Evaluation of Indonesian selected macroalgae for their antitumor and cytoprotective activity

Eka Sunarwidhi Prasedya; Mutiadevi Ariyana; Candra Dwipayana Hamdin; Aluh Nikmatullah; Susumu Yoshie; Masao Miyake; Daisuke Kobayashi; Akihiro Hazama; Haji Sunarpi

doi:10.7324/JAPS.2018.81118

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Abstract

Context: Macroalgae are known to exhibit secondary metabolites with interesting bioactive properties, including antibacterial, antioxidant, antitumor, and anti-UV effects. Indonesia is endowed with an abundance of macroalgae, yet information regarding their pharmaceutical properties remains largely unexplored.

Objective: This study evaluates the antitumor and cytoprotective effects of Indonesian selected seaweeds Acanthophora spicifera (ASE), Acanthophora muscoides (AME), Sargassum polycystum (SPE), and Sargassum crassifolium (SCE) crude ethanol extracts.

Materials and Methods: Preliminary phytochemical screening was used to determine chemical constituents in macroalgae ethanol extracts. Cytotoxicity and antiproliferative activity of macroalgae extracts were evaluated with Methyl Thiazolyl Tetrazolium (MTT) assay from 5 to 200 μg/ml concentration in human cervical cancer (HeLa) and human umbilical vein endothelium (HUVEC) cells for 72 hours. UV absorbing capabilities of macroalgae extracts were determined with UV–VIS (240–340 nm). Cytoprotective effects were evaluated by fluorescence microscopy observation of cells irradiated with UV-B for 3 minutes.

Results: AME appeared to exhibit most diverse chemical constituents. Only ASE and AME demonstrated moderate cytotoxicity (ASE-IC50 = 190 ± 24 μg/ml; AME-IC50 = 180 ± 14 μg/ml) against HeLa cells in 72 hours incubation. Furthermore, the cytotoxicity effects of all macroalgae extracts could not be detected in HUVEC cells at tested concentrations. In addition, SPE and SCE potentially reduced nuclear DNA damage induced by UV-B radiation.

Conclusion: Current results show Indonesian macroalgae possesses a broad range of possible therapeutic applications. Therefore, further advanced studies relating to the isolation of specific bioactive compounds and molecular mechanisms would be reasonable to fully utilize macroalgae potential uses in the pharmaceutical industries.

Keyword: Antiproliferative cancer cytotoxicity Indonesia macroalgae ultraviolet.

Citation:

Prasedya ES, Ariyana M, Hamdin CD, Nikmatullah A, Yoshie S, Miyake M, Kobayashi D, Hazama A, Sunarpi H. Evaluation of Indonesian selected macroalgae for their antitumor and cytoprotective activity. J App Pharm Sci, 2018; 8(11): 123–130.

