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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Effects of Galbanic Acid on Proliferation, Migration, and Apoptosis of Glioblastoma Cells Through the PI3K/Akt/MTOR Signaling Pathway

Author(s): Seyed H. Shahcheraghi, Marzieh Lotfi, Mohammad Soukhtanloo, Majid Ghayour-Mobarhan, Hossein Z. Jaliani, Hamid R. Sadeghnia* and Ahmad Ghorbani*

Volume 14, Issue 1, 2021

Published on: 12 May, 2020

Page: [79 - 87] Pages: 9

DOI: 10.2174/1874467213666200512075507

Price: $65

Abstract

Background: Glioblastoma is one of the most aggressive tumors of the central nervous system. Galbanic acid, a natural sesquiterpene coumarin, has shown favorable effects on cancerous cells in previous studies.

Objective: The aim of the present work was to evaluate the effects of galbanic acid on proliferation, migration, and apoptosis of the human malignant glioblastoma (U87) cells.

Methods: The anti-proliferative activity of the compound was determined by the MTT assay. Cell cycle alterations and apoptosis were analyzed via flow cytometry. Action on cell migration was evaluated by scratch assay and gelatin zymography. Quantitative Real-Time PCR was used to determine the expression of genes involved in cell migration (matrix metalloproteinases, MMPs) and survival (the pathways of PI3K/Akt/mTOR and WNT/β-catenin). Alteration in the level of protein Akt was determined by Western blotting.

Results: Galbanic acid significantly decreased cell proliferation, inhibited cell cycle, and stimulated apoptosis of the glioblastoma cells. Moreover, it could decrease the migration capability of glioblastoma cells, which was accompanied by inhibition in the activity and expression of MMP2 and MMP9. While galbanic acid reduced the gene expression of Akt, mTOR, and PI3K and increased the PTEN expression, it had no significant effect on WNT, β-catenin, and APC genes. In addition, the protein level of p-Akt decreased after treatment with galbanic acid. The effects of galbanic acid were observed at concentrations lower than those of temozolomide.

Conclusion: Galbanic acid decreased proliferation, cell cycle progression, and survival of glioblastoma cells through inhibiting the PI3K/Akt/mTOR pathway. This compound also reduced the migration capability of the cells by suppressing the activity and expression of MMPs.

Keywords: Apoptosis, galbanic acid, glioblastoma, migration, matrix metalloproteinase, proliferation.

