Deglucohellebrin: A Potent Agent for Glioblastoma Treatment

Author(s): Evrysthenis Vartholomatos, George A. Alexiou*, Georgios S. Markopoulos, Diamanto Lazari, Olga Tsiftsoglou, Ieremias Chousidis, Ioannis Leonardos, Athanasios P. Kyritsis

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 1 , 2020


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Graphical Abstract:


Abstract:

Background: Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis. To date, several anticancer agents have been isolated from plants. Helleborus odorus subsp. Cyclophyllus is an endemic plant of the Balcan flora. Herewith, we investigated for the first time, the anti-glioma effect of deglucohellebrin (DGH) extracted from the roots of Helleborus.

Methods: We investigated the effect of DGH in U251MG, T98G and U87G glioblastoma cell lines. We selected the T98G cells because of their inherent temozolomide resistance.

Results: The IC50 value of reduced viability for DGH was 7x10-5M in U251MG cells, 5x10-5M for the T98G cells and 4x10-5M in U87G cells during 72h treatment. DGH induced G2/M cell cycle arrest, caspace-8 activation and significant mitochondrial membrane depolarization, suggesting the activation of the intrinsic, mitochondrial- dependent apoptotic pathway. DGH and temozolomide induced changes in CDs’ expression in U251MG and T98G cells. In zebrafish, DGH did not induce toxicity or behavioral alterations.

Conclusion: The present study is the first to determine the anti-glioma activity of DGH. DGH may be a potent agent for glioblastoma treatment and further studies are needed.

Keywords: Glioblastoma, treatment, deglucohellebrin, zebrafish, prognosis, G2/M cell cycle arrest.

