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Review

Marine Cyanobacteria Compounds with Anticancer Properties: A Review on the Implication of Apoptosis

by
Margarida Costa
1,
João Costa-Rodrigues
2,
Maria Helena Fernandes
2,
Piedade Barros
3,
Vitor Vasconcelos
1,4 and
Rosário Martins
1,3,5,*
1
Marine and Environmental Research Center—CIIMAR/CIMAR, Porto University, Rua dos Bragas, 289, 4050-123 Porto, Portugal
2
Laboratory of Pharmacology and Cellular Biocompatibility, Faculty of Dental Medicine, Porto University, Rua Dr. Manuel Pereira da Silva, 4200-393 Porto, Portugal
3
Centre of Health and Environmental Research—CISA, Superior School of Health Technology of Porto, Polytechnic Institute of Porto, Rua Valente Perfeito, 322, 4400-330 Vila Nova de Gaia, Portugal
4
Faculty of Sciences, Porto University, Rua do Campo Alegre, 4169-007 Porto, Portugal
5
Institute for Molecular and Cell Biology—IBMC, Porto University, Rua do Campo Alegre 823, 4150-180 Porto, Portugal
*
Author to whom correspondence should be addressed.
Mar. Drugs 2012, 10(10), 2181-2207; https://doi.org/10.3390/md10102181
Submission received: 6 August 2012 / Revised: 11 September 2012 / Accepted: 18 September 2012 / Published: 28 September 2012
(This article belongs to the Special Issue Bioactive Compounds from Marine Microorganisms)
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Abstract

:
Marine cyanobacteria have been considered a rich source of secondary metabolites with potential biotechnological applications, namely in the pharmacological field. Chemically diverse compounds were found to induce cytoxicity, anti-inflammatory and antibacterial activities. The potential of marine cyanobacteria as anticancer agents has however been the most explored and, besides cytotoxicity in tumor cell lines, several compounds have emerged as templates for the development of new anticancer drugs. The mechanisms implicated in the cytotoxicity of marine cyanobacteria compounds in tumor cell lines are still largely overlooked but several studies point to an implication in apoptosis. This association has been related to several apoptotic indicators such as cell cycle arrest, mitochondrial dysfunctions and oxidative damage, alterations in caspase cascade, alterations in specific proteins levels and alterations in the membrane sodium dynamics. In the present paper a compilation of the described marine cyanobacterial compounds with potential anticancer properties is presented and a review on the implication of apoptosis as the mechanism of cell death is discussed.

