Potential Anticancer Effect of Carvacrol Codrugs on Human Glioblastoma Cells

Author(s): Ayşenur Yazici, Lisa Marinelli, Ivana Cacciatore, Bugrahan Emsen*, Piera Eusepi, Giuseppe Di Biase, Antonio Di Stefano, Adil Mardinoğlu, Hasan Türkez

Journal Name: Current Drug Delivery

Volume 18 , Issue 3 , 2021

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Graphical Abstract:


Background: Essential oils are considered as promising sources of novel anticancer compounds. Carvacrol (CVC), the major constituent of many aromatic plants including oregano and thymus, is endowed with curative properties on different cancers, including liver, colon, and lung. Little information is available regarding the potential of CVC for the treatment of brain cancers, notably Glioblastoma Multiforme (GBM).

Objective: In this work, we investigated the in vitro effect of CVC codrugs (CVC1-8), synthesized by direct-coupled co-drug strategies, on human glioblastoma cell line (U87-MG) for the first time.

Methods: Cell viability was detected by MTT and LDH assays while expression levels of important genes (such as EGFR, NFKB1A, AKT1, AKT2, and others) associated with GBM and inflammatory pathways were detected by PCR array.

Results: Results showed that CVC1-8 codrugs induced cytotoxicity and positive alterations in molecular responses on U87MG cells. Particularly, important pathways (such as PI3K/PTEN/AKT) involved in the onset and progression of GBM resulted in modulation by CVC3 and CVC8.

Conclusion: Our results suggest that CVC3 and CVC8 could be suitable candidates for further investigation to develop new strategies for the prevention and/or treatment of GBM.

Keywords: Anti-proliferative action, codrug strategy, carvacrol codrug, glioblastoma multiforme, gene expression.

