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Volume 10, Issue 1
  • ISSN: 2212-697X
  • E-ISSN: 2212-6988

Abstract

Background

Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be highly expressed in various types of cancer cells. On the other hand, it is well documented that chemical compounds with spiro scaffolds in their structure could be effective chemical agents against cancer types.

Objective

In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing a spiro-bridge of naphthalinone and chromanone were investigated.

Methods

The cytotoxicity effects of compounds - were evaluated by performing the MTT assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney) cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected to analyze the cell cycle and apoptosis mechanism.

Results

The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of compounds (IC value: 1.07±0.28 µM) and (IC value: 11.92±1.07 µM). None of the compounds had a toxic effect on normal HEK-293 cells, except for compound with an IC value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin, known as anti-cancer agents. Subsequently, compound with significant yield and cytotoxic activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells.

Conclusion

The selective COX-2 inhibitor compounds with spiroisoxazoline core structure could be suitable scaffolds for cytotoxic effects.

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2024-07-11
2025-01-31

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References

  1. TorreL.A. SiegelR.L. WardE.M. JemalA. Global cancer incidence and mortality rates and trends—an update.Cancer Epidemiol. Biomarkers Prev.2016251162710.1158/1055‑9965.EPI‑15‑057826667886
     [Google Scholar]
  2. MantovaniA. AllavenaP. SicaA. BalkwillF. Cancer-related inflammation.Nature2008454720343644410.1038/nature0720518650914
     [Google Scholar]
  3. TodoricJ. AntonucciL. KarinM. Targeting inflammation in cancer prevention and therapy.Cancer Prev. Res.201691289590510.1158/1940‑6207.CAPR‑16‑020927913448
     [Google Scholar]
  4. HosseiniF. Mahdian-ShakibA. Jadidi-NiaraghF. Anti‐inflammatory and anti‐tumor effects of α-l-guluronic acid (G2013) on cancer-related inflammation in a murine breast cancer model.Biomed. Pharmacother.20189879380010.1016/j.biopha.2017.12.11129571248
     [Google Scholar]
  5. KarinM. Nuclear factor-κB in cancer development and progression.Nature2006441709243143610.1038/nature0487016724054
     [Google Scholar]
  6. LiuB. QuL. YanS. Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity.Cancer Cell Int.201515110610.1186/s12935‑015‑0260‑726549987
     [Google Scholar]
  7. MarnettL.J. DuBoisR.N. COX-2: A target for colon cancer prevention.Annu. Rev. Pharmacol. Toxicol.2002421558010.1146/annurev.pharmtox.42.082301.16462011807164
     [Google Scholar]
  8. LiuX-H. YaoS. KirschenbaumA. LevineA.C. NS398, a selective cyclooxygenase-2 inhibitor, induces apoptosis and down-regulates bcl-2 expression in LNCaP cells.Cancer Res.19985819424542499766645
     [Google Scholar]
  9. CaoY. PearmanA.T. ZimmermanG.A. McIntyreT.M. PrescottS.M. Intracellular unesterified arachidonic acid signals apoptosis.Proc. Natl. Acad. Sci.20009721112801128510.1073/pnas.20036759711005842
     [Google Scholar]