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

Atashrazm F, Lowenthal RM, Woods GM, Holloway AF, Dickinson JL. Fucoidan and cancer: a multifunctional molecule with anti-tumoral potential. Mar Drugs, 2015; 13(4):2327–46. https://doi.org/10.3390/md13042327
Avato P, Migoni D, Argentieri M, Fanizzi FP, Tava A. Activity of saponins from medicago species against HeLa and MCF-7 Cell Lines and their capacity to potentiate cisplatin effect. Anticancer Agents Med Chem, 2017; 17:1508–18. https://doi.org/10.2174/1871520617666170727152805
Barbosa M, Valent2ão P, Andrade PB. Bioactive compounds from macroalgae in the new millennium: Implications for neurodegenerative diseases. Mar Drugs, 2014; 12:4934–72. https://doi.org/10.3390/md12094934
Bouhlal R, Haslin C, Chermann JC, Colliec-Jouault S, Sinquin C, Simon G, Cerantola S, Riadi H, Bourgougnon N. Antiviral activities of sulfated polysaccharides isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales). Mar Drugs, 2011; 9:1187–209. https://doi.org/10.3390/md9071187
Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod, 2004; 67:2141–53. https://doi.org/10.1021/np040106y
Cerella C, Sobolewski C, Dicato M, Diederich M. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem Pharmacol, 2010; 80:1801–15. https://doi.org/10.1016/j.bcp.2010.06.050
Cho SH, Kang SE, Cho JY, Kim AR, Park SM, Hong YK, Ahn DH. The antioxidant properties of brown seaweed (sargassum siliquastrum) extracts. J Med Food, 2007; 10(3):479–85. https://doi.org/10.1089/jmf.2006.099
Cragg GM, Newman DJ, Snader KM. Natural products in drug discovery and development. J Nat Prod, 1997; 60:52–60. https://doi.org/10.1021/np9604893
Gomes DL, Telles CBS, Costa MSSP, Almeida-Lima J, Costa LS, Keesen TSL, Rocha HAO. Methanolic extracts from brown seaweeds Dictyota cilliolata and Dictyota mestrualis induce apoptosis in human cervical adenocarcinoma HeLa cells. Molecules, 2015; 20:6573–91. https://doi.org/10.3390/molecules20046573
Gressler V, Yokoya N, Fujii M, Colepicolo P, Filho J, Torres R, Pinto E. Lipid, fatty acid, protein, amino acid and ash contents in four Brazilian red algae species. Food Chem, 2010; 120:585–90. https://doi.org/10.1016/j.foodchem.2009.10.028
Gröniger A, Sinha RP, Klisch M, Häder DP. Photoprotective compounds in cyanobacteria, phytoplankton and macroalgae – a database. J. Photochem. Photobiol. B Biol. 2000,58; 115–122.
Guiry MD, Guiry GM. AlgaeBase. World-wide electronic publication. National University of Ireland, Galway, 2018. Available via http://www.algaebase.org (Updated 4 July 2018; Accessed 2 October 2017).
Harborne JB, Nagooru MR. Phytomochemical methods: a guide to modern techniques of plant analysis. 2nd edition, Chapman and Hall, London, UK, pp 54–84, 1998.
Heo SJ, Jeon, YJ. Evaluation of diphlorethohydroxycarmalol isolated from Ishige okamurae for radical scavenging activity and its protective effect against H2O2-induced cell damage. Process Biochem, 2009; 44:412–8. https://doi.org/10.1016/j.procbio.2008.12.005
Joshi P, Vishwakarma RA, Bharate SB. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. Eur J Med Chem, 2017; 138:273–92. https://doi.org/10.1016/j.ejmech.2017.06.047
Kawaguchi S, Hayashizaki, KI. Biodiversity studies on seaweeds and sea grasses in the coastal waters of Southeast Asia. In: Nishida S, Fortes MD, Miyazaki N (eds). Coastal Marine Science in Southeast Asia. Synthesis Report of the Core University Program of the Japan Society for the Promotion of Science: Coastal Marine Science (2001–2010), pp 49–57, 2011.
Kim JA, Ahn BN, Kong CS, Kim SK. Protective effect of chromene isolated form Sargassum horneri against UV-A induced damage in skin dermal fibroblasts. Exp Dermatol, 2012; 21(8):630–1. https://doi.org/10.1111/j.1600-0625.2012.01535.x
Kim SK, Thomas NV, Li X. Anticancer compounds from marine macroalgae and their application as medicinal foods. Adv Food Nutr Res, 2011; 64:213–24. https://doi.org/10.1016/B978-0-12-387669-0.00016-8
