Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Anti-tumoral Effect of Thymelaea hirsuta L. Extracts in Colorectal Cancer Cells

Author(s): Iheb Toumi, Sonia Yatouji, Nicolas Borie, Simon Remy, Jean-Hugues Renault, Lise Chazee, Mohamed Hammami, Laurent Martiny, Emmanuelle Devarenne-Charpentier and Hassan El Btaouri*

Volume 23, Issue 6, 2023

Published on: 29 September, 2022

Page: [687 - 698] Pages: 12

DOI: 10.2174/1871520622666220826095035

Price: $65

Abstract

Background: Conventional chemotherapeutic treatment of colorectal cancer has low efficiency because of its high toxicity. Several studies identified natural compounds as potential antitumor agents by inducing cancer cell cycle arrest or apoptosis and exhibiting a potential synergy in drug combination therapy. Natural compounds derived from plants represent an important source of pharmacologic agents toward several diseases. For example, the Tunisian Thymelaeaceae plants are used in folk medicine for the treatment of different pathologies such as diabetes and hypertension.

Objective: The Thymelaea hirsuta L. extracts were evaluated for their anti-tumoral activities and their adjuvant potential that could be used in conventional colorectal cancer therapy.

Methods: Fractionation of total methanolic extract from the plant leaves provided 4 fractions using vacuum liquid chromatography. The cytotoxic activities of these fractions were tested toward colorectal cancer cells.

Results: Ethyl acetate fraction (E2 fraction) induced cell cycle arrest and apoptosis by activating caspase-3. E2 fraction inhibited cell invasion by reducing integrin α5 expression and FAK phosphorylation. Moreover, E2 fraction potentialized colorectal cancer cells to 5-FU treatment.

Conclusion: The selected plant Thymelaea hirsuta is the source of natural compounds that inhibited cell growth and invasion and induced cell cycle arrest in colorectal cancer cells. The most interesting result was their potential synergy in 5-FU combination treatment. Further analysis will identify the active compounds and confirm their role in chemotherapeutic treatment by sensitizing colorectal cancer cell to anti-cancer drugs.

Keywords: Thymelaea hirsuta, natural compounds, colorectal cancer cells, 5-Fluorouracil, apoptosis, cell cycle arrest.

