclusion

LT from VN shows promise as a therapeutic agent targeting CDK1/Cyclin B in ER+ breast cancer stem cells, supporting its potential for clinical development.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206406998251027105239
2026-01-09
2026-01-31

  • From This Site

    /content/journals/acamc/10.2174/0118715206406998251027105239
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Zhang X. Powell K. Li L. Breast cancer stem cells: Biomarkers, identification and isolation methods, regulating mechanisms, cellular origin, and beyond. Cancers 2020 12 12 3765 10.3390/cancers12123765 33327542
    [Google Scholar]
  2. Thomas A. Pommier Y. Targeting topoisomerase I in the era of precision medicine. Clin. Cancer Res. 2019 25 22 6581 6589 10.1158/1078‑0432.CCR‑19‑1089 31227499
    [Google Scholar]
  3. Liu J. Xiao Q. Xiao J. Niu C. Li Y. Zhang X. Zhou Z. Shu G. Yin G. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities. Signal Transduct. Target. Ther. 2022 7 1 3 10.1038/s41392‑021‑00762‑6 34980884
    [Google Scholar]
  4. Racaud-Sultan C. Vergnolle N. GSK3β, a master kinase in the regulation of adult stem cell behavior. Cells 2021 10 2 225 10.3390/cells10020225 33498808
    [Google Scholar]
  5. Lu Y. Schuller M. Bullen N.P. Mikolcevic P. Zonjic I. Raggiaschi R. Mikoc A. Whitney J.C. Ahel I. Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack. Nucleic Acids Res. 2025 53 4 gkaf069 10.1093/nar/gkaf069 39964479
    [Google Scholar]
  6. Gilabert M. Launay S. Ginestier C. Bertucci F. Audebert S. Pophillat M. Toiron Y. Baudelet E. Finetti P. Noguchi T. Sobol H. Birnbaum D. Borg J.P. Charafe-Jauffret E. Gonçalves A. Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS One 2014 9 8 e104302 10.1371/journal.pone.0104302 25144364
    [Google Scholar]
  7. Ghafouri-Fard S. Khoshbakht T. Hussen B.M. Dong P. Gassler N. Taheri M. Baniahmad A. Dilmaghani N.A. A review on the role of cyclin dependent kinases in cancers. Cancer Cell Int. 2022 22 1 325 10.1186/s12935‑022‑02747‑z 36266723
    [Google Scholar]
  8. Chotiner J.Y. Wolgemuth D.J. Wang P.J. Functions of cyclins and CDKs in mammalian gametogenesis. Biol. Reprod. 2019 101 3 591 601 10.1093/biolre/ioz070 31078132
    [Google Scholar]
  9. Gong Y. Li H. CDK7 in breast cancer: Mechanisms of action and therapeutic potential. Cell Commun. Signal. 2024 22 1 226 10.1186/s12964‑024‑01577‑y 38605321
    [Google Scholar]
  10. Wang Q. Bode A.M. Zhang T. Targeting CDK1 in cancer: Mechanisms and implications. NPJ Precis. Oncol. 2023 7 1 58 10.1038/s41698‑023‑00407‑7 37311884
    [Google Scholar]
  11. Silvestrini A. Meucci E. Ricerca B.M. Mancini A. Total antioxidant capacity: Biochemical aspects and clinical significance. Int. J. Mol. Sci. 2023 24 13 10978 10.3390/ijms241310978 37446156
    [Google Scholar]
  12. Li J. Zhou L. Liu Y. Yang L. Jiang D. Li K. Xie S. Wang X. Wang S. Comprehensive analysis of cyclin family gene expression in colon cancer. Front. Oncol. 2021 11 674394 10.3389/fonc.2021.674394 33996604
    [Google Scholar]
  13. Nam H.J. van Deursen J.M. Cyclin B2 and p53 control proper timing of centrosome separation. Nat. Cell Biol. 2014 16 6 535 546 10.1038/ncb2952 24776885
    [Google Scholar]
  14. Qureshi-Baig K. Ullmann P. Haan S. Letellier E. Tumor-Initiating Cells: A criTICal review of isolation approaches and new challenges in targeting strategies. Mol. Cancer 2017 16 1 40 10.1186/s12943‑017‑0602‑2 28209178