1. Introduction

Cyanobacteria are a diverse group of prokaryotic organisms that can exist in a wide range of ecosystems. Capable to develop photosynthesis, cyanobacteria constitute one of the components of the primary first level organisms in water food chains. These organisms have also important roles in nutrient cycles such as nitrogen cycle, by converting atmospheric nitrogen into an organic form, in a process that releases some residual hydrogen [1].
The first studies concerning cyanobacteria were focused on their ecological and public heath impact, due to their capacity to produce toxins with deleterious effects on plants, invertebrates and vertebrates, including humans [2,3]. In humans, toxins such as microcystins, nodularins and cylindrospermopsin were found to induce liver and kidney damage, cytotoxicity, neurotoxicity, dermal toxicity, gastrointestinal disturbances among others [4]. More recently, several studies have demonstrated that cyanobacteria also produce compounds with biotechnological and pharmaceutical interest. Important biological properties such as anticancer, anti-inflammatory and antibiotic activities have been described [5].
Marine cyanobacteria in particular have been considered a prominent source of structurally diverse and biologically active natural products [6]. The diversity in secondary metabolites is a result of the cyanobacterial capacity to integrate both Non-Ribosomal Peptide Synthethases with Polyketide Synthases. Cyanobacteria have a wide range of enzymes responsible for methylations, oxidations, tailoring and other alterations [7], resulting in chemically diverse natural products such as linear peptides [8], cyclic peptides [9], linear lipopeptides [10], depsipeptides [11], cyclic depsipeptides [12], fatty acid amides [13], swinholides [14], glicomacrolides [15] or macrolactones [16].
A large diversity of biological interactions is described between marine cyanobacteria compounds and several groups of organisms, such as bacteria [17], fungi [18,19] parasites [20] and invertebrates [21]. The role of the compounds in marine environment has been rarely elucidated but a possible explanation is that they represent a defensive handling to the surrounding predators [22]. In what concerns to humans, anti-inflammatory [23] neurotoxic [12] and anticancerigenous [24] are common bioactive properties. The cytotoxic effects of marine cyanobacteria compounds on human tumor cell lines are the most studied, with some compounds producing effects at the nanomolar range [25]. As examples, apratoxin D, produced by species of Lyngbya is potently cytotoxic to human lung cancer cells [26] and likewise, symplocamide A, isolated from Symploca sp. showed also potent cytotoxicity to lung cancer cells and neuroblastoma cells [27].
Cell death is crucial in cancer therapy. Comparing cell death mechanisms in neoplastic cells, apoptosis reveals its importance when compared with necrosis since it occurs as a physiological process to any mild cell injury or simply when cell function is finished or disturbed, occurs via a predictable and coordinated pathway, and cellular deletion does not involve inflammation [28]. In contrast, necrosis is difficult to prevent and always develops an inflammatory response and death of the surrounding cells [29]. Autophagy, also described as a mechanism of cell death, is likewise indicated as a cancer therapeutic target. However, it has a dual effect since maintaining cell survival can promote the growth of established tumors [30]. Several anticancer drugs work as apoptotic modulators, in order to eliminate silent and cleanly the unwanted cells [31,32]. Marine cyanobacteria were found to produce a wide range of compounds that revealed apoptotic properties. Apoptosis can be induced by both intrinsic and extrinsic signals, by multiple agents, as the natural flavonoid quercetin [33], the representative reactive oxygen species H2O2 [34] or even the UV radiation [35]. Apoptotic cells develop typical morphological alterations that allow its identification. During an early stage of apoptosis, called cell shrinkage, cells have a smaller size, showing a dense cytoplasm with thinner organelles [36]. Martins and co-workers demonstrated that HL-60 cells exposed to aqueous extracts of Synechocystis sp. and Synechococcus sp. strains, presented cell shrinkage showing that cells were developing apoptosis, and membrane budding, that occurs when cell is fragmented into apoptotic bodies [37]. Apoptotic cells also develop nuclear alterations, visible as nuclear fragmentation and chromatin condensation [36]. Biselyngbyaside, a macrolide glycoside produced by Lyngbya sp., was found to induce apoptosis in mature osteoclasts, revealed by nuclear condensation [38]. Marine benthic Anabaena sp. extracts were found to induce apoptosis in acute myeloid leukemia cell line, with cells showing several described typical morphological markers, such as chromatin condensation, nuclear fragmentation, surface budding and release of apoptotic bodies [39].
Besides morphological markers that allow the direct identification of an apoptotic cell, some other cellular and molecular alterations associated to apoptosis can be identified. Since several marine cyanobacteria compounds interact with important molecular targets involved in anticancer activity leading to a controlled death of tumor cells, this review aims to resume the marine cyanobacterial products that were found to inhibit the proliferation of cancer cell lines, namely by inducing apoptotic cell death. Effects of compounds on cell cycle arrest, mitochondrial dysfunctions and oxidative damage, alterations in caspase cascade, non-caspases proteases involvement, alterations in the Bcl-2 protein family and alterations in membrane sodium channel dynamics are reviewed. In order to summarize the data available in the literature, in Table 1 we present the described cyanobacterial compounds that were found to induce cytotoxic effects on a wide range of cancer cell line, and in Table 2 we describe the most relevant effects related to anticancer activity induced by marine cyanobacteria compounds.
Table
Table 1. Marine cyanobacteria compounds with potential anticancer properties.