[1]
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer, 2019, 144(8), 1941-1953.
[http://dx.doi.org/10.1002/ijc.31937] [PMID: 30350310]
[2]
Lichtenstein, P.; Holm, N.V.; Verkasalo, P.K.; Iliadou, A.; Kaprio, J.; Koskenvuo, M.; Pukkala, E.; Skytthe, A.; Hemminki, K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med., 2000, 343(2), 78-85.
[http://dx.doi.org/10.1056/NEJM200007133430201] [PMID: 10891514]
[3]
de Gramont, A.; Figer, A.; Seymour, M.; Homerin, M.; Hmissi, A.; Cassidy, J.; Boni, C.; Cortes-Funes, H.; Cervantes, A.; Freyer, G.; Papamichael, D.; Le Bail, N.; Louvet, C.; Hendler, D.; de Braud, F.; Wilson, C.; Morvan, F.; Bonetti, A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J. Clin. Oncol., 2000, 18(16), 2938-2947.
[http://dx.doi.org/10.1200/JCO.2000.18.16.2938] [PMID: 10944126]
[4]
Douillard, J.Y.; Cunningham, D.; Roth, A.D.; Navarro, M.; James, R.D.; Karasek, P.; Jandik, P.; Iveson, T.; Carmichael, J.; Alakl, M.; Gruia, G.; Awad, L.; Rougier, P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet, 2000, 355(9209), 1041-1047.
[http://dx.doi.org/10.1016/S0140-6736(00)02034-1] [PMID: 10744089]
[5]
Lin, S.R.; Fu, Y.S.; Tsai, M.J.; Cheng, H.; Weng, C.F. Natural compounds from herbs that can potentially execute as autophagy inducers for cancer therapy. Int. J. Mol. Sci., 2017, 18(7), 1412.
[http://dx.doi.org/10.3390/ijms18071412] [PMID: 28671583]
[6]
Kim, W.; Lee, W.B.; Lee, J.; Min, B.I.; Lee, H.; Cho, S.H. Traditional herbal medicine as adjunctive therapy for nasopharyngeal cancer: A systematic review and meta-analysis. Integr. Cancer Ther., 2015, 14(3), 212-220.
[http://dx.doi.org/10.1177/1534735415572881] [PMID: 25698710]
[7]
Kim, W.; Lee, W.B.; Lee, J.W.; Min, B.I.; Baek, S.K.; Lee, H.S.; Cho, S.H. Traditional herbal medicine as adjunctive therapy for breast cancer: A systematic review. Complement. Ther. Med., 2015, 23(4), 626-632.
[http://dx.doi.org/10.1016/j.ctim.2015.03.011] [PMID: 26275657]
[8]
Kuo, Y.T.; Liao, H.H.; Chiang, J.H.; Wu, M.Y.; Chen, B.C.; Chang, C.M.; Yeh, M.H.; Chang, T.T.; Sun, M.F.; Yeh, C.C.; Yen, H.R. Complementary Chinese herbal medicine therapy improves survival of patients with pancreatic cancer in Taiwan: A nationwide population-based cohort study. Integr. Cancer Ther., 2018, 17(2), 411-422.
[http://dx.doi.org/10.1177/1534735417722224] [PMID: 28774207]
[9]
Amari, N.O.; Bouzouina, M.; Berkani, A.; Lotmani, B. Phytochemical screening and antioxidant capacity of the aerial parts of Thymelaea hirsuta L. Asian Pac. J. Trop. Dis., 2014, 4(2), 104-109.
[http://dx.doi.org/10.1016/S2222-1808(14)60324-8]
[10]
Sanna, G.; Madeddu, S.; Murgia, G.; Serreli, G.; Begala, M.; Caboni, P.; Incani, A.; Franci, G.; Galdiero, M.; Giliberti, G. Potent and selective activity against human immunodeficiency virus 1 (HIV-1) of Thymelaea hirsuta extracts. Viruses, 2020, 12(6), 664.
[http://dx.doi.org/10.3390/v12060664] [PMID: 32575585]
[11]
Djeridane, A.; Yousfi, M.; Nadjemi, B.; Maamri, S.; Djireb, F.; Stocker, P. Phenolic extracts from various Algerian plants as strong inhibitors of porcine liver carboxylesterase. J. Enzyme Inhib. Med. Chem., 2006, 21(6), 719-726.
[http://dx.doi.org/10.1080/14756360600810399] [PMID: 17252945]
[12]