Davis, M.E. Glioblastoma: overview of disease and treatment. Clin. J. Oncol. Nurs., 2016, 20(Suppl. 5), S2-S8.
[http://dx.doi.org/10.1188/16.CJON.S1.2-8] [PMID: 27668386]
Shah, U.; Morrison, T. A review of the symptomatic management of malignant gliomas in adults. J. Natl. Compr. Canc. Netw., 2013, 11(4), 424-429.
[http://dx.doi.org/10.6004/jnccn.2013.0057] [PMID: 23584345]
Young, R.M.; Jamshidi, A.; Davis, G.; Sherman, J.H. Current trends in the surgical management and treatment of adult glioblastoma. Ann. Transl. Med., 2015, 3(9), 121.
[PMID: 26207249]
Mehner, M.; Kubelt, C.; Adamski, V.; Schmitt, C.; Synowitz, M.; Held-Feindt, J. Combined treatment of AT101 and demethoxycurcumin yields an enhanced anti-proliferative effect in human primary glioblastoma cells. J. Cancer Res. Clin. Oncol., 2020, 146(1), 117-126.
[http://dx.doi.org/10.1007/s00432-019-03107-7] [PMID: 31844979]
Crespo, I.; Vital, A.L.; Gonzalez-Tablas, M. Patino, Mdel.C.; Otero, A.; Lopes, M.C.; de Oliveira, C.; Domingues, P.; Orfao, A.; Tabernero, M.D. Molecular and genomic alterations in glioblastoma multiforme. Am. J. Pathol., 2015, 185(7), 1820-1833.
[http://dx.doi.org/10.1016/j.ajpath.2015.02.023] [PMID: 25976245]
Ngo, T.; Corrales, A.; Bourne, T.; Elmojahid, S.; Lam, K.S.; Díaz, E. Alternative splicing of MXD3 and its regulation of MXD3 levels in glioblastoma. Front. Mol. Biosci., 2019, 6, 5.
[http://dx.doi.org/10.3389/fmolb.2019.00005] [PMID: 30838212]
Muñoz-Hidalgo, L.; San-Miguel, T.; Megías, J.; Monleón, D.; Navarro, L.; Roldán, P.; Cerdá-Nicolás, M.; López-Ginés, C. Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma. Neoplasia, 2020, 22(1), 10-21.
[http://dx.doi.org/10.1016/j.neo.2019.09.001] [PMID: 31751860]
Lesgards, J-F.; Baldovini, N.; Vidal, N.; Pietri, S. Anticancer activities of essential oils constituents and synergy with conventional therapies: a review. Phytother. Res., 2014, 28(10), 1423-1446.
[http://dx.doi.org/10.1002/ptr.5165] [PMID: 24831562]
Bhalla, Y.; Gupta, V.K.; Jaitak, V. Anticancer activity of essential oils: a review. J. Sci. Food Agric., 2013, 93(15), 3643-3653.
[http://dx.doi.org/10.1002/jsfa.6267] [PMID: 23765679]
Baser, K.H.C. Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils. Curr. Pharm. Des., 2008, 14(29), 3106-3119.
[http://dx.doi.org/10.2174/138161208786404227] [PMID: 19075694]
Arunasree, K.M. Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231. Phytomedicine, 2010, 17(8-9), 581-588.
[http://dx.doi.org/10.1016/j.phymed.2009.12.008] [PMID: 20096548]
Makrane, H.; El Messaoudi, M.; Melhaoui, A.; El Mzibri, M.; Benbacer, L.; Aziz, M. Cytotoxicity of the aqueous extract and organic fractions from Origanum majorana on human breast cell line MDA-MB-231 and human colon cell line HT-29. Adv. Pharmacol. Sci., 2018, 2018, 3297193.
[http://dx.doi.org/10.1155/2018/3297193] [PMID: 30210537]
Slamenová, D.; Horváthová, E.; Sramková, M.; Marsálková, L. DNA-protective effects of two components of essential plant oils carvacrol and thymol on mammalian cells cultured in vitro . Neoplasma, 2007, 54(2), 108-112.
[PMID: 17319782]
Liang, W.Z.; Lu, C.H. Carvacrol-induced [Ca2+]i rise and apoptosis in human glioblastoma cells. Life Sci., 2012, 90(17-18), 703-711.
[http://dx.doi.org/10.1016/j.lfs.2012.03.027] [PMID: 22480511]
Ashraf, Z.; Rafiq, M.; Nadeem, H.; Hassan, M.; Afzal, S.; Waseem, M.; Afzal, K.; Latip, J. Carvacrol derivatives as mushroom tyrosinase inhibitors; synthesis, kinetics mechanism and molecular docking studies. PLoS One, 2017, 12(5), e0178069.
[http://dx.doi.org/10.1371/journal.pone.0178069] [PMID: 28542395]
Marinelli, L.; Di Stefano, A.; Cacciatore, I. Carvacrol and its derivatives as antibacterial agents. Phytochem. Rev., 2018, 17, 903-921.
