Table 1.
Marine compounds isolated from algae with antitumor and cytotoxic activities and intracellular signaling pathways involved.
| Algae | Compound | Chemical class | Intracellular signaling pathways | References |
|---|---|---|---|---|
| OCHROPHYTA (BROWN ALGAE) | ||||
| Ecklonia cava | Dieckol | Polyphenol | Induces a downregulation of FAK signaling pathway mediated by the scavenging of intracellular reactive oxygen species (ROS), influencing migration and invasion of HT1080 cells. | Park and Jeon, 2012 |
| Potent inhibitor for tumor promoter-mediated MAPK-signaling pathways, leading to Activator Protein 1 (AP-1) and Metalloproteinase (MMP)−9 activation by regulating cancer cell motility. | Oh et al., 2011 | |||
| Ecklonia cava | 6,6′-bieckol | Polyphenol | Acts as a suppressor of MMP-2 and MMP-9 expressions by downregulating Nuclear Factor kappa-light-chain-enhancer of Activated B cells (NF-κB) and inhibits the migration of HT1080 cells. In addition, cell morphology and shape are affected in 3D culture condition. | Zhang et al., 2010 |
| Ecklonia Cava | Dioxinodehydroeckol | Phloroglucinol derivative | Induction of apoptosis through NF-κB family and NF-κB -dependent pathway. | Kong et al., 2009 |
| Ecklonia cava | Fucodiphloroethol G | Phlorotannin | Promotes inhibition of AP-N, MMPs (-2,-9) and c-fos by blocking signal transduction of MAPK and Akt pathways in Vascular Endothelial Growth Factor (VEGF)-induced EVC304 and EA.hy926 cells. | Li et al., 2011 |
| Eisenia bicyclis | Diphlorethohydroxycarmalol (DC) | Phlorotannin | Induces apoptosis on HL60 cells through the accumulation of sub-G1 cell population along with nuclear condensation, the reduction of Bcl-2 expression and the depletion of mitochondrial membrane potential (ΔΨm). | Kang et al., 2012 |
| Hizikia fusiformis | HFGP | Glycoprotein | Induces on HepG2 cells apoptosis and sub-G1 phase arrest. The expressions of Fas, Fas-associated death domain protein, Bax, and Bad were significantly upregulated in HFGP-treated cells. Moreover, HFGP induces the translocation of Bax to the mitochondria and the release of cytochrome c into the cytosol. | Ryu et al., 2012 |
| Hydroclathrus clathratus | H3-a1 | Sulfated polysaccharide | Induces significant arrest of sub-G1 phase on HL-60 and MCF-7 cells. In vivo, it inhibits tumor growth at doses of 20 and 50 mg Kg−1 in tumor-bearing BALB/c mice. Moreover, it suppresses ascitic sarcoma 180 tumor growth and prolongs the lifespan of the tumor-bearing mice by ~30–40%. H3-a1 compound also increases the tumor necrosis factor-alpha (TNF-α) level in mouse serum. | Wang et al., 2010 |
| Undaria pinnatifida | Fucoidan | Sulfated polysaccharide | Capable of suppress the proliferation of HLF cells by AMPK-associated inhibition of fatty acid synthesis and G1/S transition. | Kawaguchi et al., 2015 |
| Promotes apoptosis via ROS-mediated mitochondrial pathway on SMMC-7721 cells. | Yang et al., 2013 | |||
| Induces intrinsic and extrinsic apoptosis by stimulating ERK1/2 MAPK, deactivating P38 MAPK and PI3K/Akt signaling pathways and downregulating Wnt/β-catenin signaling pathway on prostate cancer cells (PC-3). | Boo et al., 2013 | |||
| Undaria pinnatifida | Fucoxanthin | Carotenoid | Increases the efficiency of cisplatin treatment on HepG2 cell line. Reduces cell viability. Increases Bax/Bcl-2 ratio, probably through inhibition of NF-κB, and ERCC1 expression through ERK and PI3K/AKT pathways. | Liu et al., 2013 |
| Cladosiphonokamuranus Tokida | Fucoxanthinol | Carotenoid | Inhibits Akt and Activator protein-1 pathways that influenced the suppression of cell growth, migration and invasion and the induction of apoptosis on osteosarcoma cells. | Rokkaku et al., 2013 |
| Sargassum siliquastrum | Sargachromanol E | Meroditerpenoid | Induction of apoptosis on HL-60 cells mediated by Caspase-3 activation. Apoptosis accompanied by downregulation of Bcl-xL, upregulation of Bax, activation of Caspase−3, and cleavage of poly (ADP-ribose) polymerase (PARP). | Heo et al., 2011 |