Kim EY, Choi YH, Lee JI, Kim IH, Nam TJ. Antioxidant Activity of Oxygen Evolving Enhancer Protein 1 Purified from Capsosiphon fulvescens.J.Food.Sci,2014;80(6):H1412-7. https://doi.org/10.1111/1750-3841.12883
Kintzios SE. Terrestrial plant-derived anticancer agents and plant species used in anticancer research. Crit Rev Plant Sci, 2006; 25:79–113. https://doi.org/10.1080/07352680500348824
Lee MH, Kim YK, Yoon NY, Shim KB, Aminina NM, Kadnikova IA, Lim,CW. Study on UV absorption materials derived from red algae Gloiopeltis fucatas and Mazzaella sp. in Russia. Fish Aquat Sci, 2012; 15:361–3. https://doi.org/10.5657/FAS.2012.0361
Luo M, Shao B, Nie W, Wei XW, Li YL, Wang BL, He ZY, Liang X, Ye TH, Wei YQ. Antitumor and adjuvant activity of λ-carrageenan by stimulating immune response in cancer immunotherapy. Sci Rep, 2015; 5:11062. https://doi.org/10.1038/srep11062
Mayer AMS, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci, 2010; 31:255–65. https://doi.org/10.1016/j.tips.2010.02.005
Na HJ, Moon PD, Lee HJ, Kim HR, Chae HJ, Shin T, Seo Y, Hong SH, Kim HM. Regulatory effect of atopic allergic reaction by Carpopeltis affinis. J Ethnopharmacol, 2005; 101:43–8. https://doi.org/10.1016/j.jep.2005.03.026
Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivates. Drug Disc Today, 2015; 21:204–7. https://doi.org/10.1016/j.drudis.2015.01.009
Pavia H, Brock E. Extrinsic factors influencing phlorotannin production in the brown alga. Mar Ecol Prog Ser, 2000; 193:285–94. https://doi.org/10.3354/meps193285
Pavia H, Cervin G, Lindgren A, Aberg P. Effects of UV- B radiation and simulated herbivory on phlorotannins in the brown alga Ascophyllum nodosum. Mar Ecol Prog Ser, 1997;157:139-146. https://doi.org/10.3354/meps157139
Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Boo SJ, Yoon WJ, Kang HK, Yoo ES, Koh YS, Ko MH, Lee NH, Hyun JW. The ethyl acetate fraction of Sargassum muticum attenuates ultraviolet B radiation-induced apoptotic cell death via regulation of AMPK- caspase-dependent signaling pathways in human HaCaT keratinocytes. Pharm Biol, 2014; 52(9):1110–8. https://doi.org/10.3109/13880209.2013.879186
Ponce NM, Pujol CA, Damonte EB, Flores ML, Stortz CA. Fucoidans from the brown seaweed Adenocystis utricularis: extraction methods, antiviral activity and structural studies. Carbohydr Res, 2003; 338:153–65. https://doi.org/10.1016/S0008-6215(02)00403-2
Prasedya ES, Miyake M, Kobayashi D, Hazama A. Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging. BMC Complement Altern Med, 2016; 16:270. https://doi.org/10.1186/s12906-016-1199-5
Qin D, Ren R, Jia C, Lu Y, Yang Q, Chen L, Wu X, Zhu J, Guo Y, Yang P, Zhou Y, Zhu N, Bi B, Liu T. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell Physiol Biochem, 2018; 46:1849–60. https://doi.org/10.1159/000489369
Shi D, Li X, Li J, Guo S, Su H, Fan X. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chinese J Oceanol Limnol, 2010; 28:96–8. https://doi.org/10.1007/s00343-010-9213-0
Sulistijo. Buku modul rumput laut (Macroalga). Pusat Penelitian Oceanografi Lembaga Ilmu Pengetahuan Indonesia, Jakarta, 2009.
Tarman K, Lindequist U, Wende K, Porzel A, Arnold N, Wessjohann LA. Isolation of a new natural product and cytotoxic and antimicrobial activities of extracts from fungi of Indonesian marine habitats. Mar Drugs, 2011; 9(3):294–306. https://doi.org/10.3390/md9030294
Vasanthi HR, Rajamanickam GV, Saraswathy A. Tumoricidal effect of the red algae Acanthophora spicifera on Ehrlich's ascites carcinoma in mice, Seaweed Res. UntilNet, 2004; 25:217–24.
Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine, 2009; 16:97–110. https://doi.org/10.1016/j.phymed.2008.12.018
