P129, a pyrazole ring-containing isolongifolanone-derivate: synthesis and investigation of anti-glioma action mechanism.
Apoptosis
CDK-2
Cell cycle arrest
Glioblastoma
Pyrazole
Treatment
isolongifolanone derivate
Journal
Discover. Oncology
ISSN: 2730-6011
Titre abrégé: Discov Oncol
Pays: United States
ID NLM: 101775142
Informations de publication
Date de publication:
06 Jan 2024
06 Jan 2024
Historique:
received:
25
06
2023
accepted:
03
01
2024
medline:
7
1
2024
pubmed:
7
1
2024
entrez:
6
1
2024
Statut:
epublish
Résumé
Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial-mesenchymal transition. Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood-brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.
Sections du résumé
BACKGROUND
BACKGROUND
Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G
METHODS
METHODS
We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial-mesenchymal transition.
RESULTS
RESULTS
Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood-brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G
CONCLUSION
CONCLUSIONS
The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.
Identifiants
pubmed: 38184514
doi: 10.1007/s12672-024-00858-9
pii: 10.1007/s12672-024-00858-9
doi:
Types de publication
Journal Article
Langues
eng
Pagination
6Subventions
Organisme : Natural Science Foundation of Jiangsu Province
ID : BK20220611
Organisme : Jilin Province Science and Technology Development Planning Project
ID : 20200801023GH
Organisme : Health and Wellness Technology Enhancement Project of Jilin Province
ID : 2022LC105
Organisme : the S&T Development Planning Program of Jilin Province
ID : YDZJ202201ZYTS073
Organisme : the S&T Development Planning Program of Jilin Province
ID : 20200404101YY
Organisme : National Nature and Science Foundation of China
ID : 81672505
Organisme : Jilin Province Medical and Health Talent Project
ID : JLSWSRCZX 2021-052
Informations de copyright
© 2024. The Author(s).
Références
Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, et al. Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer. 2022;21(1):39. https://doi.org/10.1186/s12943-022-01513-z .
doi: 10.1186/s12943-022-01513-z
pubmed: 35135556
pmcid: 8822752
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106 .
doi: 10.1093/neuonc/noab106
pubmed: 34185076
pmcid: 8328013
Xu S, Tang L, Li X, Fan F, Liu Z. Immunotherapy for glioma: current management and future application. Cancer Lett. 2020;476:1–12. https://doi.org/10.1016/j.canlet.2020.02.002 .
doi: 10.1016/j.canlet.2020.02.002
pubmed: 32044356
Nicholson JG, Fine HA. Diffuse glioma heterogeneity and its therapeutic implications. Cancer Discov. 2021;11(3):575–90. https://doi.org/10.1158/2159-8290.Cd-20-1474 .
doi: 10.1158/2159-8290.Cd-20-1474
pubmed: 33558264
Horbinski C, Nabors LB, Portnow J, Baehring J, Bhatia A, Bloch O, et al. NCCN Guidelines® Insights: central nervous system cancers, version 2.2022. J Natl Compr Cancer Netw JNCCN. 2023;21(1):12–20. https://doi.org/10.6004/jnccn.2023.0002 .
doi: 10.6004/jnccn.2023.0002
pubmed: 36634606
Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74–88. https://doi.org/10.1038/s41580-021-00404-3 .
doi: 10.1038/s41580-021-00404-3
pubmed: 34508254
Sun YS, Thakur K, Hu F, Zhang JG, Wei ZJ. Icariside II inhibits tumorigenesis via inhibiting AKT/Cyclin E/ CDK 2 pathway and activating mitochondria-dependent pathway. Pharmacol Res. 2020;152:104616. https://doi.org/10.1016/j.phrs.2019.104616 .
doi: 10.1016/j.phrs.2019.104616
pubmed: 31883767
Galimberti F, Thompson SL, Liu X, Li H, Memoli V, Green SR, et al. Targeting the cyclin E-Cdk-2 complex represses lung cancer growth by triggering anaphase catastrophe. Clin Cancer Res. 2010;16(1):109–20. https://doi.org/10.1158/1078-0432.Ccr-09-2151 .
doi: 10.1158/1078-0432.Ccr-09-2151
pubmed: 20028770
Arteaga CL. Cdk inhibitor p27Kip1 and hormone dependence in breast cancer. Clin Cancer Res. 2004;10(1 Pt 2):368s-s371. https://doi.org/10.1158/1078-0432.ccr-031204 .
doi: 10.1158/1078-0432.ccr-031204
pubmed: 14734493
Wang Y, Shi W, Wu C, Wan L, Zhao Y, Zhang C, et al. Pyrazole ring-containing isolongifolanone derivatives as potential CDK2 inhibitors: evaluation of anticancer activity and investigation of action mechanism. Biomed Pharmacother. 2021;139:111663. https://doi.org/10.1016/j.biopha.2021.111663 .