Bnouham, M.; Benalla, W.; Bellahcen, S.; Hakkou, Z.; Ziyyat, A.; Mekhfi, H.; Aziz, M.; Legssyer, A. Antidiabetic and antihypertensive effect of a polyphenol-rich fraction of Thymelaea hirsuta L. in a model of neonatal streptozotocin-diabetic and NG -nitro-l-arginine methyl ester-hypertensive rats. J. Diabetes, 2012, 4(3), 307-313.
[http://dx.doi.org/10.1111/j.1753-0407.2012.00202.x] [PMID: 22519949]
[13]
Badawy, A.; Hassanean, H.; Ibrahim, A.K.; Habib, E.S.; El-Magd, M.A.; Ahmed, S.A. Isolates from Thymelaea hirsuta inhibit progression of hepatocellular carcinoma in vitro and in vivo. Nat. Prod. Res., 2021, 35(11), 1799-1807.
[http://dx.doi.org/10.1080/14786419.2019.1643859] [PMID: 31315443]
[14]
Qasem, H.A.; Aouad, M.R.; Al-Abdulkarim, H.A.; Al-Farraj, E.S.; Attar, R.M.S.; El-Metwaly, N.M.; Abu-Dief, A.M. Tailoring of some novel bis-hydrazone metal chelates, spectral based characterization and DFT calculations for pharmaceutical applications and in-silico treatments for verification. J. Mol. Struct., 2022, 1264, 133263.
[http://dx.doi.org/10.1016/j.molstruc.2022.133263]
[15]
El-Lateef, H.; Khalaf, M.; Shehata, M.; Abu-Dief, A.; Fabrication, D.F.T. Fabrication, DFT calculation, and molecular docking of two Fe(III) imine chelates as anti-COVID-19 and pharmaceutical drug candidate. Int. J. Mol. Sci., 2022, 23(7), 3994.
[http://dx.doi.org/10.3390/ijms23073994] [PMID: 35409353]
[16]
Chambers, M.C.; Maclean, B.; Burke, R.; Amodei, D.; Ruderman, D.L.; Neumann, S.; Gatto, L.; Fischer, B.; Pratt, B.; Egertson, J.; Hoff, K.; Kessner, D.; Tasman, N.; Shulman, N.; Frewen, B.; Baker, T.A.; Brusniak, M.Y.; Paulse, C.; Creasy, D.; Flashner, L.; Kani, K.; Moulding, C.; Seymour, S.L.; Nuwaysir, L.M.; Lefebvre, B.; Kuhlmann, F.; Roark, J.; Rainer, P.; Detlev, S.; Hemenway, T.; Huhmer, A.; Langridge, J.; Connolly, B.; Chadick, T.; Holly, K.; Eckels, J.; Deutsch, E.W.; Moritz, R.L.; Katz, J.E.; Agus, D.B.; MacCoss, M.; Tabb, D.L.; Mallick, P. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol., 2012, 30(10), 918-920.
[http://dx.doi.org/10.1038/nbt.2377] [PMID: 23051804]
[17]
Dührkop, K.; Fleischauer, M.; Ludwig, M.; Aksenov, A.A.; Melnik, A.V.; Meusel, M.; Dorrestein, P.C.; Rousu, J.; Böcker, S. SIRIUS 4: A rapid tool for turning tandem mass spectra into metabolite structure information. Nat. Methods, 2019, 16(4), 299-302.
[http://dx.doi.org/10.1038/s41592-019-0344-8] [PMID: 30886413]
[18]
Dührkop, K.; Shen, H.; Meusel, M.; Rousu, J.; Böcker, S. Searching molecular structure databases with tandem mass spectra using CSI:FingerID. Proc. Natl. Acad. Sci. USA, 2015, 112(41), 12580-12585.
[http://dx.doi.org/10.1073/pnas.1509788112] [PMID: 26392543]
[19]
Brábek, J.; Mierke, C.T.; Rösel, D.; Veselý, P.; Fabry, B. The role of the tissue microenvironment in the regulation of cancer cell motility and invasion. Cell Commun. Signal., 2010, 8(1), 22.
[http://dx.doi.org/10.1186/1478-811X-8-22] [PMID: 20822526]
[20]
McLean, G.W.; Carragher, N.O.; Avizienyte, E.; Evans, J.; Brunton, V.G.; Frame, M.C. The role of focal-adhesion kinase in cancer-A new therapeutic opportunity. Nat. Rev. Cancer, 2005, 5(7), 505-515.
[http://dx.doi.org/10.1038/nrc1647] [PMID: 16069815]
[21]
Mitra, S.K.; Schlaepfer, D.D. Integrin-regulated FAK–Src signaling in normal and cancer cells. Curr. Opin. Cell Biol., 2006, 18(5), 516-523.