Graphical Abstract

[1]
Shu, C.; Yan, X.; Zhang, X.; Wang, Q.; Cao, S.; Wang, J. Tumor-induced mortality in adult primary supratentorial glioblastoma multiforme with different age subgroups. Future Oncol., 2019, 15(10), 1105-1114.
[http://dx.doi.org/10.2217/fon-2018-0719] [PMID: 30880453]
[2]
Xing, W.J.; Zou, Y.; Han, Q.L.; Dong, Y.C.; Deng, Z.L.; Lv, X.H.; Jiang, T.; Ren, H. Effects of epidermal growth factor receptor and phosphatase and tensin homologue gene expression on the inhibition of U87MG glioblastoma cell proliferation induced by protein kinase inhibitors. Clin. Exp. Pharmacol. Physiol., 2013, 40(1), 13-21.
[http://dx.doi.org/10.1111/1440-1681.12026] [PMID: 23110505]
[3]
Tykocki, T.; Eltayeb, M. Ten-year survival in glioblastoma. A systematic review. J. Clin. Neurosci., 2018, 54, 7-13.
[http://dx.doi.org/10.1016/j.jocn.2018.05.002] [PMID: 29801989]
[4]
Zuccarini, M.; Giuliani, P.; Ziberi, S.; Carluccio, M.; Iorio, P.D.; Caciagli, F.; Ciccarelli, R. The role of Wnt signal in glioblastoma development and progression: a possible new pharmacological target for the therapy of this tumor. Genes (Basel), 2018, 9(2), 105.
[http://dx.doi.org/10.3390/genes9020105] [PMID: 29462960]
[5]
Mecca, C.; Giambanco, I.; Donato, R.; Arcuri, C. Targeting mTOR in glioblastoma: rationale and preclinical/clinical evidence. Dis. Markers, 2018, 20189230479
[http://dx.doi.org/10.1155/2018/9230479] [PMID: 30662577]
[6]
Li, X.; Wu, C.; Chen, N.; Gu, H.; Yen, A.; Cao, L.; Wang, E.; Wang, L. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget, 2016, 7(22), 33440-33450.
[http://dx.doi.org/10.18632/oncotarget.7961] [PMID: 26967052]
[7]
Lee, C.Y. Strategies of temozolomide in future glioblastoma treatment. OncoTargets Ther., 2017, 10, 265-270.
[http://dx.doi.org/10.2147/OTT.S120662] [PMID: 28123308]
[8]
Hosseini, A.; Ghorbani, A. Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J. Phytomed., 2015, 5(2), 84-97.
[PMID: 25949949]
[9]
Mohtashami, L.; Ghows, N.; Tayarani-Najaran, Z.; Iranshahi, M. Galbanic Acid-Coated Fe3O4 Magnetic Nanoparticles with Enhanced Cytotoxicity to Prostate Cancer Cells. Planta Med., 2019, 85(2), 169-178.
[http://dx.doi.org/10.1055/a-0721-1886] [PMID: 30180257]
[10]
Kim, Y.H.; Shin, E.A.; Jung, J.H.; Park, J.E.; Koo, J.; Koo, J.I.; Shim, B.S.; Kim, S-H. Galbanic acid potentiates TRAIL induced apoptosis in resistant non-small cell lung cancer cells via inhibition of MDR1 and activation of caspases and DR5. Eur. J. Pharmacol., 2019, 847, 91-96.
[http://dx.doi.org/10.1016/j.ejphar.2019.01.028] [PMID: 30689998]
[11]
Afsharzadeh, M.; Abnous, K.; Yazdian-Robati, R.; Ataranzadeh, A.; Ramezani, M.; Hashemi, M. Formulation and evaluation of anticancer and antiangiogenesis efficiency of PLA-PEG nanoparticles loaded with galbanic acid in C26 colon carcinoma, in vitro and in vivo. J. Cell. Physiol., 2019, 234(5), 6099-6107.
[http://dx.doi.org/10.1002/jcp.27346] [PMID: 30378118]
[12]
Zhang, Y.; Kim, K.H.; Zhang, W.; Guo, Y.; Kim, S.H.; Lü, J. Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells. Int. J. Cancer, 2012, 130(1), 200-212.
[http://dx.doi.org/10.1002/ijc.25993] [PMID: 21328348]
[13]
Oh, B.S.; Shin, E.A.; Jung, J.H.; Jung, D.B.; Kim, B.; Shim, B.S.; Yazdi, M.C.; Iranshahi, M.; Kim, S.H. Apoptotic effect of galbanic acid via activation of caspases and inhibition of Mcl-1 in H460 non-small lung carcinoma cells. Phytother. Res., 2015, 29(6), 844-849.