  10. PengH.L. ZhangG.S. LiuJ.H. GongF.J. LiR.J. Dup-697, a specific COX-2 inhibitor, suppresses growth and induces apoptosis on K562 leukemia cells by cell-cycle arrest and caspase-8 activation.Ann. Hematol.200887212112910.1007/s00277‑007‑0385‑417999062
     [Google Scholar]
  11. SheQ.B. SolitD.B. YeQ. O’ReillyK.E. LoboJ. RosenN. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.Cancer Cell20058428729710.1016/j.ccr.2005.09.00616226704
     [Google Scholar]
  12. LiuB. ShiZ. FengJ. TaoH. Celecoxib, a cyclooxygenase‐2 inhibitor, induces apoptosis in human osteosarcoma cell line MG‐63 via down‐regulation of PI3K/Akt.Cell Biol. Int.200832549450110.1016/j.cellbi.2007.10.00818078766
     [Google Scholar]
  13. SobolewskiC. CerellaC. DicatoM. GhibelliL. DiederichM. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies.Int. J. Cell Biol.2010201012110.1155/2010/21515820339581
     [Google Scholar]
  14. CaoY. PrescottS.M. Many actions of cyclooxygenase‐2 in cellular dynamics and in cancer.J. Cell. Physiol.2002190327928610.1002/jcp.1006811857443
     [Google Scholar]
  15. StewartZ.A. WestfallM.D. PietenpolJ.A. Cell-cycle dysregulation and anticancer therapy.Trends Pharmacol. Sci.200324313914510.1016/S0165‑6147(03)00026‑912628359
     [Google Scholar]
  16. NakanishiY. KamijoR. TakizawaK. HatoriM. NagumoM. Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines.Eur. J. Cancer200137121570157810.1016/S0959‑8049(01)00160‑511506967
     [Google Scholar]
  17. MasferrerJ.L. IsaksonP.C. SeibertK. Cyclooxygenase-2 inhibitors: A new class of anti-inflammatory agents that spare the gastrointestinal tract.Gastroenterol. Clin. North Am.199625236337210.1016/S0889‑8553(05)70252‑19229578
     [Google Scholar]
  18. VaneJ.R. BakhleY.S. BottingR.M. Cyclooxygenases 1 and 2.Annu. Rev. Pharmacol. Toxicol.19983819712010.1146/annurev.pharmtox.38.1.979597150
     [Google Scholar]
  19. WolfeM.M. LichtensteinD.R. SinghG. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.N. Engl. J. Med.1999340241888189910.1056/NEJM19990617340240710369853
     [Google Scholar]
  20. NussmeierN.A. WheltonA.A. BrownM.T. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.N. Engl. J. Med.2005352111081109110.1056/NEJMoa05033015713945
     [Google Scholar]
  21. AbolhasaniH. ZarghiA. AbolhasaniA. Design, synthesis and in vitro cytotoxicity evaluation of new 3′, 4′-bis (3, 4, 5-trisubstituted)-4‘H-spiro [indene-2, 5’-isoxazol]-1 (3H)-one derivatives as promising anticancer agents.Lett. Drug Des. Discov.201411101149116110.2174/1570180811666140704172442
     [Google Scholar]
  22. AbolhasaniH. DastmalchiS. Hamzeh-MivehroudM. DaraeiB. ZarghiA. Design, synthesis and biological evaluation of new tricyclic spiroisoxazoline derivatives as selective COX-2 inhibitors and study of their COX-2 binding modes via docking studies.Med. Chem. Res.201625585886910.1007/s00044‑016‑1534‑x
     [Google Scholar]
  23. SakhujaR. PandaS.S. KhannaL. KhuranaS. JainS.C. Design and synthesis of spiro[indole-thiazolidine]spiro[indole-pyrans] as antimicrobial agents.Bioorg. Med. Chem. Lett.201121185465546910.1016/j.bmcl.2011.06.12121782421
     [Google Scholar]
  24. YoussefM.M. AminM.A. Microwave assisted synthesis of some new heterocyclic spiro-derivatives with potential antimicrobial and antioxidant activity.Molecules201015128827884010.3390/molecules1512882721131902
     [Google Scholar]
  25. VelikorodovA.V. IonovaV.A. DegtyarevO.V. SukhenkoL.T. Synthesis and antimicrobial and antifungal activity of carbamate-functionized spiro compounds.Pharm. Chem. J.2013461271571910.1007/s11094‑013‑0876‑7