[http://dx.doi.org/10.1016/j.ceb.2006.08.011] [PMID: 16919435]
[22]
Mitra, A.K.; Sawada, K.; Tiwari, P.; Mui, K.; Gwin, K.; Lengyel, E. Ligand-independent activation of c-Met by fibronectin and α5β1-integrin regulates ovarian cancer invasion and metastasis. Oncogene, 2011, 30(13), 1566-1576.
[http://dx.doi.org/10.1038/onc.2010.532] [PMID: 21119598]
[23]
Gerber, D.E. Targeted therapies: A new generation of cancer treatments. Am. Fam. Physician, 2008, 77(3), 311-319.
[PMID: 18297955]
[24]
Pardini, B.; Kumar, R.; Naccarati, A.; Novotny, J.; Prasad, R.B.; Forsti, A.; Hemminki, K.; Vodicka, P.; Lorenzo Bermejo, J. 5-Fluorouracil-based chemotherapy for colorectal cancer and MTHFR/MTRR genotypes. Br. J. Clin. Pharmacol., 2011, 72(1), 162-163.
[http://dx.doi.org/10.1111/j.1365-2125.2010.03892.x] [PMID: 21204909]
[25]
Assed Bastos, D.; Coelho Ribeiro, S.; de Freitas, D.; Hoff, P.M. Review: Combination therapy in high-risk stage II or stage III colon cancer: Current practice and future prospects. Ther. Adv. Med. Oncol., 2010, 2(4), 261-272.
[http://dx.doi.org/10.1177/1758834010367905] [PMID: 21789139]
[26]
Pratheeshkumar, P.; Sreekala, C.; Zhang, Z.; Budhraja, A.; Ding, S.; Son, Y.O.; Wang, X.; Hitron, A.; Hyun-Jung, K.; Wang, L.; Lee, J.C.; Shi, X. Cancer prevention with promising natural products: Mechanisms of action and molecular targets. Anticancer. Agents Med. Chem., 2012, 12(10), 1159-1184.
[http://dx.doi.org/10.2174/187152012803833035] [PMID: 22583402]
[27]
Sun, L.; Zhou, W.; Zhang, H.; Guo, Q.; Yang, W.; Li, B.; Sun, Z.; Gao, S.; Cui, R. Modulation of multiple signaling pathways of the plant-derived natural products in cancer. Front. Oncol., 2019, 9, 1153.
[http://dx.doi.org/10.3389/fonc.2019.01153] [PMID: 31781485]
[28]
Thomford, N.; Senthebane, D.; Rowe, A.; Munro, D.; Seele, P.; Maroyi, A.; Dzobo, K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int. J. Mol. Sci., 2018, 19(6), 1578.
[http://dx.doi.org/10.3390/ijms19061578] [PMID: 29799486]
[29]
Bnouham, M.; Merhfour, F.Z.; Legssyer, A.; Mekhfi, H.; Maâllem, S.; Ziyyat, A. Antihyperglycemic activity of Arbutus unedo, Ammoides pusilla and Thymelaea hirsuta. Pharmazie, 2007, 62(8), 630-632.
[PMID: 17867561]
[30]
Trigui, M.; Hsouna, A.B.; Tounsi, S.; Jaoua, S. Chemical composition and evaluation of antioxidant and antimicrobial activities of Tunisian Thymelaea hirsuta with special reference to its mode of action. Ind. Crops Prod., 2013, 41, 150-157.
[http://dx.doi.org/10.1016/j.indcrop.2012.04.011]
[31]
Elhady, S.S.; Abdelhameed, R.F.A.; El-Ayouty, M.M.; Ibrahim, A.K.; Habib, E.S.; Elgawish, M.S.; Hassanean, H.A.; Safo, M.K.; Nafie, M.S.; Ahmed, S.A. New antiproliferative triflavanone from Thymelaea hirsuta-Isolation, structure elucidation and molecular docking studies. Molecules, 2021, 26(3), 739.
[http://dx.doi.org/10.3390/molecules26030739] [PMID: 33572651]
[32]
Bertoli, C.; Skotheim, J.M.; de Bruin, R.A.M. Control of cell cycle transcription during G1 and S phases. Nat. Rev. Mol. Cell Biol., 2013, 14(8), 518-528.
[http://dx.doi.org/10.1038/nrm3629] [PMID: 23877564]
[33]
Zaldua, N.; Llavero, F.; Artaso, A.; Gálvez, P.; Lacerda, H.M.; Parada, L.A.; Zugaza, J.L. Rac1/p21-activated kinase pathway controls retinoblastoma protein phosphorylation and E2F transcription factor activation in B lymphocytes. FEBS J., 2016, 283(4), 647-661.