[http://dx.doi.org/10.1002/ptr.5320] [PMID: 25753585]
[14]
Eskandani, M.; Abdolalizadeh, J.; Hamishehkar, H.; Nazemiyeh, H.; Barar, J. Galbanic acid inhibits HIF-1α expression via EGFR/HIF-1α pathway in cancer cells. Fitoterapia, 2015, 101, 1-11.
[http://dx.doi.org/10.1016/j.fitote.2014.12.003] [PMID: 25510323]
[15]
Zhang, Q.; Qiao, H.; Wu, D.; Lu, H.; Liu, L.; Sang, X.; Li, D.; Zhou, Y. Curcumin potentiates the galbanic acid-induced anti-tumor effect in non-small cell lung cancer cells through inhibiting Akt/mTOR signaling pathway. Life Sci., 2019, 239117044
[http://dx.doi.org/10.1016/j.lfs.2019.117044] [PMID: 31715187]
[16]
Dai, Z.; Wang, L.; Wang, X.; Zhao, B.; Zhao, W.; Bhardwaj, S.S.; Ye, J.; Yin, Z.; Zhang, J.; Zhao, S. Oxymatrine induces cell cycle arrest and apoptosis and suppresses the invasion of human glioblastoma cells through the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3. Oncol. Rep., 2018, 40(2), 867-876.
[http://dx.doi.org/10.3892/or.2018.6512] [PMID: 29989652]
[17]
Kim, K-H.; Lee, H-J.; Jeong, S-J.; Lee, H-J.; Lee, E-O.; Kim, H-S.; Zhang, Y.; Ryu, S-Y.; Lee, M-H.; Lü, J.; Kim, S.H. Galbanic acid isolated from Ferula assafoetida exerts in vivo anti-tumor activity in association with anti-angiogenesis and anti-proliferation. Pharm. Res., 2011, 28(3), 597-609.
[http://dx.doi.org/10.1007/s11095-010-0311-7] [PMID: 21063754]
[18]
Sajjadi, M.; Karimi, E.; Oskoueian, E.; Iranshahi, M.; Neamati, A. Galbanic acid: Induced antiproliferation in estrogen receptor-negative breast cancer cells and enhanced cellular redox state in the human dermal fibroblasts. J. Biochem. Mol. Toxicol., 2019, 33(11)e22402
[http://dx.doi.org/10.1002/jbt.22402] [PMID: 31576639]
[19]
O’Donnell, J.S.; Massi, D.; Teng, M.W.L.; Mandala, M. PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux. Semin. Cancer Biol., 2018, 48, 91-103.
[http://dx.doi.org/10.1016/j.semcancer.2017.04.015] [PMID: 28467889]
[20]
Zhang, K.; Zhu, S.; Liu, Y.; Dong, X.; Shi, Z.; Zhang, A.; Liu, C.; Chen, L.; Wei, J.; Pu, P.; Zhang, J.; Jiang, T.; Han, L.; Kang, C. ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/β-catenin activity. Cancer Lett., 2015, 357(1), 404-411.
[http://dx.doi.org/10.1016/j.canlet.2014.11.047] [PMID: 25434796]
[21]
Saxton, R.A.; Sabatini, D.M. mTOR signaling in growth, metabolism, and disease. Cell, 2017, 168(6), 960-976.
[http://dx.doi.org/10.1016/j.cell.2017.02.004] [PMID: 28283069]
[22]
Koul, D. PTEN signaling pathways in glioblastoma. Cancer Biol. Ther., 2008, 7(9), 1321-1325.
[http://dx.doi.org/10.4161/cbt.7.9.6954] [PMID: 18836294]
[23]
Smith, J.S.; Tachibana, I.; Passe, S.M.; Huntley, B.K.; Borell, T.J.; Iturria, N.; O’Fallon, J.R.; Schaefer, P.L.; Scheithauer, B.W.; James, C.D.; Buckner, J.C.; Jenkins, R.B. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl. Cancer Inst., 2001, 93(16), 1246-1256.
[http://dx.doi.org/10.1093/jnci/93.16.1246] [PMID: 11504770]
[24]
Paw, I.; Carpenter, R.C.; Watabe, K.; Debinski, W.; Lo, H-W. Mechanisms regulating glioma invasion. Cancer Lett., 2015, 362(1), 1-7.
[http://dx.doi.org/10.1016/j.canlet.2015.03.015] [PMID: 25796440]
[25]
Rao, J.S. Molecular mechanisms of glioma invasiveness: the role of proteases. Nat. Rev. Cancer, 2003, 3(7), 489-501.
[http://dx.doi.org/10.1038/nrc1121] [PMID: 12835669]

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