Spalletta, S.; Flati, V.; Toniato, E.; Di Gregorio, J.; Marino, A.; Pierdomenico, L.; Marchisio, M.; D’Orazi, G.; Cacciatore, I.; Robuffo, I. Carvacrol reduces adipogenic differentiation by modulating autophagy and ChREBP expression. PLoS One, 2018, 13(11), e0206894.
[http://dx.doi.org/10.1371/journal.pone.0206894] [PMID: 30418986]
Cacciatore, I.; Di Giulio, M.; Fornasari, E.; Di Stefano, A.; Cerasa, L.S.; Marinelli, L.; Turkez, H.; Di Campli, E.; Di Bartolomeo, S.; Robuffo, I.; Cellini, L.; Cellini, L. Carvacrol codrugs: a new approach in the antimicrobial plan. PLoS One, 2015, 10(4), e0120937.
[http://dx.doi.org/10.1371/journal.pone.0120937] [PMID: 25859852]
Turkez, H.; Nóbrega, F.R.D.; Ozdemir, O.; Bezerra Filho, C.D.S.M.; Almeida, R.N.; Tejera, E.; Perez-Castillo, Y.; Sousa, D.P. NFBTA: a potent cytotoxic agent against glioblastoma. Molecules, 2019, 24(13), 2411.
[http://dx.doi.org/10.3390/molecules24132411] [PMID: 31261921]
Emsen, B.; Aslan, A.; Turkez, H.; Joughi, A.; Kaya, A. The anti- cancer efficacies of diffractaic, lobaric, and usnic acid: in vitro inhibition of glioma. J. Cancer Res. Ther., 2018, 14(5), 941-951.
[http://dx.doi.org/10.4103/0973-1482.177218] [PMID: 30197329]
Cacciatore, I.; Fornasari, E.; Marinelli, L.; Eusepi, P.; Ciulla, M.; Ozdemir, O.; Tatar, A.; Turkez, H.; Di Stefano, A. Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma. Eur. J. Pharm. Sci., 2017, 109, 402-411.
[http://dx.doi.org/10.1016/j.ejps.2017.08.030] [PMID: 28860082]
Turkez, H.; Tozlu, O.O.; Lima, T.C.; de Brito, A.E.M.; de Sousa, D.P. A comparative evaluation of the cytotoxic and antioxidant activity of Mentha crispa essential oil, its major constituent rotundifolone, and analogues on human glioblastoma. Oxid. Med. Cell. Longev., 2018, 2018, 2083923.
[http://dx.doi.org/10.1155/2018/2083923] [PMID: 30057673]
Cacciatore, I.; Fornasari, E.; Di Stefano, A.; Marinelli, L.; Cerasa, L.S.; Turkez, H.; Aydin, E.; Moretto, A.; Ferrone, A.; Pesce, M.; di Giacomo, V.; Reale, M.; Costantini, E.; Di Giovanni, P.; Speranza, L.; Felaco, M.; Patruno, A. Development of glycine-α-methyl-proline-containing tripeptides with neuroprotective properties. Eur. J. Med. Chem., 2016, 108, 553-563.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.003] [PMID: 26717205]
Ahmadi-Beni, R.; Khoshnevisan, A. An overview of crucial genes involved in stemness of glioblastoma multiforme. Neurochem. J., 2017, 11, 259-265.
Suntres, Z.E.; Coccimiglio, J.; Alipour, M. The bioactivity and toxicological actions of carvacrol. Crit. Rev. Food Sci. Nutr., 2015, 55(3), 304-318.
[http://dx.doi.org/10.1080/10408398.2011.653458] [PMID: 24915411]
Aydın, E.; Türkez, H.; Keleş, M.S. The effect of carvacrol on healthy neurons and N2a cancer cells: some biochemical, anticancerogenicity and genotoxicity studies. Cytotechnology, 2014, 66(1), 149-157.
[http://dx.doi.org/10.1007/s10616-013-9547-5] [PMID: 23553016]
Luo, Y.; Wu, J-Y.; Lu, M-H.; Shi, Z.; Na, N.; Di, J-M. Carvacrol alleviates prostate cancer cell proliferation, migration, and invasion through regulation of PI3K/Akt and MAPK signaling pathways. Oxid. Med. Cell. Longev., 2016, 2016, 1469693.
[http://dx.doi.org/10.1155/2016/1469693] [PMID: 27803760]
Yin, Q.H.; Yan, F.X.; Zu, X.Y.; Wu, Y.H.; Wu, X.P.; Liao, M.C.; Deng, S.W.; Yin, L.L.; Zhuang, Y.Z. Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2. Cytotechnology, 2012, 64(1), 43-51.
[http://dx.doi.org/10.1007/s10616-011-9389-y] [PMID: 21938469]
Li, Z.; Zhao, X.; Huang, C.; Gong, X. Recent advances in green fabrication of luminescent solar concentrators using nontoxic quantum dots as fluorophores. J. Mater. Chem. C Mater. Opt. Electron. Devices, 2019, 7, 12373-12387.
