Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents)
  4. Fast Track Articles
  5. Fast Track Article
image of In vivo, In vitro, and In silico Studies of Umbelliferone and Irinotecan on MDA-MB-231 Breast Cancer Cell Line and Drosophila melanogaster Larvae

Abstract

Aims

Deaths from cancer are still very common all over the world and continue to be the focus of scientific research. Chemotherapy is one of the primary treatments used to prevent deaths from cancer. Side effects of chemotherapeutic drugs and resistance of cells to drugs are essential problems that limit the treatment process. Drug combination therapy is regarded as a significant application that inhibits the growth of tumors and is anticipated to provide a solution for the issues encountered. The combination therapy aims at a synergistic effect that will limit drug resistance and cytotoxic effects with appropriate drug combinations. In this context, we aim to investigate the , effects of single and combined doses of umbelliferone and irinotecan, known for their anticarcinogenic and curative effects, on MDA-MB-231 breast cancer cell lines and the model organism .

Background

Irinotecan is currently used as an anticarcinogenic drug. Anticarcinogenic effects of umbelliferone have also been detected. The and impacts of single and combined doses use of these two agents are not yet available in the literature.

Objective

This study aims to determine the anticarcinogenic effects of single and combined use of umbelliferone and irinotecan at the molecular level. It also attempts to determine the binding energies of chemicals to cancer-related proteins through docking and molecular dynamic studies.

Method

The cytotoxic effects of individual and combinational doses of umbelliferone and irinotecan on the MDA-MB-231 cell line and were calculated by XTT and probit analyses. IC values for the cancer cells, LC, and LC values for were found. Gene expression analysis was performed to determine the effects of chemical agents on miR-7, miR-11, and miR-14, and their expression levels were found. The sequences of miRNAs not found in the literature were determined, and their molecular imaging was performed. In addition, the binding energies of irinotecan and umbelliferone to Bcl-2, Bad, and Akt1 proteins, which are known to have apoptotic effects, were found by the molecular docking method. Molecular dynamics studies of Bad proteins and chemicals were also performed. The drug potential of chemicals was determined by ADME/T analysis.

Result

The cytotoxic effect on cells was calculated, and the IC value of umbelliferone was calculated as 158 µM, the IC value of irinotecan was calculated as 48,3 µM and the IC value was calculated as 20 µM. In the probit analysis performed to calculate the cytotoxic effects of drugs on the LC value of umbelliferone was 2,5 µM, and the LC value was 13,4 µM. The LC value of irinotecan was found to be 0,1 µM, and the LC value was 0,28 µM. It was concluded that single and combined doses of chemicals in the invasion experiment significantly affected the spread of cells. As a result of expression analysis, a significant increase in Hsa-miR-7 ( miRNA-7, Hsa-miR-14 ( miRNA-14 and Hsa-miR-11( miRNA-11 expression was observed in cells treated with umbelliferone irinotecan compared to the control groups.

Conclusion

In our study, it can be concluded that the cytotoxic effects of individual and combination doses of umbelliferone and irinotecan on MDA-MB-231 cells and larvae are significant. In addition, the effects of umbelliferone and irinotecan on the expression level of miR-7, which is a common and human miRNA, should be widely investigated. Expression analyses and docking studies of Hsa-miR-11 and Hsa-miR-14, which have been newly studied and are not in data repositories, are important for cancer research. In particular, the expression and binding energy of these miRNAs in new drug combinations and the expression level in different cancer cell lines are important for future studies. Another crucial point is that tests using different model species validate the usage of drugs at both single and mixed dosages.

Other

As a result of this study, the and effects of single and combined doses of umbelliferone and irinotecan were determined. In future studies, it would be useful to determine the binding energies of umbelliferone and irinotecan to other cancer-related proteins and to find their interactions with different miRNAs. Additionally, studies on different model organisms are also important.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206340868241018075528
2024-10-29
2024-12-04