Table 1. Marine cyanobacteria compounds with potential anticancer properties.
CompoundSourceClass of compoundCytoxicity assayHuman cell line testedReference
Ankaraholide AGeitlerinemaGlycosilated swinholideMTTNCI-H460 lung tumor[14]
SRBMDA-MB-435 breast carcinoma[14]
Apratoxin ALyngbya majusculaCyclic depsipeptideSRBKB oral epidermoid cancer and LoVo colon cancer[40,41]
MTTU2OS osteosarcoma, HT29 colon adenocarcinoma and HeLa cervical carcinoma[42]
Apratoxins B-CLyngbya sp.Cyclic depsipeptidesMTTKB oral epidermoid cancer and LoVo colon cancer[40]
Apratoxin DLyngbya majuscula and Lyngbya sordidaCyclic depsipeptideMTTH-460 lung cancer[26]
Apratoxin ELyngbya bouilloniCyclic depsipeptideMTTU2OS osteosarcoma, HT29 colon adenocarcinoma and HeLa epithelial carcinoma[42]
Apratoxins F and GLyngbya bouilloniCyclic depsipeptidesMTTH-460 lung cancer[43]
Hemocytometer countingHCT-116 colorectal cancer cells[43]
Aurilide BLyngbya majusculaCyclic depsipeptideMTTH-460 lung tumor[24]
Aurilide CLyngbya majusculaCyclic depsipeptideMTTNCI-H460 lung tumor[24]
Belamide ASymploca sp.Linear tetrapeptideNon-specifiedHCT-116 colon cancer[8]
BisebromoamideLyngbya sp.PeptideSRBHeLa S3 epithelial carcinoma[44]
BiselyngbyasideLyngbya sp.GlicomacrolideSRBHeLa S3 epithelial carcinoma, SNB-78 central nervous system cancer and NCI H522 lung cancer[15]
Calothrixin ACalothrixPentacyclic indolophenanthridine3H-thymidine incorporationHeLa epithelial carcinoma[45]
MTTLeukemia CEM[46]
Calothrixin BCalothrixPentacyclic indolophenanthridineMTT HeLa epithelial carcinoma[47]
Leukemia CEM[46]
Caylobolide ALyngbya majusculaMacrolactoneNon-specifiedHCT-116 colon tumor[48]
Caylobolide BPhormidium spp.MacrolactoneMTTHT29 colorectal adenocarcinoma and HeLa cervical carcinoma[16]
Coibamide ALeptolyngbya sp.Cyclic depsipeptideMTTLung cancer NCI-H460, breast cancer MDA-MB-231, melanoma LOX IMVI, leukemia HL-60 and astrocytoma SNB75[49]
Cryptophycin 1Nostoc spp.Cyclic depsipeptideCell morphology examinationMDA-MB-435 mammary adenocarcinoma and SKOV3 ovarian carcinoma[50]
AlamarBlue dye reductionLeukemia U937, CCRF-CEM and HL-60, colon carcinoma HT-29, GC3 and Caco-2, mammary carcinoma MCF-7 and MDA-MB-231 and cervical carcinoma HeLa[51]
Dolastatin 10Symploca sp.Linear PentapeptideMTTLung A549 carcinoma[52]
Human lung cancer cells: NCI-H69, -H82, -H446 and -H510[53]
Human DU-145 prostate cancer cell line[54]
[3H] ThymidineSeveral lymphoma cell lines[55]
Trypan blue dyeReh lymphoblastic leukemia[56]
Dolastatin 12Leptolyngbya sp.Cyclic depsipeptideMTTA549 lung carcinoma[52]
DragonamideLyngbya majusculaLipopeptideNon-specifiedA-549 lung epithelial adenocarcinoma, HT-29 colon adenocarcinoma and MEL-28 melanoma[57]
Ethyl Tumonoate AOscillatoria margaritiferaPeptideMTTH-460 lung cancer[58]
Hoiamide AAssemblage of Lyngbya majuscule and Phormidium gracileCyclic depsipeptideNon-specifiedH-460 lung cancer[59]
Hoiamide BCyanobacterial sampleCyclic depsipeptideNon-specifiedH-460 lung cancer[59]
Homodolastatin 16Lyngbya majusculaCyclic depsipeptideMTTWHCO1 and WHCO6 esophageal cancer and ME180 cervical cancer[60]
Isomalyngamide A and A-1Lyngbya majusculaFatty acid amidesMTTBreast cancer MCF-7 and MDA-MB-231[13]
Jamaicamides A-CLyngbya majusculaPolyketide-PeptidesMTTH-460 lung cancer[61]
KalkitoxinLyngbya majusculaLipopeptideTrypan blue dyeHCT-116 colon[62]
Lagunamide CLyngbya majusculaCyclic depsipeptideMTTLung adenocarcinoma A549, cancer prostate PC3, ileocecal colorectal cancer HCT8 and ovary cancer SK-OV[63]
LargazoleSymploca sp.Cyclic depsipeptideMTTMDA-MB-23I breast cancer and U2OS osteosarcoma[64]
A549 lung cancer and HCT-116 colorectal carcinoma[65]
Lyngbyabellin ALyngbya majusculaCyclic depsipeptideNon-specifiedKB nasopharyngeal carcinoma and LoVo colon adenocarcinoma[66]
LyngbyalosideLyngbya sp.GlicomacrolideNon-specifiedKB nasopharyngeal carcinoma and LoVo colon adenocarcinoma[67]
Majusculamide CLyngbya majusculaCyclic depsipeptideNon-specifiedOvarian carcinoma OVCAR-3, kidney cancer A498, lung cancer NCI-H460, colorectal cancer KM20L2 and glioblastoma SF-295[68]
Malevamide DSymploca hydnoidesPeptide esterNon-specifiedLung cancer A-549, colon cancer HT-29 and melanoma MEL-28.[69]
Malyngamide 2Lyngbya sordidaFatty acid amineMTTH-460 lung cancer[23]
Malyngamide C, J and KLyngbya majusculaFatty acid aminesMTTH-460 lung cancer[70]
Malyngolide dimmerLyngbya majusculaCyclodepsideMTTH-460 lung cancer[71]
Nostocyclopeptide A1 and A2Nostoc sp.Cyclic heptapeptidesNon-specifiedKB oral epidermoid cancer and LoVo colon cancer[72]
ObyanamideLyngbya confervoidesCyclic depsipeptideNon-specifiedKB oral epidermoid cancer and LoVo colon cancer[73]
PalauamideLyngbya sp.Cyclic depsipeptideNon-specifiedCervical carcinoma HeLa, lung adenocarcinoma A549 and gastrocarcinoma BGC[74]
KB oral epidermoid cancer[75]
Palmyramide ALyngbya majusculaCyclic depsipeptideMTTH-460 lung cancer[76]
Pitipeptolides A-BLyngbya majusculaCyclic depsipeptidesNon-specifiedLoVo colon cancer[77]
MTTHT29 colon adenocarcinoma and MCF-7 breast cancer[17]
Pitipeptolide CLyngbya majusculaCyclic depsipeptideMTTHT29 colon adenocarcinoma and MCF-7 breast cancer[17]
PitiprolamideLyngbya majusculaCyclic depsipeptideMTTHCT116 colorectal carcinoma and MCF7 breast adenocarcinoma[78]
PseudodysideninLyngbya majusculaLipopeptideNon-specifiedA-549 lung adenocarcinoma, HT-29 colon adenocarcinoma and MEL-28 melanoma[57]
Somocystinamide ALyngbya majusculaLipopeptideXTTJurkat and CEM leukemia, A549 lung carcinoma, Molt4 T leukemia, M21 melanoma and U266 myeloma[79]
SymplocamideSymploca sp.Cyclic peptideNon-specifiedH-460 lung cancer[27]
Symplostatin 1Symploca hydnoidesLinear PentapeptideSRBMDA-MB-435 breast carcinoma and NCI/ADR ovarian carcinoma[25]
Epidermoid carcinoma cell line[80]
TasiamideSymploca sp.Cyclic peptideNon-specifiedKB oral epidermoid cancer and LoVo colon cancer[81]
Tasiamide BSymploca sp.PeptideNon-specifiedKB oral epidermoid cancer[82]
Tasipeptins A-BSymploca sp.Cyclic depsipeptidesNon-specifiedKB oral epidermoid cancer[83]
UlongapeptinLyngbya sp.Cyclic depsipeptideNon-specifiedKB oral epidermoid cancer[84]
Veraguamides A-GSymploca cf. hydnoidesCyclic depsipeptidesMTTH-460 lung cancer[85]
