Abstract
Ethanol extracts of Caulerpa racemose (Forsskål) J.Agardh, 1873, Dictyopteris acrostichoides (J.Agardh) Bornet, 1885, Halimeda opuntia (Linnaeus) J.V.Lamouroux, 1816, and Polycladia myrica (S.G.Gmelin) Draima, Ballesteros, F.Rousseau & T.Thibaut, 2010, were tested for their cytotoxicity against human hepatoma, human breast adenocarcinoma, and human colon adenocarcinoma cell lines. Dictyopteris acrostichoides displayed cytotoxicity against human hepatoma, human breast adenocarcinoma, and human colon adenocarcinoma with IC50 values of 11.65, 9.28, and 16.86 µg/ml, respectively, in comparison to doxorubicin as a positive control (IC50 5.72, 5.17, and 5.81 µg/ml, respectively). Metabolic profiling of the D. acrostichoides extract characterized seventeen metabolites. In silico analysis indicated 1-(3-oxo-undecyldisulfanyl)-undecan-3-one was the most active epidermal growth factor receptor inhibitor, while 1-(3-oxo-undecyldisulfanyl)-undecan-3-one and di(3-acetoxy-5-undecenyl) disulfide were the most active vascular endothelial growth factor inhibitors. Furthermore, the ethanol extract of D. acrostichoides was tested against epidermal growth factor receptor kinase (IC50 0.11 µg/ml) compared to lapatinib as a positive control (IC50 0.03 µg/ml), and against vascular endothelial growth factor (IC50 0.276 µg/ml) compared to sorafenib as a positive control (IC50 0.049 µg/ml).
Graphical Abstract
![](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs43450-023-00474-8/MediaObjects/43450_2023_474_Figa_HTML.png)
Avoid common mistakes on your manuscript.
Introduction
Among the therapeutic targets for cancer, the abnormal expression of the epidermal growth factor receptor (EGFR) is strongly associated with various malignancies such as breast, ovarian, non-small-cell lung, prostate, and colon cancers. The EGFR has been confirmed to be closely related to tumor growth, progression, and metastasis. The poor prognosis of cancer patients prompts extensive studies on the EGFR signaling pathway (Allam et al. 2020). Vascular endothelial growth factor (VEGF) is secreted by tumors and induces a mitogenic response through its binding to one of three tyrosine kinase receptors (VEGFR-1 to -3) on nearby endothelial cells; inhibition of this signaling pathway should block angiogenesis and subsequent tumor growth (Dziobek et al. 2019). The Ochrophyta, Polycladia myrica (S.G.Gmelin) Draisma, Ballesteros, F.Rousseau & T.Thibaut 2010, belongs to the family Sargassaceae while Dictyopteris acrostichoides (J.Agardh) Bornet, 1885, belongs to family Dictyotaceae. Caulerpa racemosa (Forsskål) J.Agardh, 1873, is a Chlorophyta that belongs to the family Caulerpaceae, and Halimeda opuntia (Linnaeus) J.V.Lamouroux, 1816 belongs to the family Halimedaceae (Guiry and Guiry 2023). Dictyotaceae is considered one of the most important brown algae in the treatment of tumors. The alga Dictyopteris sp. is an important group of marine seaweeds and is excessively distributed, known by their identified ocean smell due to its secondary metabolites including C11-hydrocarbons and sulfur compounds. Dictyopteris has a broad variety of phytoconstituents, which were reported to have antitumor, antimicrobial, alpha-amylase inhibitors, and anti-inflammatory activities; Dictyopteris acrostichoides has shown a wide range of biological activities, but its phytoconstituents are still elusive (Rushdi et al. 2022a). Thus, the current study characterizes the cytotoxic potential of ethanol extract of four algae including Caulerpa racemosa, Dictyopteris acrostichoides, Halimeda opuntia, and Polycladia myrica against HepG2 (human hepatoma), MCF-7 (human breast adenocarcinoma), and Caco-2 (human colon adenocarcinoma) cells assisted by both LC-HR-ESI–MS spectrometry metabolomics and molecular docking analyses to detect the chemical metabolites as well as their possible mode of action.