doi: 10.1016/j.biopha.2021.111663
pubmed: 34243605
Li J, Li J, Fang H, Yang H, Wu T, Shi X, et al. Isolongifolene alleviates liver ischemia/reperfusion injury by regulating AMPK-PGC1α signaling pathway-mediated inflammation, apoptosis, and oxidative stress. Int Immunopharmacol. 2022;113(Pt A):109185. https://doi.org/10.1016/j.intimp.2022.109185 .
doi: 10.1016/j.intimp.2022.109185
pubmed: 36252482
Khan MF, Alam MM, Verma G, Akhtar W, Akhter M, Shaquiquzzaman M. The therapeutic voyage of pyrazole and its analogs: a review. Eur J Med Chem. 2016;120:170–201. https://doi.org/10.1016/j.ejmech.2016.04.077 .
doi: 10.1016/j.ejmech.2016.04.077
pubmed: 27191614
Ma C, Wang Y, Dong F, Wang Z, Zhao Y, Shan Y, et al. Synthesis and antitumor activity of isolongifoleno[7,8-d]thiazolo[3,2-a]pyrimidine derivatives via enhancing ROS level. Chem Biol Drug Des. 2019;94(2):1457–66. https://doi.org/10.1111/cbdd.13522 .
doi: 10.1111/cbdd.13522
pubmed: 30920166
Wang Y, Wu C, Zhang Q, Shan Y, Gu W, Wang S. Design, synthesis and biological evaluation of novel β-pinene-based thiazole derivatives as potential anticancer agents via mitochondrial-mediated apoptosis pathway. Bioorg Chem. 2019;84:468–77. https://doi.org/10.1016/j.bioorg.2018.12.010 .
doi: 10.1016/j.bioorg.2018.12.010
pubmed: 30576910
Mu BX, Li Y, Ye N, Liu S, Zou X, Qian J, et al. Understanding apoptotic induction by Sargentodoxa cuneata-Patrinia villosa herb pair via PI3K/AKT/mTOR signalling in colorectal cancer cells using network pharmacology and cellular studies. J Ethnopharmacol. 2023. https://doi.org/10.1016/j.jep.2023.117342 .
doi: 10.1016/j.jep.2023.117342
pubmed: 38065349
Cheng B, Li T, Li F. Study on the multitarget mechanism of alliin activating autophagy based on network pharmacology and molecular docking. J Cell Mol Med. 2022;26(22):5590–601. https://doi.org/10.1111/jcmm.17573 .
doi: 10.1111/jcmm.17573
pubmed: 36271672
pmcid: 9667524
Chen R, Chen Y, Xiong P, Zheleva D, Blake D, Keating MJ, et al. Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells. Leukemia. 2022;36(6):1596–608. https://doi.org/10.1038/s41375-022-01553-w .
doi: 10.1038/s41375-022-01553-w
pubmed: 35383271
pmcid: 9162916
Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res. 2004;10(12 Pt 2):4270s-s4275. https://doi.org/10.1158/1078-0432.Ccr-040020 .
doi: 10.1158/1078-0432.Ccr-040020
pubmed: 15217973
De Azevedo WF Jr, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E, Kim SH. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci U S A. 1996;93(7):2735–40. https://doi.org/10.1073/pnas.93.7.2735 .
doi: 10.1073/pnas.93.7.2735
pubmed: 8610110
pmcid: 39700
Bhardwaj P, Biswas GP, Mahata N, Ghanta S, Bhunia B. Exploration of binding mechanism of triclosan towards cancer markers using molecular docking and molecular dynamics. Chemosphere. 2022;293:133550. https://doi.org/10.1016/j.chemosphere.2022.133550 .
doi: 10.1016/j.chemosphere.2022.133550
pubmed: 34999105
Zhang A, Guo Z, Ren JX, Chen H, Yang W, Zhou Y, et al. Development of an MCL-1-related prognostic signature and inhibitors screening for glioblastoma. Front Pharmacol. 2023;14:1162540. https://doi.org/10.3389/fphar.2023.1162540 .
doi: 10.3389/fphar.2023.1162540
pubmed: 37538176
pmcid: 10394558
Horbinski C, Berger T, Packer RJ, Wen PY. Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours. Nat Rev Neurol. 2022;18(9):515–29. https://doi.org/10.1038/s41582-022-00679-w .
doi: 10.1038/s41582-022-00679-w
pubmed: 35729337
Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299–312. https://doi.org/10.3322/caac.21613 .