WewakazoleLyngbya sordidaCyclic dodecapeptideMTTH-460 lung cancer[23]
WewakpeptinsLyngbya semiplenaDepsipeptidesMTTH-460 lung cancer[11]
MTT: 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; XTT: 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; SBR: Sulforhodamine B.
Table
Table 2. Relevant anticancer cell effects induced by marine cyanobacteria compounds.
Table 2. Relevant anticancer cell effects induced by marine cyanobacteria compounds.
CompoundSourceClass of compoundModel testedCell effectReference
AlotamideLyngbya bouilloniiCyclic depsipeptideMurine cerebrocortical neuronsCalcium influx promotion[12]
Ankaraholide AGeitlerinemaGlycosilated swinholideRat aorta A-10 cellsLoss of filamentous (F)-actin[14]
AntillatoxinLyngbya majusculaLipopeptidePrimary rat cerebellar granule cellsVoltage-gated sodium channel activation[86]
CHL 1610 Chinese hamster lung cells[87]
Antillatoxin BLyngbya majusculaLipopeptideneuro-2a mouse neuroblastoma cellsSodium channel activation[10]
Apratoxin ALyngbya majusculaCyclic depsipeptideHuman HeLa cervical carcinoma cellsCell cycle inhibition[88]
Human U2OS osteosarcoma cellsSecretory pathway inhibition[89]
Aurilide BLyngbya majusculaCyclic depsipeptideRat aorta A-10 cellsMicrofilament disruption[24]
Belamide ASymploca sp.Linear tetrapeptideRat aorta A-10 cellsMicrotubule disruption[8]
BisebromoamideLyngbya sp.PeptideHuman HeLa epithelial carcinoma cellsActin filaments stabilization[90]
Normal rat kidney cells extracellular signal regulated protein kinaseProtein kinase inhibition[44]
Bouillomides A-BLyngbya bouilloniiDepsipeptidesElastase and chymotrypsinSerine proteases inhibition[91]
Calothrixin ACalothrixPentacyclic indolophenanthridineHuman leukemia CEM cellsCell cycle inhibition[46]
Calothrixin BCalothrixPentacyclic indolophenanthridineHuman HeLa epithelial carcinoma cellsCell cycle inhibition[45]
Human HeLa epithelial carcinoma cellsOxidative stress induction[45]
Coibamide ALeptolyngbya sp.Cyclic depsipeptideHuman NCI-H460 lung cancer cell lineCell cycle inhibition[49]
Cryptophycin 1Nostoc spp.Cyclic depsipeptideHuman MDA-MB-435 mammary adenocarcinoma and SKOV3 ovarian carcinoma cellsCell cycle inhibition[50]
Human MDA-MB-435 mammary adenocarcinomaCaspase-3 protein activation[50]
Curacin ALyngbya majusculaLipopeptideTubulinTubulin polymerization inhibition[92]
Human A549 lung carcinoma cellsBad protein levels increase[52]
Human A549 lung carcinoma cellsCaspase-3 protein activation[52]
Bovine β-tubulinTubulin polymerization inhibition[93]
Dolastatin 10Symploca sp.Linear PentapeptideHuman Reh lymphoblastic leukemia cellsBcl-2 protein reduction[56]
Human lung cancer cells: NCI-H69 and -H510Bcl-2 protein phosphorylation[53]
Human A549 lung carcinoma cellsBad protein levels increase[52]
Human A549 lung carcinoma cellsCaspase-3 protein activation[52]
Dolastatin 12Leptolyngbya sp.Cyclic depsipeptideRat aorta A-10 cellsMicrofilament disruptor[94]
Grassystatin A-BLyngbya confervoidesLinear depsipeptidesCathepsins D and EProteases inhibition[95]
HectochlorinLyngbya majusculaLipopeptideHuman CA46 Burkitt lymphoma cellsCell cycle inhibition[18]
Hermitamides A-BLyngbya majusculaLipopeptideHuman HEK embryonic kidney cellsVoltage-gated sodium channel inhibition[96]
Hoiamide AAssemblage of Lyngbya majuscule and Phormidium gracileCyclic depsipeptidePrimary cultures of neocortical neurons from embryonic miceSodium channel activation[59,97]
Hoiamide BCyanobacterial sampleCyclic depsipeptidePrimary cultures of neocortical neurons from embryonic miceSodium influx stimulation[59]
KalkitoxinLyngbya majusculaLipopeptidePrimary rat cerebellar granule neuron culturesCalcium influx inhibition[98]
Kempopeptin ALyngbya sp.Cyclic depsipeptideBovine pancreatic α-chymotrypsin, porcine pancreatic elastaseSerine Protease Inhibition[99]
Kempopeptin BLyngbya sp.Cyclic depsipeptideTrypsinSerine Protease Inhibition[99]
Largamides A-CLyngbya confervoidesCyclic depsipeptidesPorcine pancreatic elastaseSerine protease inhibition[100]
Largamides D-GOscillatoria sp.Cyclic depsipeptidesα-chymotrypsinSerine protease inhibition[101]
Lyngbyabellin ALyngbya majusculaCyclic depsipeptideHuman CA46 Burkitt lymphoma cellsCell cycle inhibition[18]
Rat aorta A-10 cellsMicrofilament disruption[66]
Lyngbyabellin BLyngbya majusculaCyclic depsipeptideHuman CA46 Burkitt lymphoma cellsCell cycle inhibition[18]
Lyngbyastatin 1Lyngbya majusculaCyclic depsipeptideRat aorta A-10 cellsMicrofilament disruption[94]
Lyngbyastatin 4Lyngbya confervoidesCyclic depsipeptideBovine pancreatic α-chymotrypsin and porcine pancreatic elastaseSerine protease inhibition[102]
Lyngbyastatin 5-7Lyngbya spp.Cyclic depsipeptidesPorcine pancreatic elastaseSerine protease inhibition[103]
Lyngbyastatin 8-10Lyngbya semiplenaCyclic depsipeptidesPorcine pancreatic elastaseSerine protease inhibition[104]
Malevamide ESymploca laete-viridisDepsipeptideHuman HEK embryonic kidney cellsCalcium influx inhibition[105]
MolassamideDichothrix utahensisDepsipeptideBovine pancreatic α-chymotrypsin and porcine pancreatic elastaseSerine protease inhibition[106]
Palmyramide ALyngbya majusculaCyclic depsipeptideMouse neuroblastoma neuro-2a cellsSodium channel inhibition[76]
PalmyrolideAssemblage of Leptolyngbya cf. and Oscillatoria spp.MacrolideMouse neuroblastoma neuro-2a cellsSodium influx inhibition[107]
Murine cerebrocortical neuronsInhibition of calcium oscillations[107]
Pitipeptolides A and BLyngbya majusculaCyclic depsipeptidesElastaseSerine protease stimulation[77]
Pompanopeptin ALyngbya confervoidesCyclic peptidePorcine pancreatic trypsinSerine protease inhibition[108]
SymplocamideSymploca sp.Cyclic peptideChymotrypsinSerine protease inhibition[27]
Symplostatin 1Symploca hydnoidesLinear PentapeptideRat aorta A-10 and human HeLa cervical carcinoma cellsCell cycle inhibition[25]
Rat aorta A-10 cellsMicrotubule depolymerization[109]
Human MDA-MB-435 breast carcinoma cellsBcl-2 phosphorylation[25]
Human MDA-MB-435 breast carcinoma cellsCaspase-3 protein activity stimulation[25]
Symplostatin 3Symploca sp. Rat aorta A-10 cellsMicrotubule depolymerization[110]
Tiglicamides A-CLyngbya confervoidesCyclic depsipeptidesPorcine pancreatic elastaseSerine protease inhibition[111]