Materials and Methods
All used chemicals were of analytical grade and purchased from Sigma (USA), Merck (Germany), and SD Fine Chemicals (India). Caulerpa racemosa (Forsskål) J.Agardh, 1873, Caulerpaceae; Dictyopteris acrostichoides (J.Agardh) Bornet, 1885, Dictyotaceae; Halimeda opuntia (Linnaeus) J.V.Lamouroux, 1816, Halimedaceae; and Polycladia myrica (S.G.Gmelin) Draima, Ballesteros, F.Rousseau & T.Thibaut, 2010, Sargassaceae, samples were collected in August 2021 from various locations along the coastal region of Hurghada City coast line, Red Sea (27° 17′ 01.0″N and 33° 46′ 21.0″E), Egypt. The voucher numbers (Da-08/2021, Cr-08/2021, Ho-08/2021, and Pm-08/2021) were deposited in the herbarium unit at the Department of Pharmacognosy, Faculty of Pharmacy, South Valley University, Qena, Egypt. The samples were collected in sterilized polyethylene bags, and kept in an icebox, for transportation to the laboratory. Samples were rinsed with distilled water to remove any associated debris and allowed to air dry before being ground to a fine powder. The air-dried powdered algal materials (200 g) were separately extracted with 70% ethanol to get crude extracts from C. racemose (16 g), D. acrostichoides (23 g), H. opuntia (9 g), and P. myrica (28 g). The obtained solvent-free residues were stored at 4 °C for subsequent analysis. Cytotoxicity of the ethanol extracts was evaluated in cell lines manipulating the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay according to Cheng et al. (2017) against MCF-7 (human breast adenocarcinoma), Caco2 (human colon adenocarcinoma), and HepG2 (human hepatoma) cell lines. EGFR assay was performed according Huang et al (2021), while VEGFR assay was performed according Elrazaz et al (2021). Molecular modeling and visualization processes were performed within EGFR and VEGFR using Molecular Operating Environment (MOE 2019.0102, 2020; Chemical Computing Group, Montreal, QC, Canada). Metabolomic profiling of the ethanol extracts of D. acrostichoides was performed using analytical techniques of liquid chromatography high-resolution electrospray ionization mass spectrometry (Attia et al. 2022). The co-crystal structure was retrieved from the RCSB Protein Data Bank (PDB code 3UG2 for EGFR and 3CJG for VEGFR). The resulting docking poses were visually inspected, and the pose of the lowest binding free energy value was considered (Abdel-Rahman et al. 2022).
Results and Discussion
Epidermal growth factor receptor stimulates tumor growth and progression through several mechanisms. The expression of transcription, mutation, and/or gene amplification may be the cause of EGFR activation in tumor cells. The increased protein and transcribed levels of EGFR will correspond to poor prognosis in several cancers such as lung cancer and colorectal cancer (Allam et al. 2020). The VEGFR has multiple immediate effects on cancer cells and is known to have a major contribution to angiogenesis that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessel formation (Dziobek et al. 2019). LC-HR-MS analysis (Fig. 1S) for dereplication purposes was adopted for the identification of metabolites from ethanol extract of Dictyopteris acrostichoides (Table 1S). The dereplication study of the metabolites against the DNP (Dictionary of Natural Products) (Buckingham 2014) and Marin Lit databases (Munro and Blunt 2023) resulted in the identification of 17 compounds. Ethanol extract of D. acrostichoides as a source of bioactive natural products resulted in the detection of α-dictyopterol (1), β-dictyopterol (2) (Etsuro et al. 1966), germacra-1(10),4(15)-11-trien-5S-ol (3) (Toshi et al. 1964), 4α,5β-dihydroxycubenol (4), cadinan-1,4,5-triol (5) (Qiao et al. 2009), (1R,3R,4S,11R)-3,4;7,8-bisepoxydolabellan-12(18)-ene (6) (Wright et al. 1990), chromenol (7) (Wang et al. 2018), dictyochromenol (8) (Li et al. 2022), isochromazonarol (9), chromazonarol (10), 2-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl] benzene-1,4-diol (11), zonaric acid (12), (Ishibashi et al. 2013), isozonarol (13), zonarol (14) (Fenical et al. 1973), and dictyvaric acid (15) (Song et al. 2005), (3-oxo-undecyldisulfanyl)-undecan-3-one (16) (Schnitzler et al. 1998), and di(3-acetoxy-5-undecenyl) disulfide (17) (Moore et al. 1972) from LC-HR-ESI–MS metabolic profiling of the ethanol extract of D. acrostichoides.