  • From This Site

    /content/journals/acamc/10.2174/0118715206340868241018075528
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Bilder D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 2004 18 16 1909 1925 10.1101/gad.1211604 15314019
    [Google Scholar]
  2. Gao X. Neufeld T.P. Pan D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways. Dev. Biol. 2000 221 2 404 418 10.1006/dbio.2000.9680 10790335
    [Google Scholar]
  3. Mehlen P. Puisieux A. Metastasis: A question of life or death. Nat. Rev. Cancer 2006 6 6 449 458 10.1038/nrc1886 16723991
    [Google Scholar]
  4. Milne A.N. Carneiro F. O’Morain C. Offerhaus G.J.A. Nature meets nurture: Molecular genetics of gastric cancer. Hum. Genet. 2009 126 5 615 628 10.1007/s00439‑009‑0722‑x 19657673
    [Google Scholar]
  5. Chabner B.A. Roberts T.G. Jr Chemotherapy and the war on cancer. Nat. Rev. Cancer 2005 5 1 65 72 10.1038/nrc1529 15630416
    [Google Scholar]
  6. Yardley D.A. Drug resistance and the role of combination chemotherapy in improving patient outcomes. Int. J. Breast Cancer 2013 2013 1 15 10.1155/2013/137414 23864953
    [Google Scholar]
  7. Greenberg P.A. Hortobagyi G.N. Smith T.L. Ziegler L.D. Frye D.K. Buzdar A.U. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J. Clin. Oncol. 1996 14 8 2197 2205 10.1200/JCO.1996.14.8.2197 8708708
    [Google Scholar]
  8. Bailly C. Irinotecan: 25 years of cancer treatment. Pharmacol. Res. 2019 148 104398 10.1016/j.phrs.2019.104398 31415916
    [Google Scholar]
  9. Shitara T. Shimada A. Hanada R. Matsunaga T. Kawa K. Mugishima H. Sugimoto T. Mimaya J. Manabe A. Tsurusawa M. Tsuchida Y. Irinotecan for children with relapsed solid tumors. Pediatr. Hematol. Oncol. 2006 23 2 103 110 10.1080/08880010500457152 16651238
    [Google Scholar]
  10. Kciuk M. Marciniak B. Kontek R. Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview. Int. J. Mol. Sci. 2020 21 14 4919 10.3390/ijms21144919 32664667
    [Google Scholar]
  11. Hassanein E.H.M. Ali F.E.M. Sayed M.M. Mahmoud A.R. Jaber F.A. Kotob M.H. Abd-Elhamid T.H. Umbelliferone potentiates intestinal protective effect of Lactobacillus Acidophilus against methotrexate-induced intestinal injury: Biochemical and histological study. Tissue Cell 2023 82 102103 10.1016/j.tice.2023.102103 37178526
    [Google Scholar]
  12. Choi G.Y. Kim H.B. Cho J.M. Sreelatha I. Lee I.S. Kweon H.S. Sul S. Kim S.A. Maeng S. Park J.H. Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model. Nutrients 2023 15 10 2351 10.3390/nu15102351 37242234
    [Google Scholar]
  13. Yu S.M. Hu D.H. Zhang J.J. Umbelliferone exhibits anticancer activity via the induction of apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells. Mol. Med. Rep. 2015 12 3 3869 3873 10.3892/mmr.2015.3797 25997538
    [Google Scholar]
  14. Shen J.Q. Zhang Z.X. Shen C.F. Liao J.Z. Anticarcinogenic effect of Umbelliferone in human prostate carcinoma: An in vitro study. J. BUON 2017 22 1 94 101 28365941
    [Google Scholar]
  15. Kumar V. Ahmed D. Verma A. Anwar F. Ali M. Mujeeb M. Umbelliferone β-D-galactopyranoside from Aegle marmelos (L.) corr. an ethnomedicinal plant with antidiabetic, antihyperlipidemic and antioxidative activity. BMC Complement. Altern. Med. 2013 13 1 273 10.1186/1472‑6882‑13‑273 24138888
    [Google Scholar]
  16. Salam S. Velli S.K. Krishnan P. Selvanathan I. Murugan M. Subramaniam N. Thiruvengadam D. Anti-cancer efficacy of umbelliferone against benzo (a) pyrene-induced lung carcinogenesis in Swiss albino mice. MJB 2018 5 79 89