Peng, J.; Zhao, X.; Wang, W.; Gong, X. Durable self-cleaning surfaces with superhydrophobic and highly oleophobic properties. Langmuir, 2019, 35(25), 8404-8412.
[http://dx.doi.org/10.1021/acs.langmuir.9b01507] [PMID: 31192609]
Liang, J.; Huang, C.; Gong, X. Silicon nanocrystals and their composites: syntheses, fluorescence mechanisms, and biological applications. ACS Sustain. Chem.& Eng., 2019, 7, 18213-18227.
Hede, S.M.; Nazarenko, I.; Nistér, M.; Lindström, M.S. Novel perspectives on p53 function in neural stem cells and brain tumors. J. Oncol., 2011, 2011, 852970.
[http://dx.doi.org/10.1155/2011/852970] [PMID: 21209724]
Wen, P.Y.; Lee, E.Q.; Reardon, D.A.; Ligon, K.L.; Alfred, Y.W.K. Current clinical development of PI3K pathway inhibitors in glioblastoma. Neuro-oncol., 2012, 14(7), 819-829.
[http://dx.doi.org/10.1093/neuonc/nos117] [PMID: 22619466]
Omuro, A.M.P.; Faivre, S.; Raymond, E. Lessons learned in the development of targeted therapy for malignant gliomas. Mol. Cancer Ther., 2007, 6(7), 1909-1919.
[http://dx.doi.org/10.1158/1535-7163.MCT-07-0047] [PMID: 17620423]
Turner, K.M.; Sun, Y.; Ji, P.; Granberg, K.J.; Bernard, B.; Hu, L.; Cogdell, D.E.; Zhou, X.; Yli-Harja, O.; Nykter, M.; Shmulevich, I.; Yung, W.K.; Fuller, G.N.; Zhang, W. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. Proc. Natl. Acad. Sci. USA, 2015, 112(11), 3421-3426.
[http://dx.doi.org/10.1073/pnas.1414573112] [PMID: 25737557]
Chen, R.Q.; Xu, X.H.; Liu, F.; Li, C.Y.; Li, Y.J.; Li, X.R.; Jiang, G.Y.; Hu, F.; Liu, D.; Pan, F.; Qiu, X.Y.; Chen, X.Q. The binding of PD-L1 and Akt facilitates glioma cell invasion upon starvation via Akt/autophagy/F-actin signaling. Front. Oncol., 2019, 9, 1347.
[http://dx.doi.org/10.3389/fonc.2019.01347] [PMID: 31850228]
Lu, X.; Xue, B.; Zhang, T.; Zhou, X.; Zhang, Y. Down-regulation of microRNA-10a mediates the anti-tumor effect of icaritin in A549 cells via the PTEN/AKT and ERK pathway. Gen. Physiol. Biophys., 2019, 38(6), 525-533.
[http://dx.doi.org/10.4149/gpb_2019041] [PMID: 31829310]
Han, F.; Hu, R.; Yang, H.; Liu, J.; Sui, J.; Xiang, X.; Wang, F.; Chu, L.; Song, S. PTEN gene mutations correlate to poor prognosis in glioma patients: a meta-analysis. OncoTargets Ther., 2016, 9, 3485-3492.
[PMID: 27366085]
Majewska, E.; Szeliga, M. AKT/GSK3β signaling in glioblastoma. Neurochem. Res., 2017, 42(3), 918-924.
[http://dx.doi.org/10.1007/s11064-016-2044-4] [PMID: 27568206]
Tao, T.; Lu, X.; Yao, L.; Wang, J.; Shi, Y.; Luo, H.; Liu, N.; You, Y. [Expression of FOS protein in glioma and its effect on the growth of human glioma cells]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013, 30(3), 293-296.
Dörsam, B.; Fahrer, J. The disulfide compound α-lipoic acid and its derivatives: a novel class of anticancer agents targeting mitochondria. Cancer Lett., 2016, 371(1), 12-19.
[http://dx.doi.org/10.1016/j.canlet.2015.11.019] [PMID: 26604131]
Saha, S.K.; Lee, S.B.; Won, J.; Choi, H.Y.; Kim, K.; Yang, G-M.; Dayem, A.A.; Cho, S-G. Correlation between oxidative stress, nutrition, and cancer initiation. Int. J. Mol. Sci., 2017, 18(7), 1544.
[http://dx.doi.org/10.3390/ijms18071544] [PMID: 28714931]
Perri, M.; Aiello, F.; Cione, E.; Carullo, G.; Amendola, L.; Mazzotta, S.; Caroleo, M.C. Investigation of TNBC in vitro antiproliferative effects of versatile pirrolo[1,2-a]quinoxaline compounds. Front. Mol. Biosci., 2019, 6, 12.
[http://dx.doi.org/10.3389/fmolb.2019.00012] [PMID: 30915341]

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Article Details

Year: 2021
Published on: 27 October, 2020
Page: [350 - 356]
Pages: 7
DOI: 10.2174/1567201817666201027123424
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