     [Google Scholar]
  26. Abdel-RahmanA.H. KeshkE.M. HannaM.A. El-BadyS.M. Synthesis and evaluation of some new spiro indoline-based heterocycles as potentially active antimicrobial agents.Bioorg. Med. Chem.20041292483248810.1016/j.bmc.2003.10.06315080944
     [Google Scholar]
  27. RajA.A. RaghunathanR. SrideviKumari MR, Raman N. Synthesis, antimicrobial and antifungal activity of a new class of spiro pyrrolidines.Bioorg. Med. Chem.200311340741910.1016/S0968‑0896(02)00439‑X12517436
     [Google Scholar]
  28. UmamatheswariS. BalajiB. RamanathanM. KabilanS. Synthesis, antimicrobial evaluation and QSAR studies of novel piperidin-4-yl-5-spiro-thiadiazoline derivatives.Bioorg. Med. Chem. Lett.201020236909691410.1016/j.bmcl.2010.10.00221035335
     [Google Scholar]
  29. HafezH.N. HegabM.I. Ahmed-FaragI.S. El-GazzarA.B.A. A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9′,2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents.Bioorg. Med. Chem. Lett.200818164538454310.1016/j.bmcl.2008.07.04218667305
     [Google Scholar]
  30. Abdel-RahmanM.A. HusseinE.M. HusseinM.A. Synthesis and characterization of novel anti-inflammatory poly(spiro thiazolidinone)s.Des. Monomers Polym.201619765066010.1080/15685551.2016.1198881
     [Google Scholar]
  31. PoojariS. Anti-inflammatory, antibacterial and molecular docking studies of novel spiro-piperidine quinazolinone derivatives.J. Taibah Univ. Sci.201711349751110.1016/j.jtusci.2016.10.003
     [Google Scholar]
  32. KumarR.S. AntonisamyP. AlmansourA.I. Functionalized spirooxindole-indolizine hybrids: Stereoselective green synthesis and evaluation of anti-inflammatory effect involving TNF-α and nitrite inhibition.Eur. J. Med. Chem.201815241742310.1016/j.ejmech.2018.04.06029751235
     [Google Scholar]
  33. AbolhasaniH. ZarghiA. Hamzeh-MivehroudM. AlizadehA.A. Shahbazi MojarradJ. DastmalchiS. In-silico investigation of tubulin binding modes of a series of novel antiproliferative spiroisoxazoline compounds using docking studies.Iran. J. Pharm. Res.201514114114725561920
     [Google Scholar]
  34. ChandeM.S. VermaR.S. BarveP.A. KhanwelkarR.R. VaidyaR.B. AjaikumarK.B. Facile synthesis of active antitubercular, cytotoxic and antibacterial agents: A Michael addition approach.Eur. J. Med. Chem.200540111143114810.1016/j.ejmech.2005.06.00416040160
     [Google Scholar]
  35. GirgisA.S. MabiedA.F. StawinskiJ. Synthesis and DFT studies of an antitumor active spiro-oxindole.New J. Chem.201539108017802710.1039/C5NJ01109D
     [Google Scholar]
  36. GirgisA.S. PandaS.S. FaragI.S.A. Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids.Org. Biomol. Chem.20151361741175310.1039/C4OB02149E25502495
     [Google Scholar]
  37. NunesR.C. RibeiroC.J.A. Monteiro Â, Rodrigues CMP, Amaral JD, Santos MMM. In vitro targeting of colon cancer cells using spiropyrazoline oxindoles.Eur. J. Med. Chem.201713916817910.1016/j.ejmech.2017.07.05728800455
     [Google Scholar]
  38. ReddyC.N. NayakV.L. ManiG.S. Synthesis and biological evaluation of spiro[cyclopropane-1,3′-indolin]-2′-ones as potential anticancer agents.Bioorg. Med. Chem. Lett.201525204580458610.1016/j.bmcl.2015.08.05626330077
     [Google Scholar]
  39. NajimN. BathichY. ZainM.M. HamzahA.S. ShaameriZ. Evaluation of the bioactivity of novel spiroisoxazoline typecompounds against normal and cancer cell lines.Molecules201015129340935310.3390/molecules1512934021169884