![figure b](http://media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs43450-023-00474-8/MediaObjects/43450_2023_474_Figb_HTML.png)
(1R,3R,4S,11R)-3,4;7,8-Bisepoxydolabellan-12(18)-ene (6) is a dolabellane diterpene, typical product of algae of the genus Dictyota (Rushdi et al. 2022b); this mixing (Dictyota and Dictyopteris) must have occurred during the collection process. The cytotoxic potential obtained results revealed that the ethanol extract of D. acrostichoides had promising cytotoxicity activities against HepG2, MCF-7, and Caco-2 cell lines with IC50 values of 11.65, 9.28, and 16.86 µg/ml, respectively, compared to doxorubicin (IC50 5.72, 5.17, and 5.81 µg/ml, respectively); thus, it was further subjected to other assays while other extracts of C. racemosa, H. opuntia, and P. myrica did not show cytotoxic activities against tested cell lines. Further screen of ethanol extract of D. acrostichoides displayed in vitro activity against EGFR (IC50 0.11 µg/ml) compared to lapatinib as a positive control (IC50 0.03 ± 0.002 µg/ml) and against VEGF (IC50 0.276 µg/ml) compared to sorafenib as a positive control (IC50 0.049 ± 0.003 µg/ml). Most compounds showed hydrogen bonding with the gatekeeper mutant Met790. Interestingly, compounds 17 and 16 showed higher docking scores than Gefitinib (Table 2S, Fig. 2S–4S). Compounds (2, 5, 8–15) were of good binding energies ranging from − 6.9734 to − 6.1317 kcal/mol while (1, 3–4, 6–7) were of fair binding energies less than 6 kcal/mol. The docking on VEGFR revealed that most compounds formed hydrogen bonding with Asp 1044 like that of the ligand KIM. Compound 17 has a binding score (− 8.2601 kcal/mol more than ligand KIM (− 7.8176 kcal/mol) while compounds 16 and 12 showed − 7.4368 and − 7.0233 kcal/mol, respectively (Table 3S, Fig. 4S–6S). Compounds 8–13 and 15 showed good binding energies ranging from − 6.8160 to − 6.3920 kcal/mol. Most compounds formed hydrogen bonding with Asp 1044 like that of the ligand KIM.
Conclusions
Dictyopteris acrostichoides ethanol extract displayed cytotoxicity against HepG2, MCF-7, and CACO-2 (IC50 11.65, 9.28, and 16.86 µg/ml, respectively) compared to doxorubicin as a positive control (IC50 5.72, 5.17, and 5.81 µg/ml, respectively). Furthermore, the ethanol extract of D. acrostichoides was tested against EGFR (IC50 0.11 µg/ml) compared to lapatinib as a positive control (IC50 0.03 µg/m) and against VEGF (IC50 0.276 µg/ml) compared to sorafenib as a positive control (IC50 0.049 µg/ml). Seventeen metabolites were identified from the ethanol extract of D. acrostichoides but were detected using LC-HR-ESI–MS for dereplication purposes. 1-(3-Oxo-undecyldisulfanyl)-undecan-3-one (16) confirmed considerable interaction energies and formed substantial interactions EGFR binding site in the cancer cell receptors. Interestingly, di(3-acetoxy-5-undecenyl) disulfide (17) confirmed considerable interaction energies and formed substantial interactions VEGFR binding site.