2. Cell Cycle Arrest

Cell cycle is a delicate mechanism that comprises cell growth and its division into two daughter cells. Some substances are able to disturb the normal functioning of this mechanism compromising cell viability, a consequence that can be directly related with apoptosis. A common cellular damage induced by marine cyanobacteria compounds is the disruption of microtubules and actin proteins [112]. As these proteins are directly involved in mitosis, alterations in the normal functioning of the cell cycle occur. The most frequent consequence is G2/M phase arrest. Cryptophycin 52, a macrocyclic depsipeptide analogue of the naturally occurring cryptophycins isolated from the marine cyanobacteria Nostoc spp. [113], and calothrixin A, a indolophenanthridine isolated from Calothrix, are two examples of bioactive metabolites that induced, in different human cancer cell lines, a cell cycle arrest in G2/M phase [45]. Dolastatins are cytotoxic peptides that were initially isolated from the sea hare Dolabella auricularia and later found to be produced by marine cyanobacterial strains [109]. To explore their anticancer potential, several synthetic analogues were produced. Dolastatin 10, found in Symploca, and its non-cyanobacterial analogue, dolastatin 15, were both found to induce an arrest in the same cell cycle phase, G2/M phase, inducing apoptosis [52,114]. Symplostatin 1, another analogue of dolastatin 10 and cryptophycin 1, a dolastatin 52 analogue, were also responsible for a G2/M arrest in human cancer cells and for disturbances in the formation of mitotic spindles [25,113,114]. Calothrixin A, beyond an arrest in G2/M phase in a leukemia cell line at 1 μM and 10 μM, is also responsible for a cumulative arrest in S phase [46]. Hectochlorin and lyngbyabellins are structurally related lipopeptide and cyclic depsipeptides isolated from the genus Lyngbya. Both hectochlorin and lyngbyabellin B are described to induce an arrest in G2/M phase in a human Burkitt lymphoma cell line, accompanied with a related increase in binucleated cells and an apparent thickening of the microfilaments [18]. Nagarajan and co-workers [115] suggested that the inhibition of cell cycle proliferation by lyngbyabellins is assigned to a thiazole ring and dichlorinated components (Figure 1), once these compounds were all found to inhibit cell cycle proliferation [18,116].
Marinedrugs 10 02181 g001 1024
Figure 1. Chemical structures of the marine cyanobacterial secondary metabolites hectochlorin and lyngbyabellins A and B.
Figure 1. Chemical structures of the marine cyanobacterial secondary metabolites hectochlorin and lyngbyabellins A and B.
Marinedrugs 10 02181 g001
Besides G2/M phase arrest effects in G1 phase are also described. Khan and co-workers [46] reported a G1 phase arrest after treatment with a low concentration (0.1 μM) of calothrixin B. The same effect was demonstrated by Ma et al. [88] in a cervical carcinoma cell line treated with the cyclic depsipeptide apratoxin A (50 nM). Coibamide, a potent cytotoxic cyclic depsipeptide, founded in a Panamanian Leptolyngbya sp., was also described as capable to cause a significant dose dependent increase in the number of cells in G1 phase of the cell cycle [49].

3. Mitochondrial Dysfunctions and Oxidative Damage

Mitochondria have essential functions in aerobic cells, and interferences in its normal behavior are crucial to determine cell fate [117]. A dysfunction in these organelles imbalances the cell redox potential, inducing damages in cell components that can lead, in the cases that pro-survival mechanisms fail, to apoptosis [118]. To the best of our knowledge, no study relating marine cyanobacterial natural products with mitochondrial dysfunctions has been done. However aurilide, a cyclodepsipeptide isolated from the sea hare Dolabella auricularia and related with the marine cyanobacterial aurilides A and B, is described to induce a dysfunction in mitochondria. HeLa cells, when treated with this metabolite exhibited mitochondria fragmentation, visible by MitoTracker Red staining [119].
Oxidative stress is a cell condition that can be triggered by mitochondrial disorders. It can occur due to an overproduction of reactive oxygen species (ROS) or to a decrease in antioxidant levels [120]. Calothrixin A is described as an oxidative stress inducer in Jurkat human T cells, since they show an increase on intracellular ROS content after treatment with that molecule [45]. DNA damage is also a consequence directly associated to the oxidative stress, and it is commonly observed as a result of exposure to cyanobacterial secondary metabolites. As expected, besides an increase in ROS, calothrixin A foments DNA fragmentation [45]. DNA fragmentation is the most common DNA damage observed. Dolastatin 10 induced DNA damage on several human lymphoma cell lines [55] and on lung cancer cells [52]. Cryptophycins 1 and 52 are also metabolites that were found to induce DNA fragmentation [50,113].
External nuclei alterations can be also a consequence of oxidative stress. Binucleated cells are frequently observed as a response to cyanobacterial products, as swinholide A, isolated from cyanobacterial samples of Symploca cf. sp. [14] or lyngbyabellin [116]. Symplostatin 1 was found to induce an abnormal nuclear convolution in a rat aorta cell line, leading to the breakdown of nucleus and the formation of numerous micronuclei [25].
To counterbalance the deleterious effects of ROS, cells developed a complex antioxidant system. The antioxidant enzymes, like superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST) and several peroxidases, constitute the front line, with important scavenging functions. Some other molecules, with low molecular weight, have crucial roles, such as glutathione, ascorbate or phenolic compounds [121]. The capacity of marine cyanobacterial natural products to interfere with the antioxidant system of human cells is not well elucidated. Evidences indicate that pigments are the compounds with higher antioxidant activity. Carotenoids isolated from the marine Trichodesmium are responsible for an antioxidative protection, observed with ferric reducing/antioxidant power assay [122]. In the same study, extracts from marine strains of Anabaena, Cyanothece, Prochlorothrix and Synechococcus showed antioxidant properties, but mainly in the protein extract [122]. Also the major phycobiliprotein, c-phycocyanin, from both Lyngbya and Phormidium, is capable to scavenge ROS, in particular peroxyl and hydroxyl radicals [123]. It was also suggested that this antioxidant capacity is resultant from the covalent linked tetrapyrole chromophore with phycocyanobilin [123].