    [Google Scholar]
  17. Irinotecan 2023 Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Irinotecan(accessed on 28-9-2024)
  18. Umbelliferone 2023 Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Umbelliferone(accessed on 28-9-2024)
  19. Mazimba O. Umbelliferone: Sources, chemistry and bioactivities review. Bulletin of Faculty of Pharmacy 2017 55 223 232
    [Google Scholar]
  20. Parhoodeh P. Rahmani M. Hashim N.M. Sukari M.A. Lian C. ChengLian G.E. Lignans and other constituents from aerial parts of Haplophyllum villosum. Molecules 2011 16 3 2268 2273 10.3390/molecules16032268 21383663
    [Google Scholar]
  21. Singh R. Singh B. Singh S. Kumar N. Kumar S. Arora S. Umbelliferone – An antioxidant isolated from Acacia nilotica (L.). Willd. Ex. Del. Food Chem. 2010 120 3 825 830 10.1016/j.foodchem.2009.11.022
    [Google Scholar]
  22. Rodriguez L.G. Wu X. Guan J.L. Wound-Healing Assay. Methods Mol. Biol. 2005 294 023 030 10.1385/1‑59259‑860‑9:023 15576902
    [Google Scholar]
  23. Shaw L.M. Tumor cell invasion assays Methods Mol. Biol. 2005 294 097 106 10.1385/1‑59259‑860‑9:097 15576908
    [Google Scholar]
  24. Atli E. Tamtürk E. Investigation of developmental and reproductive effects of resveratrol in Drosophila melanogaster. Toxicol. Res. (Camb.) 2022 11 1 101 107 10.1093/toxres/tfab123 35237415
    [Google Scholar]
  25. Kozomara A. Birgaoanu M. Griffiths-Jones S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 2019 47 D1 D155 D162 10.1093/nar/gky1141 30423142
    [Google Scholar]
  26. Sarzynska J. Popenda M. Antczak M. Szachniuk M. RNA tertiary structure prediction using RNACOMPOSER in CASP15. Proteins 2023 91 12 1790 1799 10.1002/prot.26578 37615316
    [Google Scholar]
  27. Trott O. Olson A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010 31 2 455 461 10.1002/jcc.21334 19499576
    [Google Scholar]
  28. Mooers B.H.M. Shortcuts for faster image creation in PyMOL. Protein Sci. 2020 29 1 268 276 10.1002/pro.3781
    [Google Scholar]
  29. Bitencourt-Ferreira G. de Azevedo W.F. Jr Docking with swissdock. Methods Mol. Biol. 2019 2053 189 202 10.1007/978‑1‑4939‑9752‑7_12 31452106
    [Google Scholar]
  30. Murail S. de Vries S.J. Rey J. Moroy G. Tufféry P. SeamDock: An Interactive and Collaborative Online Docking Resource to Assist Small Compound Molecular Docking. Front. Mol. Biosci. 2021 8 716466 10.3389/fmolb.2021.716466 34604303
    [Google Scholar]
  31. 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]
  32. Yalçınkaya S. Yalçın Azarkan S. Karahan Çakmakçı A.G. Determination of the effect of L. plantarum AB6-25, L. plantarum MK55 and S. boulardii T8-3C microorganisms on colon, cervix, and breast cancer cell lines: Molecular docking, and molecular dynamics study. J. Mol. Struct. 2022 1261 132939 10.1016/j.molstruc.2022.132939
    [Google Scholar]
  33. Bekker H. Berendsen H.J.C. Dijkstra E.J. Achterop S. Vondrumen R.V. Vanderspoel D. Gromacs-a parallel computer for molecular-dynamics simulations. 4th international conference on computational physics World Scientific Publishing 1993 252 256
    [Google Scholar]
  34. Abraham M.J. Murtola T. Schulz R. Páll S. Smith J.C. Hess B. Lindahl E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015 1-2 19 25 10.1016/j.softx.2015.06.001
    [Google Scholar]
  35. Lindorff-Larsen K. Piana S. Palmo K. Maragakis P. Klepeis J.L. Dror R.O. Shaw D.E. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins 2010 78 8 1950 1958 10.1002/prot.22711 20408171
    [Google Scholar]