doi: 10.3322/caac.21613
pubmed: 32478924
Wang Z, Zhang Y, Song J, Yang Y, Xu X, Li M, et al. A novel isolongifolanone based fluorescent probe with super selectivity and sensitivity for hypochlorite and its application in bio-imaging. Anal Chim Acta. 2019;1051:169–78. https://doi.org/10.1016/j.aca.2018.11.028 .
doi: 10.1016/j.aca.2018.11.028
pubmed: 30661614
Li H, Lei B, Xiang W, Wang H, Feng W, Liu Y, et al. Differences in protein expression between the U251 and U87 cell lines. Turk Neurosurg. 2017;27(6):894–903. https://doi.org/10.5137/1019-5149.Jtn.17746-16.1 .
doi: 10.5137/1019-5149.Jtn.17746-16.1
pubmed: 27651343
Pan Z, Luo Y, Xia Y, Zhang X, Qin Y, Liu W, et al. Cinobufagin induces cell cycle arrest at the S phase and promotes apoptosis in nasopharyngeal carcinoma cells. Biomed Pharmacother. 2020;122:109763. https://doi.org/10.1016/j.biopha.2019.109763 .
doi: 10.1016/j.biopha.2019.109763
pubmed: 31918288
Yang S, Evens AM, Prachand S, Singh AT, Bhalla S, David K, et al. Mitochondrial-mediated apoptosis in lymphoma cells by the diterpenoid lactone andrographolide, the active component of Andrographis paniculata. Clinl Cancer Res. 2010;16(19):4755–68. https://doi.org/10.1158/1078-0432.Ccr-10-0883 .
doi: 10.1158/1078-0432.Ccr-10-0883
Niland S, Riscanevo AX, Eble JA. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms23010146 .
doi: 10.3390/ijms23010146
pubmed: 35008569
pmcid: 8745566
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015 .
doi: 10.1016/j.cell.2010.03.015
pubmed: 20371345
pmcid: 2862057
Brabletz S, Schuhwerk H, Brabletz T, Stemmler MP. Dynamic EMT: a multi-tool for tumor progression. Embo j. 2021;40(18):e108647. https://doi.org/10.15252/embj.2021108647 .
doi: 10.15252/embj.2021108647
pubmed: 34459003
pmcid: 8441439
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17(2):93–115. https://doi.org/10.1038/nrc.2016.138 .
doi: 10.1038/nrc.2016.138
pubmed: 28127048
pmcid: 5345933
Suski JM, Braun M, Strmiska V, Sicinski P. Targeting cell-cycle machinery in cancer. Cancer Cell. 2021;39(6):759–78. https://doi.org/10.1016/j.ccell.2021.03.010 .
doi: 10.1016/j.ccell.2021.03.010
pubmed: 33891890
pmcid: 8206013
Ng SS, Cheung YT, An XM, Chen YC, Li M, Li GH, et al. Cell cycle-related kinase: a novel candidate oncogene in human glioblastoma. J Natl Cancer Inst. 2007;99(12):936–48. https://doi.org/10.1093/jnci/djm011 .
doi: 10.1093/jnci/djm011
pubmed: 17565152
Li Y, Yin W, Wang X, Zhu W, Huang Y, Yan G. Cholera toxin induces malignant glioma cell differentiation via the PKA/CREB pathway. Proc Natl Acad Sci U S A. 2007;104(33):13438–43. https://doi.org/10.1073/pnas.0701990104 .
doi: 10.1073/pnas.0701990104
pubmed: 17679696
pmcid: 1940034
Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, et al. Targeting CDK2 in cancer: challenges and opportunities for therapy. Drug Discov Today. 2020;25(2):406–13. https://doi.org/10.1016/j.drudis.2019.12.001 .
doi: 10.1016/j.drudis.2019.12.001
pubmed: 31839441
Au-Yeung G, Lang F, Azar WJ, Mitchell C, Jarman KE, Lackovic K, et al. Selective targeting of cyclin E1-amplified high-grade serous ovarian cancer by cyclin-dependent kinase 2 and AKT inhibition. Clin Cancer Res. 2017;23(7):1862–74. https://doi.org/10.1158/1078-0432.Ccr-16-0620 .
doi: 10.1158/1078-0432.Ccr-16-0620
pubmed: 27663592
Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A. 2013;110(48):19489–94. https://doi.org/10.1073/pnas.1314302110 .
doi: 10.1073/pnas.1314302110
pubmed: 24218601
pmcid: 3845173
Scaltriti M, Eichhorn PJ, Cortés J, Prudkin L, Aura C, Jiménez J, et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A. 2011;108(9):3761–6. https://doi.org/10.1073/pnas.1014835108 .