References
Abdel-Rahman IAM, Attia EZ, Aly OM, Saber H, Rushdi MI, Abdelmohsen UR (2022) Metabolite profiling of green algae Halimeda opuntia to target hepatitis C virus-796 polymerase inhibitors assisted by molecular docking. S Afr J Bot 151:538–543. https://doi.org/10.1016/j.sajb.2022.10.038
Allam HA, Aly EE, Farouk AKBAW, El Kerdawy AM, Rashwan E, Abbass SES (2020) Design and synthesis of some new 2,4,6-trisubstituted quinazoline EGFR inhibitors as targeted anticancer agents. Bioorg Chem 98:103726. https://doi.org/10.1016/j.bioorg.2020.103726
Attia EZ, Youssef NH, Saber H, Rushdi MI, Abdel-Rahman IAM, Darwish AG, Abdelmohsen UR (2022) Halimeda opuntia and Padina pavonica extracts improve growth and metabolic activities in maize under soil-saline conditions. Appl Phycol 34:3189–3203. https://doi.org/10.1007/s10811-022-02844-6
Buckingham J (2014) Dictionary of natural products. https://doi.org/10.1007/978-1-4899-3314-0
Cheng C, Othman EM, Stopper H, Edrada-Ebel R, Hentschel U, Abdelmohsen UR (2017) Isolation of petrocidin A, a new cytotoxic cyclic dipeptide from the marine sponge-derived Bacterium Streptomyces sp. SBT348. Mar Drugs 15:383. https://doi.org/10.3390/md15120383
Dziobek K, Opławski M, Grabarek BO, Zmarzły N, Tomala B, Halski T, Leśniak E, Januszyk K, Brus R, Kiełbasiński R, Boroń D (2019) Changes in the expression profile of VEGF-A, VEGF-B, VEGFR-1, VEGFR-2 in different grades of endometrial cancer. Curr Pharm Biotechnol 20:955–963. https://doi.org/10.2174/1389201020666190717092448
Elrazaz EZ, Serya RAT, Ismail NSM, Albohy A, Abou El Ella DA, Abouzid KAM (2021) Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations. Bioorg Chem 113:105019. https://doi.org/10.1016/j.bioorg.2021.105019
Etsuro K, Motowo I, Koji Y, Tadashi M, Toshi I (1966) Sesquiterpenes from Dictyopteris divaricata. II. Dictyopterol and dictyopterone. Bull Chem Soc Jpn 39:2509–2512. https://doi.org/10.1246/bcsj.39.2509
Fenical W, Sims JJ, Sqatrito D, Wing RM, Radlick P (1973) Zonarol and isozonarol, fungitoxic hydroquinones from the brown seaweed Dictyopteris zonarioides. J Org Chem 38:2383–2386. https://doi.org/10.1021/jo00953a022
Guiry M, Guiry G (2023) AlgaeBase. World-wide electronic publication, National University of Ireland. https://www.algaebase.org/
Huang W, Xing Y, Zhu L, Zhuo J, Cai M (2021) Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2. Exp Cell Res 406:112633. https://doi.org/10.1016/j.yexcr.2021.112633
Ishibashi F, Sato S, Sakai K, Hirao S, Kuwano K (2013) Algicidal sesquiterpene hydroquinones from the brown alga Dictyopteris undulata. Biosci Biotechnol Biochem 77:1120–1122. https://doi.org/10.1271/bbb.130018
Li H-Y, Yang W-Q, Zhou X-Z, Shao F, Shen T, Guan H-Y, Zheng J, Zhang L-M (2022) Antibacterial and antifungal sesquiterpenoids: chemistry, resource, and activity. Biomol Ther 12:1271. https://doi.org/10.3390/biom12091271
Moore RE, Mistysyn J, Pettus JA (1972) (–)-Bis-(3-acetoxyundec-5-enyl) disulphide and S-(–)-3-acetoxyundec-5-enyl thioacetate, possible precursors to undeca-1,3,5-trienes in Dictyopteris. J Chem Soc Chem Commun 6:326–327. https://doi.org/10.1039/C39720000326