  36. Bjelkmar P. Larsson P. Cuendet M.A. Hess B. Lindahl E. Implementation of the CHARMM force field in GROMACS: analysis of protein stability effects from correction maps, virtual interaction sites, and water models. J. Chem. Theory Comput. 2010 6 2 459 466 10.1021/ct900549r 26617301
    [Google Scholar]
  37. Oostenbrink C. Villa A. Mark A.E. Van Gunsteren W.F. A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force‐field parameter sets 53A5 and 53A6. J. Comput. Chem. 2004 25 13 1656 1676 10.1002/jcc.20090 15264259
    [Google Scholar]
  38. Franke T.F. Tartof K.D. Tsichlis P.N. The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1. Oncogene 1994 9 1 141 148 8302573
    [Google Scholar]
  39. Coudert E. Gehant S. de Castro E. Pozzato M. Baratin D. Neto T. Sigrist C.J.A. Redaschi N. Bridge A. Bridge A.J. Aimo L. Argoud-Puy G. Auchincloss A.H. Axelsen K.B. Bansal P. Baratin D. Neto T.M.B. Blatter M-C. Bolleman J.T. Boutet E. Breuza L. Gil B.C. Casals-Casas C. Echioukh K.C. Coudert E. Cuche B. de Castro E. Estreicher A. Famiglietti M.L. Feuermann M. Gasteiger E. Gaudet P. Gehant S. Gerritsen V. Gos A. Gruaz N. Hulo C. Hyka-Nouspikel N. Jungo F. Kerhornou A. Le Mercier P. Lieberherr D. Masson P. Morgat A. Muthukrishnan V. Paesano S. Pedruzzi I. Pilbout S. Pourcel L. Poux S. Pozzato M. Pruess M. Redaschi N. Rivoire C. Sigrist C.J.A. Sonesson K. Sundaram S. Bateman A. Martin M-J. Orchard S. Magrane M. Ahmad S. Alpi E. Bowler-Barnett E.H. Britto R. A-Jee, H.B.; Cukura, A.; Denny, P.; Dogan, T.; Ebenezer, T.G.; Fan, J.; Garmiri, P.; da Costa Gonzales, L.J.; Hatton-Ellis, E.; Hussein, A.; Ignatchenko, A.; Insana, G.; Ishtiaq, R.; Joshi, V.; Jyothi, D.; Kandasaamy, S.; Lock, A.; Luciani, A.; Lugaric, M.; Luo, J.; Lussi, Y.; MacDougall, A.; Madeira, F.; Mahmoudy, M.; Mishra, A.; Moulang, K.; Nightingale, A.; Pundir, S.; Qi, G.; Raj, S.; Raposo, P.; Rice, D.L.; Saidi, R.; Santos, R.; Speretta, E.; Stephenson, J.; Totoo, P.; Turner, E.; Tyagi, N.; Vasudev, P.; Warner, K.; Watkins, X.; Zaru, R.; Zellner, H.; Wu, C.H.; Arighi, C.N.; Arminski, L.; Chen, C.; Chen, Y.; Huang, H.; Laiho, K.; McGarvey, P.; Natale, D.A.; Ross, K.; Vinayaka, C.R.; Wang, Q.; Wang, Y. Annotation of biologically relevant ligands in UniProtKB using ChEBI. Bioinformatics 2023 39 1 btac793 10.1093/bioinformatics/btac793 36484697
    [Google Scholar]
  40. Lipinski C.A. Lombardo F. Dominy B.W. Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv. Drug Deliv. Rev. 2001 46 1-3 3 26 10.1016/S0169‑409X(00)00129‑0 11259830
    [Google Scholar]
  41. Veber D.F. Johnson S.R. Cheng H.Y. Smith B.R. Ward K.W. Kopple K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002 45 12 2615 2623 10.1021/jm020017n 12036371
    [Google Scholar]
  42. Ghose A.K. Viswanadhan V.N. Wendoloski J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999 1 1 55 68 10.1021/cc9800071 10746014
    [Google Scholar]
  43. Wu M. Gao F. Li X. Guo J. Wang T. Zhang F. Study on the solubilization effect of 7-ethyl-10-hydroxycamptothecin based on molecular docking and molecular dynamics simulation. J. Mol. Model. 2023 29 2 58 10.1007/s00894‑023‑05455‑1 36715793
    [Google Scholar]
  44. Read R.D. Drosophila melanogaster as a model system for human brain cancers. Glia 2011 59 9 1364 1376 10.1002/glia.21148 21538561
    [Google Scholar]
  45. Weinkove D. Neufeld T.P. Twardzik T. Waterfield M.D. Leevers S.J. Regulation of imaginal disc cell size, cell number and organ size by Drosophila class IA phosphoinositide 3-kinase and its adaptor. Curr. Biol. 1999 9 18 1019 1029 10.1016/S0960‑9822(99)80450‑3 10508611