     [Google Scholar]
  40. SaxenaR. GuptaG. ManoharM. Spiro-oxindole derivative 5-chloro-4′,5′-diphenyl-3′-(4-(2-(piperidin-1-yl) ethoxy) benzoyl) spiro[indoline-3,2′-pyrrolidin]-2-one triggers apoptosis in breast cancer cells via restoration of p53 function.Int. J. Biochem. Cell Biol.20167010511710.1016/j.biocel.2015.11.00326556313
     [Google Scholar]
  41. EldehnaW.M. EL-Naggar DH, Hamed AR, Ibrahim HS, Ghabbour HA, Abdel-Aziz HA. One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.J. Enzyme Inhib. Med. Chem.201833130931810.1080/14756366.2017.141727629281924
     [Google Scholar]
  42. AbolhasaniH. ZarghiA. AbolhasaniA. DastmalchiS. In vitro cytotoxicity of indanonic spiroisoxazolin derivatives as anticancer agents.Iranian Cong Physio Pharma20152213104
     [Google Scholar]
  43. ZarghiA. ArfaeiS. Selective COX-2 inhibitors: A review of their structure-activity relationships.Iran. J. Pharm. Res.201110465568324250402
     [Google Scholar]
  44. Al HouariG. KerbalA. BennaniB. BabaM.F. DaoudiM. HaddaT.B. Drug design of new antitubercular agents: 1, 3-dipolar cycloaddition reaction of para-substituted-benzadoximes and 3-para-methoxy-benzyliden-isochroman-4-ones.ARKIVOC200812425010.3998/ark.5550190.0009.c05
     [Google Scholar]
  45. AbolhasaniA. HeidariF. NooriS. MousaviS. AbolhasaniH. Cytotoxicity evaluation of dimethoxy and trimethoxy indanonic spiroisoxazolines against cancerous liver cells.Curr. Chem. Biol.202014103847
     [Google Scholar]
  46. AbolhasaniH DastmalchiS ZarghiA AbolhasaniA Hamzeh-MivehrodM. Design & synthesis of novel 4'-(4-(methylsulfonyl)phenyl) 3'-p-substituted phenyl-4'H-spiro[chroman-3,5’-isoxazol]-4-one as selective COX-2 inhibitors.Res Pharma Sci2013
     [Google Scholar]
  47. AbolhasaniH. ZarghiA. Komeili MovahhedT. AbolhasaniA. DaraeiB. DastmalchiS. Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents.Bioorg. Med. Chem.20213211596010.1016/j.bmc.2020.11596033477020
     [Google Scholar]
  48. AbolhasaniA. BiriaD. AbolhasaniH. ZarrabiA. KomeiliT. Investigate of the role of glucose decorated chitosan and PLGA nanoparticles as blocking agents to glucose transporters of tumor cells.Int. J. Nanomedicine20191495359546
     [Google Scholar]
  49. MarashiyanM. KalhorH. GanjiM. RahimiH. Effects of tosyl-l-arginine methyl ester (TAME) on the APC/c subunits: An in silico investigation for inhibiting cell cycle.J. Mol. Graph. Model.20209710756310.1016/j.jmgm.2020.10756332066079
     [Google Scholar]
  50. KalhorH. SadeghiS. MarashiyanM. Identification of new DNA gyrase inhibitors based on bioactive compounds from streptomyces: structure-based virtual screening and molecular dynamics simulations approaches.J. Biomol. Struct. Dyn.202038379180610.1080/07391102.2019.158878430916622
     [Google Scholar]
  51. KalhorH. SadeghiS. AbolhasaniH. KalhorR. RahimiH. Repurposing of the approved small molecule drugs in order to inhibit SARS-CoV-2 S protein and human ACE2 interaction through virtual screening approaches.J. Biomol. Struct. Dyn.20224031299131510.1080/07391102.2020.182481632969333
     [Google Scholar]
  52. KalhorH. RahimiH. Akbari EidgahiM.R. Teimoori-ToolabiL. Novel small molecules against two binding sites of wnt2 protein as potential drug candidates for colorectal cancer: A structure based virtual screening approach.Iran. J. Pharm. Res.202019216017433224221