doi: 10.1073/pnas.1014835108
pubmed: 21321214
pmcid: 3048107
Karachi A, Dastmalchi F, Mitchell DA, Rahman M. Temozolomide for immunomodulation in the treatment of glioblastoma. Neuro Oncol. 2018;20(12):1566–72. https://doi.org/10.1093/neuonc/noy072 .
doi: 10.1093/neuonc/noy072
pubmed: 29733389
pmcid: 6231207
Huang H, Regan KM, Lou Z, Chen J, Tindall DJ. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 2006;314(5797):294–7. https://doi.org/10.1126/science.1130512 .
doi: 10.1126/science.1130512
pubmed: 17038621
Dragnev KH, Pitha-Rowe I, Ma Y, Petty WJ, Sekula D, Murphy B, et al. Specific chemopreventive agents trigger proteasomal degradation of G1 cyclins: implications for combination therapy. Clin Cancer Res. 2004;10(7):2570–7. https://doi.org/10.1158/1078-0432.ccr-03-0271 .
doi: 10.1158/1078-0432.ccr-03-0271
pubmed: 15073138
Faber AC, Chiles TC. Inhibition of cyclin-dependent kinase-2 induces apoptosis in human diffuse large B-cell lymphomas. Cell Cycle. 2007;6(23):2982–9. https://doi.org/10.4161/cc.6.23.4994 .
doi: 10.4161/cc.6.23.4994
pubmed: 18156799
Kawakami M, Mustachio LM, Liu X, Dmitrovsky E. Engaging anaphase catastrophe mechanisms to eradicate aneuploid cancers. Mol Cancer Ther. 2018;17(4):724–31. https://doi.org/10.1158/1535-7163.Mct-17-1108 .
doi: 10.1158/1535-7163.Mct-17-1108
pubmed: 29559545
pmcid: 6053917
Kawakami M, Mustachio LM, Rodriguez-Canales J, Mino B, Roszik J, Tong P, et al. Next-Generation CDK2/9 inhibitors and anaphase catastrophe in lung cancer. J Natl Cancer Inst. 2017. https://doi.org/10.1093/jnci/djw297 .
doi: 10.1093/jnci/djw297
pubmed: 28376145
pmcid: 6059250
Thomas AL, Lind H, Hong A, Dokic D, Oppat K, Rosenthal E, et al. Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells. Cell Cycle. 2017;16(15):1453–64. https://doi.org/10.1080/15384101.2017.1338988 .
doi: 10.1080/15384101.2017.1338988
pubmed: 28678584
pmcid: 5553400
Cocco E, Lopez S, Black J, Bellone S, Bonazzoli E, Predolini F, et al. Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. Br J Cancer. 2016;115(3):303–11. https://doi.org/10.1038/bjc.2016.198 .
doi: 10.1038/bjc.2016.198
pubmed: 27351214
pmcid: 4973158
Azimi A, Caramuta S, Seashore-Ludlow B, Boström J, Robinson JL, Edfors F, et al. Targeting CDK2 overcomes melanoma resistance against BRAF and Hsp90 inhibitors. Mol Syst Biol. 2018;14(3):e7858. https://doi.org/10.15252/msb.20177858 .
doi: 10.15252/msb.20177858
pubmed: 29507054
pmcid: 5836539
Pierson-Mullany LK, Lange CA. Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. Mol Cell Biol. 2004;24(24):10542–57. https://doi.org/10.1128/mcb.24.24.10542-10557.2004 .
doi: 10.1128/mcb.24.24.10542-10557.2004
pubmed: 15572662
pmcid: 533997
Jorda R, Bučková Z, Řezníčková E, Bouchal J, Kryštof V. Selective inhibition reveals cyclin-dependent kinase 2 as another kinase that phosphorylates the androgen receptor at serine 81. Biochim Biophys Acta Mol Cell Res. 2018;1865(2):354–63. https://doi.org/10.1016/j.bbamcr.2017.11.011 .
doi: 10.1016/j.bbamcr.2017.11.011
pubmed: 29157894
Opyrchal M, Salisbury JL, Iankov I, Goetz MP, McCubrey J, Gambino MW, et al. Inhibition of Cdk2 kinase activity selectively targets the CD44
doi: 10.3892/ijo.2014.2523
pubmed: 24970653
pmcid: 4121417
Mukherjee S, Conrad SE. c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. J Biol Chem. 2005;280(18):17617–25. https://doi.org/10.1074/jbc.M502278200 .
doi: 10.1074/jbc.M502278200
pubmed: 15757889
Musgrove EA, Hunter LJ, Lee CS, Swarbrick A, Hui R, Sutherland RL. Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2. J Biol Chem. 2001;276(50):47675–83. https://doi.org/10.1074/jbc.M106371200 .
doi: 10.1074/jbc.M106371200
pubmed: 11590147