[1]
Liu, Y.; Shete, S.; Etzel, C.J.; Scheurer, M.; Alexiou, G.; Armstrong, G.; Tsavachidis, S.; Liang, F-W.; Gilbert, M.; Aldape, K.; Armstrong, T.; Houlston, R.; Hosking, F.; Robertson, L.; Xiao, Y.; Wiencke, J.; Wrensch, M.; Andersson, U.; Melin, B.S.; Bondy, M. Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival. J. Clin. Oncol., 2010, 28(14), 2467-2474.
[http://dx.doi.org/10.1200/JCO.2009.26.6213] [PMID: 20368557]
[2]
Verhaak, R.G.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; Alexe, G.; Lawrence, M.; O’Kelly, M.; Tamayo, P.; Weir, B.A.; Gabriel, S.; Winckler, W.; Gupta, S.; Jakkula, L.; Feiler, H.S.; Hodgson, J.G.; James, C.D.; Sarkaria, J.N.; Brennan, C.; Kahn, A.; Spellman, P.T.; Wilson, R.K.; Speed, T.P.; Gray, J.W.; Meyerson, M.; Getz, G.; Perou, C.M.; Hayes, D.N. Cancer Genome Atlas Research Network. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 2010, 17(1), 98-110.
[http://dx.doi.org/10.1016/j.ccr.2009.12.020] [PMID: 20129251]
[3]
Kyritsis, A.P.; Levin, V.A. An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting. Cancer Chemother. Pharmacol., 2011, 67(5), 971-983.
[http://dx.doi.org/10.1007/s00280-011-1617-9] [PMID: 21442438]
[4]
Levin, V.A. Personalized medicine in neuro-oncology. CNS Oncol., 2016, 5(2), 55-58.
[http://dx.doi.org/10.2217/cns-2016-0006]
[5]
Ouyang, L.; Luo, Y.; Tian, M.; Zhang, S.Y.; Lu, R.; Wang, J.H.; Kasimu, R.; Li, X. Plant natural products: from traditional compounds to new emerging drugs in cancer therapy. Cell Prolif., 2014, 47(6), 506-515.
[http://dx.doi.org/10.1111/cpr.12143] [PMID: 25377084]
[6]
Lazari, D.; Alexiou, G.A.; Markopoulos, G.S.; Vartholomatos, E.; Hodaj, E.; Chousidis, I.; Leonardos, I.; Galani, V.; Kyritsis, A.P.N. N-(p-coumaroyl) serotonin inhibits glioblastoma cells growth through triggering S-phase arrest and apoptosis. J. Neurooncol., 2017, 132(3), 373-381.
[http://dx.doi.org/10.1007/s11060-017-2382-3] [PMID: 28365838]
[7]
Martucciello, S.; Paolella, G.; Muzashvili, T.; Skhirtladze, A.; Pizza, C.; Caputo, I.; Piacente, S. Steroids from Helleborus caucasicus reduce cancer cell viability inducing apoptosis and GRP78 down-regulation. Chem. Biol. Interact., 2018, 279, 43-50.
[http://dx.doi.org/10.1016/j.cbi.2017.11.002] [PMID: 29126784]
[8]
Maior, M.C.; Dobrotă, C. Natural compounds with important medical potential found in Helleborus sp. Cent. Eur. J. Biol., 2013, 8(3), 272-285.
[9]
Gao, H.; Popescu, R.; Kopp, B.; Wang, Z. Bufadienolides and their antitumor activity. Nat. Prod. Rep., 2011, 28(5), 953-969.
[http://dx.doi.org/10.1039/c0np00032a] [PMID: 21416078]
[10]
Watanabe, K.; Mimaki, Y.; Sakagami, H.; Sashida, Y. Bufadienolide and spirostanol glycosides from the rhizomes of helleborusorientalis. J. Nat. Prod., 2003, 66(2), 236-241.
[http://dx.doi.org/10.1021/np0203638] [PMID: 12608856]
[11]
Tsiftsoglou, O.S.; Stefanakis, M.K.; Lazari, D.M. Chemical constituents isolated from the rhizomes of Helleborus odorus subsp. cyclophyllus (Ranunculaceae). Biochem. Syst. Ecol., 2018, 79, 8-11.
[http://dx.doi.org/10.1016/j.bse.2018.04.010]
[12]
Alexiou, G.A.; Lazari, D.; Markopoulos, G.; Vartholomatos, E.; Hodaj, E.; Galani, V.; Kyritsis, A.P. Moschamine inhibits proliferation of glioblastoma cells via cell cycle arrest and apoptosis. Tumour Biol., 2017, 39(5)1010428317705744
[http://dx.doi.org/10.1177/1010428317705744] [PMID: 28475011]
[13]
Test No. 236: Fish Embryo Acute Toxicity (FET) Test. Available at:
[http://dx.doi.org/10.1787/9789264203709-en.]
[14]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[15]
Adams, M.; Alther, W.; Kessler, M.; Kluge, M.; Hamburger, M. Malaria in the Renaissance: remedies from European herbals from the 16th and 17th century. J. Ethnopharmacol., 2011, 133(2), 278-288.
[http://dx.doi.org/10.1016/j.jep.2010.10.060] [PMID: 21056649]
[16]
True, B-L.; Dreisbach, R.H. Handbook of poisoning: Prevention, diagnosis, and treatment, 13th ed; Parthenon Pub. Group: Pearl River, N.Y., 2001, p. viii.
[http://dx.doi.org/10.1201/b14640.]
[17]
Fan, C.H.; Liu, W.L.; Cao, H.; Wen, C.; Chen, L.; Jiang, G. O6-methylguanine DNA methyltransferase as a promising target for the treatment of temozolomide-resistant gliomas. Cell Death Dis., 2013, 4(10)e876
[http://dx.doi.org/10.1038/cddis.2013.388] [PMID: 24157870]
[18]
Deng, J.; Gao, G.; Wang, L.; Wang, T.; Yu, J.; Zhao, Z. CD24 expression as a marker for predicting clinical outcome in human gliomas. J. Biomed. Biotechnol., 2012, 2012517172
[http://dx.doi.org/10.1155/2012/517172]
[19]
Jackson, M.; Hassiotou, F.; Nowak, A. Glioblastoma stem-like cells: at the root of tumor recurrence and a therapeutic target. Carcinogenesis, 2015, 36(2), 177-185.
[http://dx.doi.org/10.1093/carcin/bgu243] [PMID: 25504149]
[20]
Neradil, J.; Veselska, R. Nestin as a marker of cancer stem cells. Cancer Sci., 2015, 106(7), 803-811.
[http://dx.doi.org/10.1111/cas.12691] [PMID: 25940879]
[21]
Reifenberger, G.; Sieth, P.; Niederhaus, M.; Wechsler, W. Expression of CD15 in tumours of the nervous system. Histochem. J., 1992, 24(11), 890-901.
[http://dx.doi.org/10.1007/BF01046360] [PMID: 1362199]
[22]
Goodman, L.D.; Gao, F.; Gumin, J.; Villareal, D.; Ezhilarasan, R.; Love, P.; Colman, H.; Lang, F.F.; Aldape, K.D.; Sulman, E.P. Refinement of the glioma cancer stem cell marker profile In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; Washington, DC, USA Apr 17-21, 2010.
[23]
Todaro, L.; Christiansen, S.; Varela, M.; Campodónico, P.; Pallotta, M.G.; Lastiri, J.; Sacerdote de Lustig, E.; Bal de Kier Joffé, E.; Puricelli, L. Alteration of serum and tumoral neural cell adhesion molecule (NCAM) isoforms in patients with brain tumors. J. Neurooncol., 2007, 83(2), 135-144.
[http://dx.doi.org/10.1007/s11060-006-9312-0] [PMID: 17216340]
[24]
Mäenpää, A.; Kovanen, P.E.; Paetau, A.; Jäáskeläinen, J.; Timonen, T. Lymphocyte adhesion molecule ligands and extracellular matrix proteins in gliomas and normal brain: expression of VCAM-1 in gliomas. Acta Neuropathol., 1997, 94(3), 216-225.
[http://dx.doi.org/10.1007/s004010050696] [PMID: 9292690]
[25]
Choudhary, D.; Hegde, P.; Voznesensky, O.; Choudhary, S.; Kopsiaftis, S.; Claffey, K.P.; Pilbeam, C.C.; Taylor, J.A., III Increased expression of L-selectin (CD62L) in high-grade urothelial carcinoma:A potential marker for metastatic disease. Urol. Oncol.,, 2015, 33(9), 387.e17-27.
[http://dx.doi.org/10.1016/j.urolonc.2014.12.009] [PMID: PMC4510033]
[26]
Barani, I.J.; Larson, D.A. Radiation therapy of glioblastoma. Cancer Treat. Res., 2015, 163, 49-73.


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Article Details

VOLUME: 20
ISSUE: 1
Year: 2020
Page: [103 - 110]
Pages: 8
DOI: 10.2174/1871520619666191121110848
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