4. Alterations in Caspase Cascade

Caspases are a family of cysteine aspartate proteases that act as the central executers of apoptosis. They are synthesized as inactive zymogens, which are activated after proteolytic cleavage [124]. According to their point of entrance into apoptotic process, caspases can be classified as initiators or effectors. Initiator caspases, that include -8, -9, and -10, activate the downstream effectors caspases, -3, -6 and -7, in a cascade of events that triggers a controlled and programmed cell death [125].
Marine cyanobacteria produce several compounds that are capable to induce alterations on caspases as a pathway to induce cell death. Several marine benthic cyanobacterial extracts showed to induce apoptosis partially dependent of protein caspases. Cells overexpressing LEDGF/p75, an inhibitor of cell death dependent of caspases, showed an increase in just a few number of apoptotic cells after treatment, when compared with the control [39].
Caspase-3 is the most studied caspase concerning to apoptosis induced by natural products. The activity of caspase-3 protein is increased after exposure to symplostatin 1 [25] and to the glicomacrolide biselyngbyaside [38]. Also cryptophycin 1 is described to induce apoptosis in a human ovarian carcinoma cell line, initiating the caspases cascade through caspase-3 activation [50]. The cleavage, and therefore the activation, of caspase-3 were still previously observed as a response to dolastatins 10 and 15 and to the lipopeptide curacin A [52].
Cryptophycin 52 induced an apoptosis dependent on both caspase-3 and caspase-1 activation [113]. Another study [79] also reported that apoptosis induced by somocystinamide A, a lipopeptide from Lyngbya majuscula, occurs in a caspase-8 dependent manner, since it was observed an inhibition of tumor growth selectively in the caspase-8-expressing neuroblastoma cells, when compared with cells lacking the protein.