Zamroni A, Yamao M. An assessment of farm-to-market link of Indonesian dried seaweeds: contribution of middlemen toward sustainable livelihood of small-scale fishermen in Laikang Bay. Afr J Agric Res, 2012; 7:4198–208. Atashrazm F, Lowenthal RM, Woods GM, Holloway AF, Dickinson JL. Fucoidan and cancer: a multifunctional molecule with anti-tumoral potential. Mar Drugs, 2015; 13(4):2327–46.
Avato P, Migoni D, Argentieri M, Fanizzi FP, Tava A. Activity of saponins from medicago species against HeLa and MCF-7 Cell Lines and their capacity to potentiate cisplatin effect. Anticancer Agents Med Chem, 2017; 17:1508–18. https://doi.org/10.2174/1871520617666170727152805
Barbosa M, Valent2ão P, Andrade PB. Bioactive compounds from macroalgae in the new millennium: Implications for neurodegenerative diseases. Mar Drugs, 2014; 12:4934–72. https://doi.org/10.3390/md12094934
Bouhlal R, Haslin C, Chermann JC, Colliec-Jouault S, Sinquin C, Simon G, Cerantola S, Riadi H, Bourgougnon N. Antiviral activities of sulfated polysaccharides isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales). Mar Drugs, 2011; 9:1187–209. https://doi.org/10.3390/md9071187
Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod, 2004; 67:2141–53. https://doi.org/10.1021/np040106y
Cerella C, Sobolewski C, Dicato M, Diederich M. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem Pharmacol, 2010; 80:1801–15. https://doi.org/10.1016/j.bcp.2010.06.050
Cho SH, Kang SE, Cho JY, Kim AR, Park SM, Hong YK, Ahn DH. The antioxidant properties of brown seaweed (sargassum siliquastrum) extracts. J Med Food, 2007; 10(3):479–85. https://doi.org/10.1089/jmf.2006.099
Cragg GM, Newman DJ, Snader KM. Natural products in drug discovery and development. J Nat Prod, 1997; 60:52–60. https://doi.org/10.1021/np9604893
Gomes DL, Telles CBS, Costa MSSP, Almeida-Lima J, Costa LS, Keesen TSL, Rocha HAO. Methanolic extracts from brown seaweeds Dictyota cilliolata and Dictyota mestrualis induce apoptosis in human cervical adenocarcinoma HeLa cells. Molecules, 2015; 20:6573–91. https://doi.org/10.3390/molecules20046573
Gressler V, Yokoya N, Fujii M, Colepicolo P, Filho J, Torres R, Pinto E. Lipid, fatty acid, protein, amino acid and ash contents in four Brazilian red algae species. Food Chem, 2010; 120:585–90. https://doi.org/10.1016/j.foodchem.2009.10.028
Gröniger A, Sinha RP, Klisch M, Häder DP. Photoprotective compounds in cyanobacteria, phytoplankton and macroalgae – a database. J. Photochem. Photobiol. B Biol. 2000,58; 115–122.
Guiry MD, Guiry GM. AlgaeBase. World-wide electronic publication. National University of Ireland, Galway, 2018. Available via http://www.algaebase.org (Updated 4 July 2018; Accessed 2 October 2017).
Harborne JB, Nagooru MR. Phytomochemical methods: a guide to modern techniques of plant analysis. 2nd edition, Chapman and Hall, London, UK, pp 54–84, 1998.
Heo SJ, Jeon, YJ. Evaluation of diphlorethohydroxycarmalol isolated from Ishige okamurae for radical scavenging activity and its protective effect against H2O2-induced cell damage. Process Biochem, 2009; 44:412–8. https://doi.org/10.1016/j.procbio.2008.12.005
Joshi P, Vishwakarma RA, Bharate SB. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. Eur J Med Chem, 2017; 138:273–92. https://doi.org/10.1016/j.ejmech.2017.06.047
Kawaguchi S, Hayashizaki, KI. Biodiversity studies on seaweeds and sea grasses in the coastal waters of Southeast Asia. In: Nishida S, Fortes MD, Miyazaki N (eds). Coastal Marine Science in Southeast Asia. Synthesis Report of the Core University Program of the Japan Society for the Promotion of Science: Coastal Marine Science (2001–2010), pp 49–57, 2011.
Kim JA, Ahn BN, Kong CS, Kim SK. Protective effect of chromene isolated form Sargassum horneri against UV-A induced damage in skin dermal fibroblasts. Exp Dermatol, 2012; 21(8):630–1. https://doi.org/10.1111/j.1600-0625.2012.01535.x
Kim SK, Thomas NV, Li X. Anticancer compounds from marine macroalgae and their application as medicinal foods. Adv Food Nutr Res, 2011; 64:213–24. https://doi.org/10.1016/B978-0-12-387669-0.00016-8
Kim EY, Choi YH, Lee JI, Kim IH, Nam TJ. Antioxidant Activity of Oxygen Evolving Enhancer Protein 1 Purified from Capsosiphon fulvescens.J.Food.Sci,2014;80(6):H1412-7. https://doi.org/10.1111/1750-3841.12883
Kintzios SE. Terrestrial plant-derived anticancer agents and plant species used in anticancer research. Crit Rev Plant Sci, 2006; 25:79–113. https://doi.org/10.1080/07352680500348824
Lee MH, Kim YK, Yoon NY, Shim KB, Aminina NM, Kadnikova IA, Lim,CW. Study on UV absorption materials derived from red algae Gloiopeltis fucatas and Mazzaella sp. in Russia. Fish Aquat Sci, 2012; 15:361–3. https://doi.org/10.5657/FAS.2012.0361
Luo M, Shao B, Nie W, Wei XW, Li YL, Wang BL, He ZY, Liang X, Ye TH, Wei YQ. Antitumor and adjuvant activity of λ-carrageenan by stimulating immune response in cancer immunotherapy. Sci Rep, 2015; 5:11062. https://doi.org/10.1038/srep11062
Mayer AMS, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci, 2010; 31:255–65. https://doi.org/10.1016/j.tips.2010.02.005
Na HJ, Moon PD, Lee HJ, Kim HR, Chae HJ, Shin T, Seo Y, Hong SH, Kim HM. Regulatory effect of atopic allergic reaction by Carpopeltis affinis. J Ethnopharmacol, 2005; 101:43–8. https://doi.org/10.1016/j.jep.2005.03.026
Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivates. Drug Disc Today, 2015; 21:204–7. https://doi.org/10.1016/j.drudis.2015.01.009
Pavia H, Brock E. Extrinsic factors influencing phlorotannin production in the brown alga. Mar Ecol Prog Ser, 2000; 193:285–94. https://doi.org/10.3354/meps193285
Pavia H, Cervin G, Lindgren A, Aberg P. Effects of UV- B radiation and simulated herbivory on phlorotannins in the brown alga Ascophyllum nodosum. Mar Ecol Prog Ser, 1997;157:139-146. https://doi.org/10.3354/meps157139
Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Boo SJ, Yoon WJ, Kang HK, Yoo ES, Koh YS, Ko MH, Lee NH, Hyun JW. The ethyl acetate fraction of Sargassum muticum attenuates ultraviolet B radiation-induced apoptotic cell death via regulation of AMPK- caspase-dependent signaling pathways in human HaCaT keratinocytes. Pharm Biol, 2014; 52(9):1110–8. https://doi.org/10.3109/13880209.2013.879186
Ponce NM, Pujol CA, Damonte EB, Flores ML, Stortz CA. Fucoidans from the brown seaweed Adenocystis utricularis: extraction methods, antiviral activity and structural studies. Carbohydr Res, 2003; 338:153–65. https://doi.org/10.1016/S0008-6215(02)00403-2
Prasedya ES, Miyake M, Kobayashi D, Hazama A. Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging. BMC Complement Altern Med, 2016; 16:270. https://doi.org/10.1186/s12906-016-1199-5
Qin D, Ren R, Jia C, Lu Y, Yang Q, Chen L, Wu X, Zhu J, Guo Y, Yang P, Zhou Y, Zhu N, Bi B, Liu T. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell Physiol Biochem, 2018; 46:1849–60. https://doi.org/10.1159/000489369
Shi D, Li X, Li J, Guo S, Su H, Fan X. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chinese J Oceanol Limnol, 2010; 28:96–8. https://doi.org/10.1007/s00343-010-9213-0
Sulistijo. Buku modul rumput laut (Macroalga). Pusat Penelitian Oceanografi Lembaga Ilmu Pengetahuan Indonesia, Jakarta, 2009.
Tarman K, Lindequist U, Wende K, Porzel A, Arnold N, Wessjohann LA. Isolation of a new natural product and cytotoxic and antimicrobial activities of extracts from fungi of Indonesian marine habitats. Mar Drugs, 2011; 9(3):294–306. https://doi.org/10.3390/md9030294
Vasanthi HR, Rajamanickam GV, Saraswathy A. Tumoricidal effect of the red algae Acanthophora spicifera on Ehrlich's ascites carcinoma in mice, Seaweed Res. UntilNet, 2004; 25:217–24.
Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine, 2009; 16:97–110. https://doi.org/10.1016/j.phymed.2008.12.018
Zamroni A, Yamao M. An assessment of farm-to-market link of Indonesian dried seaweeds: contribution of middlemen toward sustainable livelihood of small-scale fishermen in Laikang Bay. Afr J Agric Res, 2012; 7:4198–208.

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Atashrazm F, Lowenthal RM, Woods GM, Holloway AF, Dickinson JL. Fucoidan and cancer: a multifunctional molecule with anti-tumoral potential. Mar Drugs, 2015; 13(4):2327–46. https://doi.org/10.3390/md13042327

Avato P, Migoni D, Argentieri M, Fanizzi FP, Tava A. Activity of saponins from medicago species against HeLa and MCF-7 Cell Lines and their capacity to potentiate cisplatin effect. Anticancer Agents Med Chem, 2017; 17:1508–18. https://doi.org/10.2174/1871520617666170727152805

Barbosa M, Valent2ão P, Andrade PB. Bioactive compounds from macroalgae in the new millennium: Implications for neurodegenerative diseases. Mar Drugs, 2014; 12:4934–72. https://doi.org/10.3390/md12094934

Bouhlal R, Haslin C, Chermann JC, Colliec-Jouault S, Sinquin C, Simon G, Cerantola S, Riadi H, Bourgougnon N. Antiviral activities of sulfated polysaccharides isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales). Mar Drugs, 2011; 9:1187–209. https://doi.org/10.3390/md9071187

Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod, 2004; 67:2141–53. https://doi.org/10.1021/np040106y

Cerella C, Sobolewski C, Dicato M, Diederich M. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem Pharmacol, 2010; 80:1801–15. https://doi.org/10.1016/j.bcp.2010.06.050

Cho SH, Kang SE, Cho JY, Kim AR, Park SM, Hong YK, Ahn DH. The antioxidant properties of brown seaweed (sargassum siliquastrum) extracts. J Med Food, 2007; 10(3):479–85. https://doi.org/10.1089/jmf.2006.099

Cragg GM, Newman DJ, Snader KM. Natural products in drug discovery and development. J Nat Prod, 1997; 60:52–60. https://doi.org/10.1021/np9604893

Gomes DL, Telles CBS, Costa MSSP, Almeida-Lima J, Costa LS, Keesen TSL, Rocha HAO. Methanolic extracts from brown seaweeds Dictyota cilliolata and Dictyota mestrualis induce apoptosis in human cervical adenocarcinoma HeLa cells. Molecules, 2015; 20:6573–91. https://doi.org/10.3390/molecules20046573

Gressler V, Yokoya N, Fujii M, Colepicolo P, Filho J, Torres R, Pinto E. Lipid, fatty acid, protein, amino acid and ash contents in four Brazilian red algae species. Food Chem, 2010; 120:585–90. https://doi.org/10.1016/j.foodchem.2009.10.028

Gröniger A, Sinha RP, Klisch M, Häder DP. Photoprotective compounds in cyanobacteria, phytoplankton and macroalgae – a database. J. Photochem. Photobiol. B Biol. 2000,58; 115–122.

Guiry MD, Guiry GM. AlgaeBase. World-wide electronic publication. National University of Ireland, Galway, 2018. Available via http://www.algaebase.org (Updated 4 July 2018; Accessed 2 October 2017).

Harborne JB, Nagooru MR. Phytomochemical methods: a guide to modern techniques of plant analysis. 2nd edition, Chapman and Hall, London, UK, pp 54–84, 1998.

Heo SJ, Jeon, YJ. Evaluation of diphlorethohydroxycarmalol isolated from Ishige okamurae for radical scavenging activity and its protective effect against H2O2-induced cell damage. Process Biochem, 2009; 44:412–8. https://doi.org/10.1016/j.procbio.2008.12.005

Joshi P, Vishwakarma RA, Bharate SB. Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer. Eur J Med Chem, 2017; 138:273–92. https://doi.org/10.1016/j.ejmech.2017.06.047

Kawaguchi S, Hayashizaki, KI. Biodiversity studies on seaweeds and sea grasses in the coastal waters of Southeast Asia. In: Nishida S, Fortes MD, Miyazaki N (eds). Coastal Marine Science in Southeast Asia. Synthesis Report of the Core University Program of the Japan Society for the Promotion of Science: Coastal Marine Science (2001–2010), pp 49–57, 2011.

Kim JA, Ahn BN, Kong CS, Kim SK. Protective effect of chromene isolated form Sargassum horneri against UV-A induced damage in skin dermal fibroblasts. Exp Dermatol, 2012; 21(8):630–1. https://doi.org/10.1111/j.1600-0625.2012.01535.x

Kim SK, Thomas NV, Li X. Anticancer compounds from marine macroalgae and their application as medicinal foods. Adv Food Nutr Res, 2011; 64:213–24. https://doi.org/10.1016/B978-0-12-387669-0.00016-8

Kim EY, Choi YH, Lee JI, Kim IH, Nam TJ. Antioxidant Activity of Oxygen Evolving Enhancer Protein 1 Purified from Capsosiphon fulvescens.J.Food.Sci,2014;80(6):H1412-7. https://doi.org/10.1111/1750-3841.12883

Kintzios SE. Terrestrial plant-derived anticancer agents and plant species used in anticancer research. Crit Rev Plant Sci, 2006; 25:79–113. https://doi.org/10.1080/07352680500348824

Lee MH, Kim YK, Yoon NY, Shim KB, Aminina NM, Kadnikova IA, Lim,CW. Study on UV absorption materials derived from red algae Gloiopeltis fucatas and Mazzaella sp. in Russia. Fish Aquat Sci, 2012; 15:361–3. https://doi.org/10.5657/FAS.2012.0361

Luo M, Shao B, Nie W, Wei XW, Li YL, Wang BL, He ZY, Liang X, Ye TH, Wei YQ. Antitumor and adjuvant activity of λ-carrageenan by stimulating immune response in cancer immunotherapy. Sci Rep, 2015; 5:11062. https://doi.org/10.1038/srep11062

Mayer AMS, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci, 2010; 31:255–65. https://doi.org/10.1016/j.tips.2010.02.005

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Prasedya ES, Miyake M, Kobayashi D, Hazama A. Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging. BMC Complement Altern Med, 2016; 16:270. https://doi.org/10.1186/s12906-016-1199-5

Qin D, Ren R, Jia C, Lu Y, Yang Q, Chen L, Wu X, Zhu J, Guo Y, Yang P, Zhou Y, Zhu N, Bi B, Liu T. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell Physiol Biochem, 2018; 46:1849–60. https://doi.org/10.1159/000489369

Shi D, Li X, Li J, Guo S, Su H, Fan X. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chinese J Oceanol Limnol, 2010; 28:96–8. https://doi.org/10.1007/s00343-010-9213-0

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Mayer AMS, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE. The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci, 2010; 31:255–65. https://doi.org/10.1016/j.tips.2010.02.005

Na HJ, Moon PD, Lee HJ, Kim HR, Chae HJ, Shin T, Seo Y, Hong SH, Kim HM. Regulatory effect of atopic allergic reaction by Carpopeltis affinis. J Ethnopharmacol, 2005; 101:43–8. https://doi.org/10.1016/j.jep.2005.03.026

Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivates. Drug Disc Today, 2015; 21:204–7. https://doi.org/10.1016/j.drudis.2015.01.009

Pavia H, Brock E. Extrinsic factors influencing phlorotannin production in the brown alga. Mar Ecol Prog Ser, 2000; 193:285–94. https://doi.org/10.3354/meps193285

Pavia H, Cervin G, Lindgren A, Aberg P. Effects of UV- B radiation and simulated herbivory on phlorotannins in the brown alga Ascophyllum nodosum. Mar Ecol Prog Ser, 1997;157:139-146. https://doi.org/10.3354/meps157139

Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, Boo SJ, Yoon WJ, Kang HK, Yoo ES, Koh YS, Ko MH, Lee NH, Hyun JW. The ethyl acetate fraction of Sargassum muticum attenuates ultraviolet B radiation-induced apoptotic cell death via regulation of AMPK- caspase-dependent signaling pathways in human HaCaT keratinocytes. Pharm Biol, 2014; 52(9):1110–8. https://doi.org/10.3109/13880209.2013.879186

Ponce NM, Pujol CA, Damonte EB, Flores ML, Stortz CA. Fucoidans from the brown seaweed Adenocystis utricularis: extraction methods, antiviral activity and structural studies. Carbohydr Res, 2003; 338:153–65. https://doi.org/10.1016/S0008-6215(02)00403-2

Prasedya ES, Miyake M, Kobayashi D, Hazama A. Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging. BMC Complement Altern Med, 2016; 16:270. https://doi.org/10.1186/s12906-016-1199-5

Qin D, Ren R, Jia C, Lu Y, Yang Q, Chen L, Wu X, Zhu J, Guo Y, Yang P, Zhou Y, Zhu N, Bi B, Liu T. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell Physiol Biochem, 2018; 46:1849–60. https://doi.org/10.1159/000489369

Shi D, Li X, Li J, Guo S, Su H, Fan X. Antithrombotic effects of bromophenol, an alga-derived thrombin inhibitor. Chinese J Oceanol Limnol, 2010; 28:96–8. https://doi.org/10.1007/s00343-010-9213-0

Sulistijo. Buku modul rumput laut (Macroalga). Pusat Penelitian Oceanografi Lembaga Ilmu Pengetahuan Indonesia, Jakarta, 2009.

Tarman K, Lindequist U, Wende K, Porzel A, Arnold N, Wessjohann LA. Isolation of a new natural product and cytotoxic and antimicrobial activities of extracts from fungi of Indonesian marine habitats. Mar Drugs, 2011; 9(3):294–306. https://doi.org/10.3390/md9030294

Vasanthi HR, Rajamanickam GV, Saraswathy A. Tumoricidal effect of the red algae Acanthophora spicifera on Ehrlich's ascites carcinoma in mice, Seaweed Res. UntilNet, 2004; 25:217–24.

Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine, 2009; 16:97–110. https://doi.org/10.1016/j.phymed.2008.12.018

Zamroni A, Yamao M. An assessment of farm-to-market link of Indonesian dried seaweeds: contribution of middlemen toward sustainable livelihood of small-scale fishermen in Laikang Bay. Afr J Agric Res, 2012; 7:4198–208.