     [Google Scholar]
  53. HarrisR.E. AlshafieG.A. Abou-IssaH. SeibertK. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor.Cancer Res.20006082101210310786667
     [Google Scholar]
  54. ShengH. ShaoJ. KirklandS.C. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.J. Clin. Invest.19979992254225910.1172/JCI1194009151799
     [Google Scholar]
  55. SinghB. CookK.R. VincentL. HallC.S. MartinC. LucciA. Role of COX-2 in tumorospheres derived from a breast cancer cell line.J. Surg. Res.20111681e39e4910.1016/j.jss.2010.03.00320462604
     [Google Scholar]
  56. Singh-RangerG. MokbelK. The role of cyclooxygenase-2 (COX-2) in breast cancer, and implications of COX-2 inhibition.Eur. J. Surg. Oncol.200228772973710.1053/ejso.2002.132912431470
     [Google Scholar]
  57. LiuW. ReinmuthN. StoeltzingO. Cyclooxygenase-2 is up-regulated by interleukin-1 β in human colorectal cancer cells via multiple signaling pathways.Cancer Res.200363133632363612839952
     [Google Scholar]
  58. Singh-RangerG. SalhabM. MokbelK. The role of cyclooxygenase-2 in breast cancer (Review).Breast Cancer Res. Treat.2008109218919810.1007/s10549‑007‑9641‑517624587
     [Google Scholar]
  59. ComşaŞ. CîmpeanA.M. RaicaM. The story of MCF-7 breast cancer cell line: 40 years of experience in research.Anticancer Res.20153563147315426026074
     [Google Scholar]
  60. IncelerN. OzkanY. TuranN.N. KahramanD.C. Cetin-AtalayR. BaytasS.N. Design, synthesis and biological evaluation of novel 1,3-diarylpyrazoles as cyclooxygenase inhibitors, antiplatelet and anticancer agents.MedChemComm20189579581110.1039/C8MD00022K30108969
     [Google Scholar]
  61. LiX. QiuZ. JinQ. ChenG. GuoM. Cell cycle arrest and apoptosis in HT-29 cells induced by dichloromethane fraction from Toddalia asiatica (L.) Lam.Front. Pharmacol.2018962910.3389/fphar.2018.0062929950999
     [Google Scholar]
  62. SwiftL.H. GolsteynR.M. Cytotoxic amounts of cisplatin induce either checkpoint adaptation or apoptosis in a concentration‐dependent manner in cancer cells.Biol. Cell2016108512714810.1111/boc.20150005626871414
     [Google Scholar]
  63. PautyJ. CôtéM.F. RodrigueA. VelicD. MassonJ.Y. FortinS. Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks.Sci. Rep.2016612330210.1038/srep2330227001483
     [Google Scholar]
  64. SongS. DuL. JiangH. ZhuX. LiJ. XuJ. Paris saponin I sensitizes gastric cancer cell lines to cisplatin via cell cycle arrest and apoptosis.Med. Sci. Monit.2016223798380310.12659/MSM.89823227755523
     [Google Scholar]
  65. PfefferC. SinghA. Apoptosis: A target for anticancer therapy.Int. J. Mol. Sci.201819244810.3390/ijms1902044829393886
     [Google Scholar]
/content/journals/ccand/10.2174/012212697X274833240408033609
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Anti-cancer Activity Evaluation of Naphthalenonic and Chromanonic Spiroisoxazoline Derivatives as Selective COX-2 Inhibitors on HT29 Cell Lines
Clinical Cancer Drugs 10, E110724231864 (2024); https://doi.org/10.2174/012212697X274833240408033609
/content/journals/ccand/10.2174/012212697X274833240408033609
/content/journals/ccand/10.2174/012212697X274833240408033609
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  • Article Type:     Research Article
Keyword(s): HEK-293; HT-29; MCF-7; MTT assay; selective COX-2 inhibitors; Spiroisoxazoline

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