5. Non-Caspases Proteases Involvement

Although caspases have a central role in the apoptotic cell death developing, it is described that the process often continues after an inhibition of this proteins [126,127]. This finding suggests the implication of other executors, which promote apoptosis in the absence of caspases. It was already proposed that some other proteases, capable to support apoptosis, have caspases amplification and assistance functions [128].
Proteases are involved in the irreversibly hydrolysis of the peptide bonds in proteins, an important post-translational modification. These proteolytic enzymes are important for the control of a large number of key physiological processes, including apoptosis [129]. Apoptotic cell death induced by intracellular proteolysis of some serine proteases is already described [130]. Several cyanobacterial compounds have been described to interfere with the normal functioning of serine proteases, mainly the pancreatic elastase, chymotrypsin and trypsin, as is resumed in Table 3. Symplocamide A was described to inhibit chymotrypsin with an IC50 of 0.38 μM, with trypsin being also affected but with an IC50 of 80.2 μM, a difference greater than 200-fold [27]. The authors suggested that, to inhibit trypsin under 10 μM, a basic aminoacid residue between treonine (Thr) and 3-amino-6-hydroxy-2-piperidone (Ahp) is needed. A hydrophobic and neutral residue in this position confers to the compound a preference for chymotrypsin. Kempopeptins A and B are other two cyclodepsipeptides isolated from a Floridian collection of a marine Lyngbya sp. that reveal a strong potency to inhibit proteases activity [99]. Kempopeptin B, with a leucine (Leu) residue between Thr and Ahp (Figure 2), only inhibit trypsin activity (IC50 = 8.4 μM), but kempopeptin A, with a lysine (Lys) in the same position, inhibit both elastase (IC50 = 0.32 μM) and chymotrypsin (IC50 = 2.6 μM). Bouillomides A and B, two depsipeptides isolated from Lyngbya bouillonii and molassamide, a depsipeptide from Dichothrix utahensis, all dolastatin 13 analogues, contain 2-aminobutyric acid (Abu) between Thr and Ahp. As expected, these metabolites are chymotrypsin inhibitors [91,106]. Largamides are another family of cyclic peptides isolated from Lyngbya confervoides. Largamides D and E, with a Leu residue between Thr and Ahp, and largamides F and G, with a tyrosine (Tyr) in the same position, also inhibited chymotrypsin with IC50 range from 4.0 to 25.0 μM [101].
Pompanopeptin A, a cyclic peptide isolated from the Lyngbya confervoides and kempopeptin B, contain arginine (Arg) and lysine (Lys), respectively, between Thr and Ahp. These basic residues give to the compounds the capacity to inhibit trypsin, pompanopeptin with an IC50 of 2.4 μM and kempopeptin with 8.4 μM [99,108].
Ahp residue-containing natural products are responsible for the inhibition of elastase [99]. Lyngbyastatins 4–10, a group of compounds that contain the Ahp residue, were all described as elastase inhibitors [102,103,104] with an IC50 range from 0.03 (lyngbyastatin 4) to 210 μM (lyngbyastatin 9). Lyngbyastatins are also strong chymotrypsin inhibitors, but with less potency than elastase, IC50 = 0.3 μM [99]. The same profile is verified with the depsipeptide molassamide witch contains the Ahp residue, which is capable to inhibit the elastase activity [106]. Largamides A–C and tiglicamides A–C, depsipeptides isolated from Lyngbya confervoides are non-containing Ahp natural compounds. However, these products were all responsible for an elastase enzyme inhibition [100,111].
Table
Table 3. Marine cyanobacteria natural products with an inhibitory effect in serine proteases.
Table 3. Marine cyanobacteria natural products with an inhibitory effect in serine proteases.
CompoundSourceClass of compoundSerine protease inhibitionReference
ElastaseChymotripsinThrypsin
Bouillomide ALyngbya bouilloniiDepsipeptideIC50 = 1.9 μMIC50 = 0.17 μMNo inhibition at 100 μM[91]
Bouillomide BLyngbya bouilloniiDepsipeptideIC50 = 1.0 μMIC50 = 9.3 μMNo inhibition at 100 μM[91]
Kempopeptin ALyngbya sp.Cyclic depsipeptideIC50 = 0.32 μMIC50 = 2.6 μMIC50 > 67 μM[99]
Kempopeptin BLyngbya sp.Cyclic depsipeptideIC50 > 67 μMIC50 > 67 μMIC50 = 8.4 μM[99]
Largamide ALyngbya confervoidesCyclic depsipeptideIC50 = 1.41 μMNo inhibition at 50 μMNo inhibition at 50 μM[100]
Largamide BLyngbya confervoidesCyclic depsipeptideIC50 = 0.53 μMNo inhibition at 50 μMNo inhibition at 50 μM[100]
Largamide CLyngbya confervoidesCyclic depsipeptideIC50 = 1.15 μMNo inhibition at 50 μMNo inhibition at 50 μM[100]
Largamide DOscillatoria sp.Cyclic depsipeptideNot describedIC50 = 10.0 μMNo inhibition[101]
Largamide EOscillatoria sp.Cyclic depsipeptideNot describedIC50 = 10.0 μMNo inhibition[101]
Largamide FOscillatoria sp.Cyclic depsipeptideNot describedIC50 = 4.0 μMNo inhibition[101]
Largamide GOscillatoria sp.Cyclic depsipeptideNot describedIC50 = 25.0 μMNo inhibition[101]
Lyngbyastatin 4Lyngbya confervoidesCyclic depsipeptideIC50 = 0.03 μMIC50 = 0.30 μMNo inhibition at 30 μM[102]
Lyngbyastatin 5Lyngbya spp.Cyclic depsipeptideIC50 = 3.2 μMIC50 = 2.8 μMNo inhibition at 30 μM[103]
Lyngbyastatin 6Lyngbya spp.Cyclic depsipeptideIC50 = 2.0 μMIC50 = 2.5 μMNo inhibition at 30 μM[103]
Lyngbyastatin 7Lyngbya spp.Cyclic depsipeptideIC50 = 3.3 μMIC50 = 0.47 μMIC50 = 2.5 μMNo inhibition at 30 μM[103,104]
Lyngbyastatin 8Lyngbya semiplenaCyclic depsipeptideIC50 = 0.12 μMNot describedNot described[104]
Lyngbyastatin 9Lyngbya semiplenaCyclic depsipeptideIC50 = 0.21 μMNot describedNot described[104]
Lyngbyastatin 10Lyngbya semiplenaCyclic depsipeptideIC50 = 0.12 μMNot describedNot described[104]
MolassamideDichothrix utahensisDepsipeptideIC50 = 0.032 μMIC50 = 0.234 μMNo inhibition at 10 μM[106]
Pompanopeptin ALyngbya confervoidesCyclic peptideNot describedNot describedIC50 = 2.4 μM[108]
Symplocamide ASymploca sp.Cyclic peptideNot describedIC50 = 0.38 μMIC50 = 80.2 μM[27]
Somamide BLyngbya majuscula and Schizothrix assemblageDepsipeptideIC50 = 9.5 μMIC50 = 4.2 μMNo inhibition at 30 μM[103]
Tiglicamide ALyngbya confervoidesCyclic depsipeptideIC50 = 2.14 μMNot describedNot described[111]
Tiglicamide BLyngbya confervoidesCyclic depsipeptideIC50 = 6.99 μMNot describedNot described[111]
Tiglicamide CLyngbya confervoidesCyclic depsipeptideIC50 = 7.28 μMNot describedNot described[111]
Marinedrugs 10 02181 g002 1024
Figure 2. Chemical structures of the marine cyanobacterial secondary metabolites symplocamide and kempopeptins A and B.
Figure 2. Chemical structures of the marine cyanobacterial secondary metabolites symplocamide and kempopeptins A and B.
Marinedrugs 10 02181 g002
Pitipeptolides A and B, two cyclodepsipeptides isolated from the marine cyanobacteria Lyngbya majuscula collected at Guam, revealed a particular bioactivity. When in contact to elastase, these compounds induce a significant increase in activity: 2.76-fold and 2.55-fold, respectively, at 50 μg/mL [77]. The authors suggested that this biological activity can be attributed to the presence of hydrophobic portions in the molecule [77].
Cathepsin D is a lysosomal protease that was described to have both anti-apoptotic [131] and pro-apoptotic functions [132]. Cathepsin E, besides its function being not well studied, it was described as a cathepsin D-like protein [133]. Grassystatins A and B, two linear depsipeptides isolated from Lyngbya confervoides were found to strongly inhibit cathepsins D (IC50 = 26.5 nM and 7.27 nM, respectively) and E (IC50 = 886 pM and 354 pM) [95].

6. Alterations in the Bcl-2 Protein Family

The Bcl-2 protein family is one of the major apoptosis regulators, which functions in the modulation of the outer mitochondrial membrane. The antiapoptotic members Bcl-2 and Bcl-xL protect the membrane integrity and avoid the release of the cytochrome c, but their activity can be disturbed by the pro-apoptotic members Bax, Bad and Bid [28].
Symplostatin 1 initiates the phosphorylation of Bcl-2, inhibiting its anti-apoptotic properties in human breast cancer cells and the total content of the protein appear also to be decreased [25]. Exposure to cryptophycin 52 was responsible for Bcl-2 and Bcl-xL phosphorylation in several prostate cancer cell lines [113]. Dolastatin 10 was associated to a Bcl-2 protein content reduction [56] and suggested to induce phosphorylation of the protein [53]. These are the common defensive mechanisms, the anti-apoptotic members are downregulated by phosphorylation, to allow the mechanisms of cell survival. However, cells can develop different ways of protection and, surprisingly, the synthetic analogue of dolastatin 10, dolastatin 15, promotes the overexpression of Bcl-2 protein in four different lung cancer cell lines [134].
Catassi and co-workers studied the response of non-small cell lung cancer cells when treated with curacin and dolastatins 10 and 15 and observed that these compounds inhibit Bad phosphorylation at serine136 [52]. The authors propose that the complex allow Bad to move into the mitochondria and promotes cytochrome c release, to trigger apoptosis [52]. Apart from the cell mechanism developed, the Bcl-2 protein family seems to play a crucial role in apoptosis induced by marine cyanobacterial natural compounds.