    [Google Scholar]
  46. Montagne J. Stewart M.J. Stocker H. Hafen E. Kozma S.C. Thomas G. Drosophila S6 kinase: a regulator of cell size. Science 1999 285 5436 2126 2129 10.1126/science.285.5436.2126 10497130
    [Google Scholar]
  47. Gateff E. Schneiderman H.A. Developmental studies of a new mutant of Drosophila melanogaster: Lethal malignant brain tumor (l (2)gl 4). Am. Zool. 1967 7 760
    [Google Scholar]
  48. Truscott M. Islam A.B.M.M.K. López-Bigas N. Frolov M.V. mir-11 limits the proapoptotic function of its host gene, dE2f1. Genes Dev. 2011 25 17 1820 1834 10.1101/gad.16947411 21856777
    [Google Scholar]
  49. Xu P. Vernooy S.Y. Guo M. Hay B.A. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr. Biol. 2003 13 9 790 795 10.1016/S0960‑9822(03)00250‑1 12725740
    [Google Scholar]
  50. Pinsky I. Labeit S. Labeit D. Ivashchenko A. Characteristics of miRNA binding sites in mRNAS of human and mouse titin gene. International Journal of Biology and Chemistry 2017 10 1 25 34 10.26577/2218‑7979‑2017‑10‑1‑25‑34
    [Google Scholar]
  51. Hsiao Y.C. Yeh M.H. Chen Y.J. Liu J.F. Tang C.H. Huang W.C. Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6. Oncotarget 2015 6 35 37965 37978 10.18632/oncotarget.5700 26513016
    [Google Scholar]
  52. Kalinowski F.C. Brown R.A.M. Ganda C. Giles K.M. Epis M.R. Horsham J. Leedman P.J. microRNA-7: A tumor suppressor miRNA with therapeutic potential. Int. J. Biochem. Cell Biol. 2014 54 312 317 10.1016/j.biocel.2014.05.040 24907395
    [Google Scholar]
  53. Morales-Martínez M. Vega M.I. Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology. Int. J. Mol. Sci. 2022 23 16 9091 10.3390/ijms23169091 36012357
    [Google Scholar]
  54. Correa-Medina M. Bravo-Egana V. Rosero S. Ricordi C. Edlund H. Diez J. Pastori R.L. MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. Gene Expr. Patterns 2009 9 4 193 199 10.1016/j.gep.2008.12.003 19135553
    [Google Scholar]
  55. Hong T. Ding J. Li W. miR-7 Reverses Breast Cancer Resistance To Chemotherapy By Targeting MRP1 And BCL2. OncoTargets Ther. 2019 12 11097 11105 10.2147/OTT.S213780 31908478
    [Google Scholar]
  56. Primavera E. Palazzotti D. Barreca M.L. Astolfi A. Computer-Aided Identification of Kinase-Targeted Small Molecules for Cancer: A Review on AKT Protein. Pharmaceuticals (Basel) 2023 16 7 993 10.3390/ph16070993 37513905
    [Google Scholar]
  57. Rothenberg M.L. Irinotecan (CPT-11): recent developments and future directions--colorectal cancer and beyond. Oncologist 2001 6 1 66 80 10.1634/theoncologist.6‑1‑66 11161230
    [Google Scholar]
  58. Mirzoyan Z. Sollazzo M. Allocca M. Valenza A.M. Grifoni D. Bellosta P. Drosophila melanogaster: A Model Organism to Study Cancer. Front. Genet. 2019 10 51 10.3389/fgene.2019.00051 30881374
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206340868241018075528
Loading
In vivo, In vitro, and In silico Studies of Umbelliferone and Irinotecan on MDA-MB-231 Breast Cancer Cell Line and Drosophila melanogaster Larvae
Bentham Science Publishers ; https://doi.org/10.2174/0118715206340868241018075528
/content/journals/acamc/10.2174/0118715206340868241018075528
/content/journals/acamc/10.2174/0118715206340868241018075528
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: Irinotecan ; in silico analyses ; Drosophila melanogaster ; Umbelliferone ; breast cancer ; miRNA

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