Munro M, Blunt JW (2023) MarineLit. Dedicated to marine natural products research, University of Canterbury. https://marinlit.rsc.org/
Qiao Y-Y, Ji N-Y, Wen W, Yin X-L, Xue Q-Z (2009) A new epoxy-cadinane sesquiterpene from the marine brown alga Dictyopteris divaricata. Mar Drugs 7:600–604. https://doi.org/10.3390/md7040600
Rushdi MI, Abdel-Rahman IA, Saber H, Attia EZ, Abdelmohsen UR (2022) The natural products and pharmacological biodiversity of brown algae from the genus Dictyopteris. J Mex Chem Soc 66:154–172. https://doi.org/10.29356/jmcs.v66i1.1639
Rushdi MI, Abdel-Rahman IAM, Attia EZ, Saber H, Saber AA, Bringmann G, Abdelmohsen UR (2022b) The biodiversity of the genus Dictyota: phytochemical and pharmacological natural products prospectives. Molecules 27:672. https://doi.org/10.3390/molecules27030672
Schnitzler I, Boland W, Hay ME (1998) Organic sulfur compounds from Dictyopteris spp. deter feeding by an herbivorous amphipod (Ampithoe longimana) but not by an herbivorous sea urchin (Arbacia punctulata). J Chem Ecol 24:1715–1732. https://doi.org/10.1023/A:1020876830580
Song FH, Fan X, Xu XL, Zhao JL, Han LJ, Shi JG (2005) Chemical constituents of the brown alga Dictyopteris divaricata. J Asian Nat Prod Res 7:777–781. https://doi.org/10.1080/1028602032000169532
Toshi I, Koji Y, Tadashi M (1964) Sesquiterpenes from Dictyopteris divaricata. I. Bull Chem Soc Jpn 37:1053–1055. https://doi.org/10.1246/bcsj.37.1053
Wang H-S, Li H-J, Zhang Z-G (2018) Wu Y-C (2018) Divergent synthesis of bioactive marine meroterpenoids by palladium-catalyzed tandem Carbene Migratory Insertion. Eur J Org Chem 7:915–925. https://doi.org/10.1002/ejoc.201800026
Wright AD, Coll JC, Price IR (1990) Tropical marine algae, VII. The chemical composition of marine algae from North Queensland waters. J Nat Prod 53:845–861. https://doi.org/10.1021/np50070a012
Funding
Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB).
Author information
Authors and Affiliations
Contributions
UR was involved in the conceptualization, and supervision of project administration; EZA, MIR, IAMA, and HS were responsible for methodology, investigation, resources, data curation, and writing the original draft manuscript; EZA and MIR were involved in data curation and visualization; EZA, MIR, OMA, and URA were responsible for software, validation, formal analysis, writing, editing, and reviewing the manuscript.
Corresponding author
Ethics declarations
Ethical Approval
In this study, animal experiments were not applicable. All procedures involving human cell lines were approved by the South Valley University Research Ethics Committee (reference P.S.V.U 149).
Consent to Publish
Not applicable.
Competing Interests
The authors declare no competing interests.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Attia, E.Z., Abdel-Rahman, I.A.M., Aly, O.M. et al. In Vitro Cytotoxic Potential of Ethanol Extract of Dictyopteris acrostichoides Against Human Cancer Cells. Rev. Bras. Farmacogn. 34, 212–216 (2024). https://doi.org/10.1007/s43450-023-00474-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43450-023-00474-8