7. Alterations in Membrane Sodium Channel Dynamics

In mammal cells, a concentration gradient is necessary to keep the high levels of intracellular potassium and the low levels of sodium. This gradient is held by several ionic transporters and channels and by the capacity of cells to adapt to non-isotonic conditions, by volume regulatory mechanisms [135]. In apoptosis, a disordered volume regulation that leads to cell shrinkage during regular osmotic conditions occurs [136] leading to an early increase in the intracellular sodium concentration [137].
Marine cyanobacterial natural compounds seem to be involved in both induction and inhibition of sodium channels in neural cells. Antillatoxin, a lipopeptide isolated from Lyngbya majuscule was responsible for a rapid increase in sodium concentration inside of the cell in primary rat cerebellar granule cells [86]. Although the mechanism of interaction is not well described, the authors excluded an interaction of antillatoxin with channel neurotoxin sites 1–3, 5 and 7. Hoiamides are a class of cyclic depsipeptides with sodium channel bioactivity [59,97]. Hoiamides A and B were described to activate sodium channels in primary cultures of neocortical neurons from embryonic mice, with an IC50 of 1.7 μM and 3.9 μM, respectively [59]. In another work it was suggested that hoiamide A acts as a partial agonist at neurotoxin site 2 [97].
Palmyramide A, a cyclic depsipeptide from Lyngbya majuscule, showed to inhibit a veratridine and ouabain induced sodium overload with an IC50 value of 17.2 μM. The authors suggested that the inhibition may occur by blocking the voltage-gated sodium channel [76]. Palmyrolide, a macrolide isolated from an assemblage of Leptolyngbya cf. and Oscillatoria spp., is a stronger inhibitor of veratridine and ouabain induced sodium overload with an IC50 value of 3.70 μM [107].
Hermitamides A and B are two lipopeptides, isolated from the marine cyanobacteria Lyngbya majuscula from a Papua New Guinea collection. Hermitamide A is a sodium channel blocker that inhibits it near to 50% at 1 μM. Hermitamide B is a more potent blocker, inhibiting near to 80% at 1 μM [96]. It was proposed that the aromatic region of these compounds is important for the channel inhibition, being the indole group of hermitamide B an advantage over the phenyl ring of hermitamide A. A bioinformatic approach reveals that the connection between hermitamide B and human voltage-gated sodium channel is driven mainly by a hydrophobic interaction with residue K1237, and H-bonds between the amide group of hermitamide B with N434 and Y1586. Hydrophobic interactions between hermitamide B and F1283, F1579, L1582, V1583, Y1586, L1280, L788, F791, L792, I433, and L437 residues are also predicted [96].
Alterations in intracellular sodium levels and the interaction between cyanobacterial natural products and the sodium channels are important keys to understand the toxic mechanism and to develop possible pharmacological applications.

8. Conclusions

Marine cyanobacteria have been identified as one of the most promising groups of organisms from which novel biochemically active natural products, with potential benefits against cancer, can be isolated. Although several compounds were found to inhibit cell growth in a large variety of cancer cell lines, the pathways by which cancer cells are inhibited are still poorly elucidated. In some cases, compounds were found to induce cell death by activation of the apoptotic process; nevertheless the mechanisms underlying the apoptosis still need more investigations. Some compounds were found to create an imbalance in cellular redox potential, with mitochondria representing a central role in the process. However, more studies are needed in order to clarify if mitochondria and oxidative stress are the direct targets, or if they are just a consequence of upstream damage. Cell cycle is another disturbed process, mainly due to disruption of the microtubules and actin filaments; however there are only a few studies connecting marine cyanobacterial compounds with alterations in cell cycle and more studies are needed in order to clarify the involvement of these compounds in the process. Not surprisingly, the proteins directly involved in apoptosis, caspases, non-caspases proteases and the Bcl-2 protein family, also seem to be associated with the cyanobacterial compounds activity. Even membrane sodium channels can establish interactions with the compounds, revealing its potentially important role in the observed effects.
In summary, marine cyanobacteria seems to be clearly an important source of anticancer drugs. However, more investigations are needed in order to clarify the specific targets and the mechanisms that are behind cancer cell cytotoxicity, namely the involvement of the apoptotic process.

Acknowledgements

The authors acknowledge the Portuguese Foundation for Science and Technology (FCT) for financial support with the projects PTDC/MAR/102638/2008, PTDC/MAR/099642/2008, PTDC/MAR/102258/2008 and PesT-C/MAR/LA0015/2011. Margarida Costa has been supported with the FCT grant BTI/PTDC/MAR/102638/2008/2010-025.

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MDPI and ACS Style

Costa, M.; Costa-Rodrigues, J.; Fernandes, M.H.; Barros, P.; Vasconcelos, V.; Martins, R. Marine Cyanobacteria Compounds with Anticancer Properties: A Review on the Implication of Apoptosis. Mar. Drugs 2012, 10, 2181-2207. https://doi.org/10.3390/md10102181

AMA Style

Costa M, Costa-Rodrigues J, Fernandes MH, Barros P, Vasconcelos V, Martins R. Marine Cyanobacteria Compounds with Anticancer Properties: A Review on the Implication of Apoptosis. Marine Drugs. 2012; 10(10):2181-2207. https://doi.org/10.3390/md10102181

Chicago/Turabian Style

Costa, Margarida, João Costa-Rodrigues, Maria Helena Fernandes, Piedade Barros, Vitor Vasconcelos, and Rosário Martins. 2012. "Marine Cyanobacteria Compounds with Anticancer Properties: A Review on the Implication of Apoptosis" Marine Drugs 10, no. 10: 2181-2207. https://doi.org/10.3390/md10102181

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