    [Google Scholar]
  15. Smith S.E. Mellor P. Ward A.K. Kendall S. McDonald M. Vizeacoumar F.S. Vizeacoumar F.J. Napper S. Anderson D.H. Molecular characterization of breast cancer cell lines through multiple omic approaches. Breast Cancer Res. 2017 19 1 65 10.1186/s13058‑017‑0855‑0 28583138
    [Google Scholar]
  16. Gill B.S. Mehra R. Navgeet; Kumar, S. Vitex negundo and its medicinal value. Mol. Biol. Rep. 2018 45 6 2925 2934 10.1007/s11033‑018‑4421‑3 30311123
    [Google Scholar]
  17. Prasher P. Sharma M. Singh S.K. Gulati M. Chellappan D.K. Zacconi F. De Rubis G. Gupta G. Sharifi-Rad J. Cho W.C. Dua K. Luteolin: a flavonoid with a multifaceted anticancer potential. Cancer Cell Int. 2022 22 1 386 10.1186/s12935‑022‑02808‑3 36482329
    [Google Scholar]
  18. Ahmed S. Khan H. Fratantonio D. Hasan M.M. Sharifi S. Fathi N. Ullah H. Rastrelli L. Apoptosis induced by luteolin in breast cancer: Mechanistic and therapeutic perspectives. Phytomedicine 2019 59 152883 10.1016/j.phymed.2019.152883 30986716
    [Google Scholar]
  19. Li L. Yang L. Yang L. He C. He Y. Chen L. Dong Q. Zhang H. Chen S. Li P. Network pharmacology: A bright guiding light on the way to explore the personalized precise medication of traditional Chinese medicine. Chin. Med. 2023 18 1 146 10.1186/s13020‑023‑00853‑2 37941061
    [Google Scholar]
  20. Noor F. Tahir ul Qamar, M.; Ashfaq, U.A.; Albutti, A.; Alwashmi, A.S.S.; Aljasir, M.A. Network pharmacology approach for medicinal plants: Review and assessment. Pharmaceuticals 2022 15 5 572 10.3390/ph15050572 35631398
    [Google Scholar]
  21. Gu Y. Yu Z. Wang Y. Chen L. Lou C. Yang C. Li W. Liu G. Tang Y. admetSAR3.0: A comprehensive platform for exploration, prediction and optimization of chemical ADMET properties. Nucleic Acids Res. 2024 52 W1 W432 W438 10.1093/nar/gkae298 38647076
    [Google Scholar]
  22. Daina A. Michielin O. Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017 7 1 42717 10.1038/srep42717 28256516
    [Google Scholar]
  23. Xiong G. Wu Z. Yi J. Fu L. Yang Z. Hsieh C. Yin M. Zeng X. Wu C. Lu A. Chen X. Hou T. Cao D. ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021 49 W1 W5 W14 10.1093/nar/gkab255 33893803
    [Google Scholar]
  24. Filimonov D.A. Lagunin A.A. Gloriozova T.A. Rudik A.V. Druzhilovskii D.S. Pogodin P.V. Poroikov V.V. Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem. Heterocycl. Compd. 2014 50 3 444 457 10.1007/s10593‑014‑1496‑1
    [Google Scholar]
  25. Basnet R. Basnet B.B. Amissah O.B. Huang R. Sun Y. de Dieu Habimana J. Li Z. Network pharmacology-based virtual screening of chemical constituents from Vitexnegundo Linn’s discovered novel molecular targets for breast cancer treatment. Curr. Cancer Drug Targets 2025 25 7 10.2174/0115680096316247240715064729
    [Google Scholar]
  26. Liu H. Liu J. Chen P. Zhang X. Wang K. Lu J. Li Y. Selection and validation of optimal RT-qPCR reference genes for the normalization of gene expression under different experimental conditions in Lindera megaphylla. Plants 2023 12 11 2185 10.3390/plants12112185 37299163
    [Google Scholar]
  27. Comşa Ş. Cîmpean A.M. Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer Res. 2015 35 6 3147 3154 26026074
    [Google Scholar]