[http://dx.doi.org/10.1111/febs.13617] [PMID: 26663827]
[34]
Wang, W.; VanAlstyne, P.C.; Irons, K.A.; Chen, S.; Stewart, J.W.; Birt, D.F. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr. Cancer, 2004, 48(1), 106-114.
[http://dx.doi.org/10.1207/s15327914nc4801_14] [PMID: 15203384]
[35]
Cho, H.J.; Park, J.H.Y. Kaempferol induces cell cycle arrest in HT-29 human colon cancer cells. J. Cancer Prev., 2013, 18(3), 257-263.
[http://dx.doi.org/10.15430/JCP.2013.18.3.257] [PMID: 25337553]
[36]
Wang, C.Z.; Zhang, Z.; Wan, J.Y.; Zhang, C.F.; Anderson, S.; He, X.; Yu, C.; He, T.C.; Qi, L.W.; Yuan, C.S. Protopanaxadiol, an active ginseng metabolite, significantly enhances the effects of fluorouracil on colon cancer. Nutrients, 2015, 7(2), 799-814.
[http://dx.doi.org/10.3390/nu7020799] [PMID: 25625815]
[37]
Kee, J.Y.; Han, Y.H.; Kim, D.S.; Mun, J.G.; Park, J.; Jeong, M.Y.; Um, J.Y.; Hong, S.H. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine, 2016, 23(13), 1680-1690.
[http://dx.doi.org/10.1016/j.phymed.2016.09.011] [PMID: 27823633]
[38]
Tong, W.; Wang, Q.; Sun, D.; Suo, J. Curcumin suppresses colon cancer cell invasion via AMPK-induced inhibition of NF-κB, uPA activator and MMP9. Oncol. Lett., 2016, 12(5), 4139-4146.
[http://dx.doi.org/10.3892/ol.2016.5148] [PMID: 27895783]
[39]
Parsons, J.T. Focal adhesion kinase: The first ten years. J. Cell Sci., 2003, 116(8), 1409-1416.
[http://dx.doi.org/10.1242/jcs.00373] [PMID: 12640026]
[40]
Hamidi, H.; Ivaska, J. Every step of the way: Integrins in cancer progression and metastasis. Nat. Rev. Cancer, 2018, 18(9), 533-548.
[http://dx.doi.org/10.1038/s41568-018-0038-z] [PMID: 30002479]
[41]
Kim, Y.N.; Koo, K.H.; Sung, J.Y.; Yun, U.J.; Kim, H. Anoikis resistance: An essential prerequisite for tumor metastasis. Int. J. Cell Biol., 2012, 2012, 1-11.
[http://dx.doi.org/10.1155/2012/306879] [PMID: 22505926]
[42]
Mierke, C.T.; Frey, B.; Fellner, M.; Herrmann, M.; Fabry, B. Integrin α5β1 facilitates cancer cell invasion through enhanced contractile forces. J. Cell Sci., 2011, 124(3), 369-383.
[http://dx.doi.org/10.1242/jcs.071985] [PMID: 21224397]
[43]
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
[http://dx.doi.org/10.1016/0065-2571(84)90007-4] [PMID: 6382953]
[44]
Carnesecchi, S.; Bras-Gonçalves, R.; Bradaia, A.; Zeisel, M.; Gossé, F.; Poupon, M.F.; Raul, F. Geraniol, a component of plant essential oils, modulates DNA synthesis and potentiates 5-fluorouracil efficacy on human colon tumor xenografts. Cancer Lett., 2004, 215(1), 53-59.
[http://dx.doi.org/10.1016/j.canlet.2004.06.019] [PMID: 15374632]
[45]
Carnesecchi, S.; Langley, K.; Exinger, F.; Gosse, F.; Raul, F. Geraniol, a component of plant essential oils, sensitizes human colon cancer cells to 5-fluorouracil treatment. IARC Sci. Publ. , 2002; 156, p. 407-409.
[PMID: 12484223]
[46]
Redondo-Blanco, S.; Fernández, J.; Gutiérrez-del-Río, I.; Villar, C.J.; Lombó, F. New insights toward colorectal cancer chemotherapy using natural bioactive compounds. Front. Pharmacol., 2017, 8, 109.
[http://dx.doi.org/10.3389/fphar.2017.00109] [PMID: 28352231]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy