The oceans remain a major source of natural compounds with potential in pharmacology. In particular, during the last few decades, marine cyanobacteria have been in focus as producers of interesting bioactive compounds, especially for the treatment of cancer. In this study, the anticancer potential of extracts from twenty eight marine cyanobacteria strains, belonging to the underexplored picoplanktonic genera, Cyanobium, Synechocystis and Synechococcus, and the filamentous genera, Nodosilinea, Leptolyngbya, Pseudanabaena and Romeria, were assessed in eight human tumor cell lines. First, a crude extract was obtained by dichloromethane:methanol extraction, and from it, three fractions were separated in a Si column chromatography. The crude extract and fractions were tested in eight human cancer cell lines for cell viability/toxicity, accessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactic dehydrogenase release (LDH) assays. Eight point nine percent of the strains revealed strong cytotoxicity; 17.8% showed moderate cytotoxicity, and 14.3% assays showed low toxicity. The results obtained revealed that the studied genera of marine cyanobacteria are a promising source of novel compounds with potential anticancer activity and highlight the interest in also exploring the smaller filamentous and picoplanktonic genera of cyanobacteria.
References
[1]
Butler, M.S. The role of natural product chemistry in drug discovery. J. Nat. Prod. 2004, 67, 2141–2153.
[2]
Li, J.W.; Vederas, J.C. Drug discovery and natural products: End of an era or an endless frontier? Science 2009, 325, 161–165, doi:10.1126/science.1168243.
[3]
Nagarajan, M.; Maruthanayagam, V.; Sundararaman, M. A review of pharmacological and toxicological potentials of marine cyanobacterial metabolites. J. Appl. Toxicol. 2012, 32, 153–185, doi:10.1002/jat.1717.
[4]
Jimenez, J.I.; Vansach, T.; Yoshida, W.Y.; Sakamoto, B.; Porzgen, P.; Horgen, F.D. Halogenated fatty acid amides and cyclic depsipeptides from an eastern Caribbean collection of the cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2009, 72, 1573–1578, doi:10.1021/np900173d.
[5]
Gutierrez, M.; Tidgewell, K.; Capson, T.L.; Engene, N.; Almanza, A.; Schemies, J.; Jung, M.; Gerwick, W.H. Malyngolide dimer, a bioactive symmetric cyclodepside from the panamanian marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2010, 73, 709–711, doi:10.1021/np9005184.
[6]
Tripathi, A.; Puddick, J.; Prinsep, M.R.; Rottmann, M.; Chan, K.P.; Chen, D.Y.; Tan, L.T. Lagunamide C, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Lyngbya majuscula. Phytochemistry 2011, 72, 2369–2375, doi:10.1016/j.phytochem.2011.08.019.
[7]
Malloy, K.L.; Villa, F.A.; Engene, N.; Matainaho, T.; Gerwick, L.; Gerwick, W.H. Malyngamide 2, an oxidized lipopeptide with nitric oxide inhibiting activity from a Papua New Guinea marine cyanobacterium. J. Nat. Prod. 2011, 74, 95–98, doi:10.1021/np1005407.
Gutierrez, M.; Suyama, T.L.; Engene, N.; Wingerd, J.S.; Matainaho, T.; Gerwick, W.H. Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida. J. Nat. Prod. 2008, 71, 1099–1103, doi:10.1021/np800121a.
[10]
Han, B.; Gross, H.; Goeger, D.E.; Mooberry, S.L.; Gerwick, W.H. Aurilides B and C, cancer cell toxins from a Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2006, 69, 572–575, doi:10.1021/np0503911.
[11]
Mooberry, S.L.; Leal, R.M.; Tinley, T.L.; Luesch, H.; Moore, R.E.; Corbett, T.H. The molecular pharmacology of symplostatin 1: A new antimitotic dolastatin 10 analog. Int. J. Cancer 2003, 104, 512–521, doi:10.1002/ijc.10982.
[12]
Medina, R.A.; Goeger, D.E.; Hills, P.; Mooberry, S.L.; Huang, N.; Romero, L.I.; Ortega-Barria, E.; Gerwick, W.H.; McPhail, K.L. Coibamide A, a potent antiproliferative cyclic depsipeptide from the Panamanian marine cyanobacterium Leptolyngbya sp. J. Am. Chem. Soc. 2008, 130, 6324–6325, doi:10.1021/ja801383f.
[13]
Rubio, B.K.; Parrish, S.M.; Yoshida, W.; Schupp, P.J.; Schils, T.; Williams, P.G. Depsipeptides from a Guamanian marine cyanobacterium, Lyngbya bouillonii, with Selective Inhibition of Serine Proteases. Tetrahedron Lett. 2010, 51, 6718–6721.
[14]
Chen, X.X.; Smith, G.D.; Waring, P. Human cancer cell (Jurkat) killing by the cyanobacterial metabolite calothrixin A. J. Appl. Phycol. 2003, 15, 269–277, doi:10.1023/A:1025134106985.
[15]
Luesch, H.; Yoshida, W.Y.; Moore, R.E.; Paul, V.J.; Mooberry, S.L. Isolation, structure determination, and biological activity of Lyngbyabellin A from the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2000, 63, 611–615, doi:10.1021/np990543q.
[16]
Kalemkerian, G.P.; Ou, X.L.; Adil, M.R.; Rosati, R.; Khoulani, M.M.; Madan, S.K.; Pettit, G.R. Activity of dolastatin 10 against small-cell lung cancer in vitro and in vivo: Induction of apoptosis and bcl-2 modification. Cancer Chemother. Pharmacol. 1999, 43, 507–515, doi:10.1007/s002800050931.
[17]
LePage, K.T.; Goeger, D.; Yokokawa, F.; Asano, T.; Shioiri, T.; Gerwick, W.H.; Murray, T.F. The neurotoxic lipopeptide kalkitoxin interacts with voltage-sensitive sodium channels in cerebellar granule neurons. Toxicol. Lett. 2005, 158, 133–139, doi:10.1016/j.toxlet.2005.03.007.
Engene, N.; Choi, H.; Esquenazi, E.; Rottacker, E.C.; Ellisman, M.H.; Dorrestein, P.C.; Gerwick, W.H. Underestimated biodiversity as a major explanation for the perceived rich secondary metabolite capacity of the cyanobacterial genus Lyngbya. Environ. Microbiol. 2011, 13, 1601–1610, doi:10.1111/j.1462-2920.2011.02472.x.
Taniguchi, M.; Nunnery, J.K.; Engene, N.; Esquenazi, E.; Byrum, T.; Dorrestein, P.C.; Gerwick, W.H. Palmyramide A, a cyclic depsipeptide from a Palmyra Atoll collection of the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2010, 73, 393–398, doi:10.1021/np900428h.
[22]
McPhail, K.L.; Correa, J.; Linington, R.G.; Gonzalez, J.; Ortega-Barria, E.; Capson, T.L.; Gerwick, W.H. Antimalarial linear lipopeptides from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2007, 70, 984–988, doi:10.1021/np0700772.
[23]
Matthew, S.; Paul, V.J.; Luesch, H. Largamides A–C, tiglic acid-containing cyclodepsipeptides with elastase-inhibitory activity from the marine cyanobacterium Lyngbya confervoides. Planta Med. 2009, 75, 528–533, doi:10.1055/s-0029-1185332.
[24]
Thornburg, C.C.; Thimmaiah, M.; Shaala, L.A.; Hau, A.M.; Malmo, J.M.; Ishmael, J.E.; Youssef, D.T.; McPhail, K.L. Cyclic depsipeptides, grassypeptolides D and E and Ibu-epidemethoxylyngbyastatin 3, from a Red Sea Leptolyngbya cyanobacterium. J. Nat. Prod. 2011, 74, 1677–1685, doi:10.1021/np200270d.
[25]
Teruya, T.; Sasaki, H.; Kitamura, K.; Nakayama, T.; Suenaga, K. Biselyngbyaside, a macrolide glycoside from the marine cyanobacterium Lyngbya sp. Org. Lett. 2009, 11, 2421–2424, doi:10.1021/ol900579k.
[26]
Bopp, S.K.; Lettieri, T. Comparison of four different colorimetric and fluorometric cytotoxicity assays in a zebrafish liver cell line. BMC Pharmacol. 2008, 8, 8, doi:10.1186/1471-2210-8-8.
[27]
Vaucher, R.A.; da Motta Ade, S.; Brandelli, A. Evaluation of the in vitro cytotoxicity of the antimicrobial peptide P34. Cell Biol. Int. 2010, 34, 317–323, doi:10.1042/CBI20090025.
[28]
Kim, H.; Yoon, S.C.; Lee, T.Y.; Jeong, D. Discriminative cytotoxicity assessment based on various cellular damages. Toxicol. Lett. 2009, 184, 13–17, doi:10.1016/j.toxlet.2008.10.006.
[29]
Weyermann, J.; Lochmann, D.; Zimmer, A. A practical note on the use of cytotoxicity assays. Int. J. Pharm. 2005, 288, 369–376, doi:10.1016/j.ijpharm.2004.09.018.
[30]
Plaza, M.; Santoyo, S.; Jaime, L.; Garcia-Blairsy Reina, G.; Herrero, M.; Senorans, F.J.; Ibanez, E. Screening for bioactive compounds from algae. J. Pharm. Biomed. Anal. 2010, 51, 450–455, doi:10.1016/j.jpba.2009.03.016.
[31]
Leao, P.N.; Ramos, V.; Goncalves, P.B.; Viana, F.; Lage, O.M.; Gerwick, W.H.; Vasconcelos, V.M. Chemoecological screening reveals high bioactivity in diverse culturable portuguese marine cyanobacteria. Mar. Drugs 2013, 11, 1316–1335, doi:10.3390/md11041316.
[32]
Hrouzek, P.; Tomek, P.; Lukesova, A.; Urban, J.; Voloshko, L.; Pushparaj, B.; Ventura, S.; Lukavsky, J.; Stys, D.; Kopecky, J. Cytotoxicity and secondary metabolites production in terrestrial Nostoc strains, originating from different climatic/geographic regions and habitats: Is their cytotoxicity environmentally dependent? Environ. Toxicol. 2011, 26, 345–358, doi:10.1002/tox.20561.
[33]
Mian, P.; Heilmann, J.; Burgi, H.R.; Sticher, O. Biological screening of terrestrial and freshwater cyanobacteria for antimicrobial activity, brine shrimp lethality, and cytotoxicity. Pharm. Biol. 2003, 41, 243–247, doi:10.1076/phbi.41.4.243.15672.
[34]
Surakka, A.; Sihvonen, L.M.; Lehtimaki, J.M.; Wahlsten, M.; Vuorela, P.; Sivonen, K. Benthic cyanobacteria from the Baltic Sea contain cytotoxic Anabaena, Nodularia, and Nostoc strains and an apoptosis-inducing Phormidium strain. Environ. Toxicol. 2005, 20, 285–292, doi:10.1002/tox.20119.
[35]
Matthew, S.; Schupp, P.J.; Luesch, H. Apratoxin E, a cytotoxic peptolide from a guamanian collection of the marine cyanobacterium Lyngbya bouillonii. J. Nat. Prod. 2008, 71, 1113–1116, doi:10.1021/np700717s.
[36]
Martins, R.; Pereira, P.; Welker, M.; Fastner, J.; Vasconcelos, V.M. Toxicity of culturable cyanobacteria strains isolated from the Portuguese coast. Toxicon 2005, 46, 454–464, doi:10.1016/j.toxicon.2005.06.010.
[37]
Frazao, B.; Martins, R.; Vasconcelos, V. Are known cyanotoxins involved in the toxicity of picoplanktonic and filamentous North Atlantic marine cyanobacteria? Mar. Drugs 2010, 8, 1908–1919, doi:10.3390/md8061908.
[38]
Martins, R.; Fernandez, N.; Beiras, R.; Vasconcelos, V. Toxicity assessment of crude and partially purified extracts of marine Synechocystis and Synechococcus cyanobacterial strains in marine invertebrates. Toxicon 2007, 50, 791–799, doi:10.1016/j.toxicon.2007.06.020.
[39]
Martins, R.F.; Ramos, M.F.; Herfindal, L.; Sousa, J.A.; Skaerven, K.; Vasconcelos, V.M. Antimicrobial and cytotoxic assessment of marine cyanobacteria—Synechocystis and Synechococcus. Mar. Drugs 2008, 6, 1–11, doi:10.3390/md6010001.
[40]
Lopes, V.R.; Schmidtke, M.; Fernandes, M.H.; Martins, R.; Vasconcelos, V. Cytotoxicity in L929 fibroblasts and inhibition of herpes simplex virus type 1 Kupka by estuarine cyanobacteria extracts. Toxicol. In Vitro 2011, 25, 944–950, doi:10.1016/j.tiv.2011.03.003.
[41]
Kotai, J. Instructions for Preparation of Modified Nutrient Solution Z8 for Algae. NIVA B-11/69. NIVA 1976. Estimation of Algal Growth Potential; Norwegian Institute for Water Research: Oslo, Norway, 1972.
[42]
Rippka, R. Isolation and purification of cyanobacteria. Methods Enzymol. 1988, 167, 3–27.
[43]
Brito, A.; Ramos, V.; Seabra, R.; Santos, A.; Santos, C.L.; Lopo, M.; Ferreira, S.; Martins, A.; Mota, R.; Frazao, B. Culture-dependent characterization of cyanobacterial diversity in the intertidal zones of the Portuguese coast: A polyphasic study. Syst. Appl. Microbiol. 2012, 35, 110–119, doi:10.1016/j.syapm.2011.07.003.
[44]
Costa, M.S.; Costa, M.; Ramos, V.; Le？o, P.N.; Barreiro, A.; Vasconcelos, V.; Martins, R.; Interdisciplinary Center of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto, Porto, Portugal. Toxicity of Picocyanobacteria Isolates from a Clade of Marine. Cyanobium, 2013. unpublished work.
[45]
Leao, P.N.; Costa, M.; Ramos, V.; Pereira, A.R.; Fernandes, V.C.; Domingues, V.F.; Gerwick, W.H.; Vasconcelos, V.M.; Martins, R. Antitumor activity of hierridin B, a cyanobacterial secondary metabolite found in both filamentous and unicellular marine strains. PLoS One 2013, 8, e69562, doi:10.1371/journal.pone.0069562.
[46]
Lopes, V.R.; Ramos, V.; Martins, A.; Sousa, M.; Welker, M.; Antunes, A.; Vasconcelos, V.M. Phylogenetic, chemical and morphological diversity of cyanobacteria from Portuguese temperate estuaries. Mar. Environ. Res. 2012, 73, 7–16, doi:10.1016/j.marenvres.2011.10.005.