  28. Lee A.V. Oesterreich S. Davidson N.E. MCF-7 cells--changing the course of breast cancer research and care for 45 years. J. Natl. Cancer Inst. 2015 107 7 djv073 10.1093/jnci/djv073 25828948
    [Google Scholar]
  29. Ambrose J.M. Veeraraghavan V.P. Vennila R. Rupert S. Sathyanesan J. Meenakshisundaram R. Selvaraj S. Malayaperumal S. Kullappan M. Dorairaj S. Gujarathi J.R. Gandhamaneni S.H. Surapaneni K.M. Comparison of mammosphere formation from stem-like cells of normal breast, malignant primary breast tumors, and MCF-7 cell line. J. Egypt. Natl. Canc. Inst. 2022 34 1 51 10.1186/s43046‑022‑00152‑1 36504339
    [Google Scholar]
  30. Lee G. Wong C. Cho A. West J.J. Crawford A.J. Russo G.C. Si B.R. Kim J. Hoffner L. Jang C. Jung M. Leone R.D. Konstantopoulos K. Ewald A.J. Wirtz D. Jeong S. E-cadherin induces serine synthesis to support progression and metastasis of breast cancer. Cancer Res. 2024 84 17 2820 2835 10.1158/0008‑5472.CAN‑23‑3082 38959339
    [Google Scholar]
  31. Vikram R. Chou W.C. Hung S.C. Shen C.Y. Tumorigenic and metastatic role of CD44−/low/CD24−/low cells in luminal breast cancer. Cancers 2020 12 5 1239 10.3390/cancers12051239 32423137
    [Google Scholar]
  32. Wang S.H. Wu C.H. Tsai C.C. Chen T.Y. Tsai K.J. Hung C.M. Hsu C.Y. Wu C.W. Hsieh T.H. Effects of Luteolin on human breast cancer using gene expression Array: Inferring novel genes. Curr. Issues Mol. Biol. 2022 44 5 2107 2121 10.3390/cimb44050142 35678671
    [Google Scholar]
  33. Aljohani A.I. Toss M.S. Green A.R. Rakha E.A. The clinical significance of cyclin B1 (CCNB1) in invasive breast cancer with emphasis on its contribution to lymphovascular invasion development. Breast Cancer Res. Treat. 2023 198 3 423 435 10.1007/s10549‑022‑06801‑2 36418517
    [Google Scholar]
  34. Mir M.A. CDK1 dysregulation in breast cancer. Therapeutic potential of cell cycle kinases in breast cancer. Springer 2023 195 210 10.1007/978‑981‑19‑8911‑7_9
    [Google Scholar]
  35. Mir M. Khan S. Aisha S. Therapeutic potential of cell cycle kinases in breast cancer. Therapeutic potential of Cell. Cycle Kinases in Breast Cancer; Springer Nature Singapore Pte Ltd.: Singapore 2023 10.1007/978‑981‑19‑8911‑7
    [Google Scholar]
  36. Liu X. Zhang B. Hua Y. Li C. Li X. Kong D. Nucleosomes represent a crucial target for the intra-S phase checkpoint in response to replication stress. Sci. Adv. 2025 11 20 eadr3673 10.1126/sciadv.adr3673 40378213
    [Google Scholar]
  37. Chu X. Tian W. Ning J. Xiao G. Zhou Y. Wang Z. Zhai Z. Tanzhu G. Yang J. Zhou R. Cancer stem cells: Advances in knowledge and implications for cancer therapy. Signal Transduct. Target. Ther. 2024 9 1 170 10.1038/s41392‑024‑01851‑y 38965243
    [Google Scholar]
  38. Pyo Y. Kwon K.H. Jung Y.J. Anticancer potential of flavonoids: Their role in cancer prevention and health benefits. Foods 2024 13 14 2253 10.3390/foods13142253 39063337
    [Google Scholar]
  39. Rakoczy K. Kaczor J. Sołtyk A. Szymańska N. Stecko J. Sleziak J. Kulbacka J. Baczyńska D. Application of luteolin in neoplasms and nonneoplastic diseases. Int. J. Mol. Sci. 2023 24 21 15995 10.3390/ijms242115995 37958980
    [Google Scholar]
  40. Wang Y. Zhang S. Li F. Zhou Y. Zhang Y. Wang Z. Zhang R. Zhu J. Ren Y. Tan Y. Qin C. Li Y. Li X. Chen Y. Zhu F. Therapeutic target database 2020: Enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res. 2020 48 D1 D1031 D1041 31691823
    [Google Scholar]
  41. Daina A. Michielin O. Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019 47 W1 W357 W364 10.1093/nar/gkz382 31106366
    [Google Scholar]
  42. Szklarczyk D. Santos A. von Mering C. Jensen L.J. Bork P. Kuhn M. STITCH 5: Augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016 44 D1 D380 D384 10.1093/nar/gkv1277 26590256
    [Google Scholar]
  43. Huang L. Jin K. Lan H. Luteolin inhibits cell cycle progression and induces apoptosis of breast cancer cells through downregulation of human telomerase reverse transcriptase. Oncol. Lett. 2019 17 4 3842 3850 10.3892/ol.2019.10052 30930986
    [Google Scholar]
  44. Tuorkey M.J. Molecular targets of luteolin in cancer. Eur. J. Cancer Prev. 2016 25 1 65 76 10.1097/CEJ.0000000000000128 25714651
    [Google Scholar]
  45. Raina R. Pramodh S. Rais N. Haque S. Shafarin J. Bajbouj K. Hamad M. Hussain A. Luteolin inhibits proliferation, triggers apoptosis and modulates Akt/mTOR and MAP kinase pathways in HeLa cells. Oncol. Lett. 2021 21 3 192 10.3892/ol.2021.12452 33574931
    [Google Scholar]
  46. Balkrishna A. Sharma Y. Dabas S. Arya V. Dabas A. Molecular mechanism of cynodon dactylon phytosterols targeting MAPK3 and PARP1 to combat epithelial ovarian cancer: A multifaceted computational approach. Cell Biochem. Biophys. 2024 82 3 2625 2650 10.1007/s12013‑024‑01375‑w 38961033
    [Google Scholar]
  47. Farooqi A.A. Butt G. El-Zahaby S.A. Attar R. Sabitaliyevich U.Y. Jovic J.J. Tang K.F. Naureen H. Xu B. Luteolin mediated targeting of protein network and microRNAs in different cancers: Focus on JAK-STAT, NOTCH, mTOR and TRAIL-mediated signaling pathways. Pharmacol. Res. 2020 160 105188 10.1016/j.phrs.2020.105188 32919041
    [Google Scholar]
  48. Amberger J.S. Bocchini C.A. Schiettecatte F. Scott A.F. Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015 43 D1 D789 D798 10.1093/nar/gku1205 25428349
    [Google Scholar]
  49. Letunic I. Bork P. Interactive Tree of Life (iTOL) v6: Recent updates to the phylogenetic tree display and annotation tool. Nucleic Acids Res. 2024 52 W1 W78 W82 10.1093/nar/gkae268 38613393
    [Google Scholar]
  50. Mousavian Z. Khodabandeh M. Sharifi-Zarchi A. Nadafian A. Mahmoudi A. StrongestPath: A Cytoscape application for protein–protein interaction analysis. BMC Bioinformatics 2021 22 1 352 10.1186/s12859‑021‑04230‑4 34187355
    [Google Scholar]
  51. Thomas P.D. Ebert D. Muruganujan A. Mushayahama T. Albou L.P. Mi H. PANTHER: Making genome‐scale phylogenetics accessible to all. Protein Sci. 2022 31 1 8 22 10.1002/pro.4218 34717010
    [Google Scholar]
  52. Zhou Y. Zhou B. Pache L. Chang M. Khodabakhshi A.H. Tanaseichuk O. Benner C. Chanda S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 2019 10 1 1523 10.1038/s41467‑019‑09234‑6 30944313
    [Google Scholar]
  53. Kanehisa M. Furumichi M. Sato Y. Matsuura Y. Ishiguro-Watanabe M. KEGG: biological systems database as a model of the real world. Nucleic Acids Res. 2025 53 D1 D672 D677 10.1093/nar/gkae909 39417505
    [Google Scholar]
  54. Sherman B.T. Panzade G. Imamichi T. Chang W. DAVID Ortholog: an integrative tool to enhance functional analysis through orthologs. Bioinformatics 2024 40 10 btae615 10.1093/bioinformatics/btae615 39412445
    [Google Scholar]
  55. Pathan M. Keerthikumar S. Ang C.S. Gangoda L. Quek C.Y.J. Williamson N.A. Mouradov D. Sieber O.M. Simpson R.J. Salim A. Bacic A. Hill A.F. Stroud D.A. Ryan M.T. Agbinya J.I. Mariadason J.M. Burgess A.W. Mathivanan S. FunRich: An open access standalone functional enrichment and interaction network analysis tool. Proteomics 2015 15 15 2597 2601 10.1002/pmic.201400515 25921073
    [Google Scholar]
  56. Papatheodorou I. Fonseca N.A. Keays M. Tang Y.A. Barrera E. Bazant W. Burke M. Füllgrabe A. Fuentes A.M.P. George N. Huerta L. Koskinen S. Mohammed S. Geniza M. Preece J. Jaiswal P. Jarnuczak A.F. Huber W. Stegle O. Vizcaino J.A. Brazma A. Petryszak R. Expression Atlas: Gene and protein expression across multiple studies and organisms. Nucleic Acids Res. 2018 46 D1 D246 D251 10.1093/nar/gkx1158 29165655
    [Google Scholar]
  57. Ma J. Pan Z. Du H. Chen X. Zhu X. Hao W. Zheng Q. Tang X. Luteolin induces apoptosis by impairing mitochondrial function and targeting the intrinsic apoptosis pathway in gastric cancer cells. Oncol. Lett. 2023 26 2 327 10.3892/ol.2023.13913 37415631
    [Google Scholar]
  58. Li F.N. Zhang Q.Y. Li O. Liu S.L. Yang Z.Y. Pan L.J. Zhao C. Gong W. Shu Y.J. Dong P. ESRRA promotes gastric cancer development by regulating the CDC25C/CDK1/CyclinB1 pathway via DSN1. Int. J. Biol. Sci. 2021 17 8 1909 1924 10.7150/ijbs.57623 34131395
    [Google Scholar]
  59. Singh Tuli H. Rath P. Chauhan A. Sak K. Aggarwal D. Choudhary R. Sharma U. Vashishth K. Sharma S. Kumar M. Yadav V. Singh T. Yerer M.B. Haque S. Luteolin, a potent anticancer compound: From chemistry to cellular interactions and synergetic perspectives. Cancers 2022 14 21 5373 10.3390/cancers14215373 36358791
    [Google Scholar]
  60. Duda P. Akula S.M. Abrams S.L. Steelman L.S. Martelli A.M. Cocco L. Ratti S. Candido S. Libra M. Montalto G. Cervello M. Gizak A. Rakus D. McCubrey J.A. Targeting GSK3 and associated signaling pathways involved in cancer. Cells 2020 9 5 1110 10.3390/cells9051110 32365809
    [Google Scholar]
  61. Qiao X. Zhang Y. Sun L. Ma Q. Yang J. Ai L. Xue J. Chen G. Zhang H. Ji C. Gu X. Lei H. Yang Y. Liu C. Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis. eLife 2021 10 e65418 10.7554/eLife.65418 34318746
    [Google Scholar]
  62. Romaniuk-Drapała A. Totoń E. Taube M. Idzik M. Rubiś B. Lisiak N. Breast cancer stem cells and tumor heterogeneity: Characteristics and therapeutic strategies. Cancers 2024 16 13 2481 10.3390/cancers16132481 39001543
    [Google Scholar]
  63. Massacci G. Perfetto L. Sacco F. The Cyclin-dependent kinase 1: More than a cell cycle regulator. Br. J. Cancer 2023 129 11 1707 1716 10.1038/s41416‑023‑02468‑8 37898722
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206406998251027105239
Loading
Network Pharmacology Reveals Luteolin From Vitex Negundo Novel Targets CDK1/Cyclin B In ER+ Breast Cancer Stem Cells
Bentham Science Publishers ; https://doi.org/10.2174/0118715206406998251027105239
/content/journals/acamc/10.2174/0118715206406998251027105239
/content/journals/acamc/10.2174/0118715206406998251027105239
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: Luteolin (LT) ; cell cycle regulation ; breast cancer stem cells (BCSCs) ; CDK1/cyclin b complex ; molecular docking ; network pharmacology

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