| Ascophyllum nodosum | Ascophyllan | Sulfated polysaccharide | Reduces N-Cadherin levels and increases E-Cadherin, which lead to the inhibition of migration and adhesion of B16 cell line. | Abu et al., 2015 |
| Laminaria digitata | Laminarin | Polysaccharide | Induces apoptosis and cell cycle arrest at sub-G1 and G2/M phases on human colon cancer cells (HT-29) and suppresses ErbB signaling pathway activation. | Park et al., 2013 |
| Laminaria japonica | LJGP | Glycoprotein | Supresses cell proliferation and induces apoptosis on HT-29 cells mediated through Fas signaling pathway, mitochondrial pathway and cell cycle arrest. | Go et al., 2010 |
| Sargassum horneri | SHPSA | Polysaccharide | Inhibits the proliferation of human colon cancer cells (DLD) by increasing the accumulation of cells at G2/M phase and inducing the apoptosis of DLD cells. | Wang S. et al., 2015 |
| Sargassum vulgare | PSV1 | Sulfated polysaccharide | It blocks tubulogenesis and VEGF secretion on rabbit aorta endothelial cells using Matrigel. Inhibitory effect on angiogenesis. | Guerra Dore et al., 2013 |
| Leathesia nana | Bis(2,3-Dibromo-4,5- dihydroxybenzyl) ether (BDDE) | Bromophenol | Induces apoptosis on K562 cells by a mitochondrial mediated pathway. Induces ROS generation and arrests cell cycle in S phase. Interacts with the minor groove of DNA and inhibits Topoisomerase I activity. | Liu et al., 2012 |
| Displays in vitro anti-angiogenic activity by suppressing significantly vascular endothelial cells (HUVEC) proliferation, migration, and tube formation, without any effect on the preformed vascular tube. Decreases the levels of VEGF and VEGFR proteins and inhibits the VEGF downstream signaling molecules, including mTOR and Src, while activates Akt and ERK. On zebrafish embryos, blocks sub-intestinal vessel formation and exhibits toxicity when used in higher concentrations (in vivo). | Qi et al., 2015 | |||
| Sargassum siliquastrum | 9′-cis-(6′R) fucoxanthin (FcA) 13′-cis-(6′R) fucoxanthin complex (FcB) |
Carotenoid | Both compounds reduce MMP-2, MMP-9 and mRNA levels, and the migration of HT1080 cells. Moreover, increase the expression of MMP inhibition factors (MMP-1) and suppress significantly the transcriptional activity of NF-κB, c-Jun N-terminal kinase (JNK), as well as p38 mitogen-activated protein kinase activity. | Nguyen et al., 2014 |
| Sargassum stenophyllum | SargA | Sulfated polysaccharide | In vitro, induces a decrease of B16F10 cells migration and viability. In vivo, causes the inhibition of tumor growth with no systemic toxicity and exhibits an anti-angiogenic effect. | Dias et al., 2005 |
| Sargassum macrocarpum | Tuberatolide B (TTB) | Meroterpenoid | TTB reduces the cell viability of several cancer cells lines (MDA-MB-231, MDA-MB-453, MCF-7, A549, H1299, HCT-116, SW620, CT26, PC-3, and DU145) by apoptosis decreasing Bcl2 expression and increasing the Caspase-3 and PARP cleavage. Promotes γH2AX foci formation and phosphorylation of several proteins (Chk2 and H2AX) related to DNA damage. In addition TTB promotes the production of ROS inhibiting STAT3 activation, which result in the decrease of the levels of cyclin D1, MMP-9, survivin, VEGF, and IL-6. Its activity seems to be mediated by ROS production and consequently inhibition of STAT3 signaling. | Choi et al., 2017 |
| Stoechospermum marginatum | 5(R), 19-diacetoxy-15,18 (R and S), dihydro spata-13, 16(E)-diene (DDSD) |
Spatane diterpenoid | In vitro DDSD induces cell cycle arrest at the S-phase and cell death by apoptosis on B16F10 melanoma cells. This compound promotes the generation of ROS, and consequently alterations in the ratio of Bax/Bcl-2 and in the mitochondrial transmembrane potential (ΔΨm), phosphatidylserine externalization, release of cytochrome c to the cytoplasm, Caspase activation, nuclear condensation, and fragmentation of DNA. Moreover, the results suggest that DDSD induces apoptosis through deregulating PI3K/AKT signaling pathway. In vivo, DDSD inhibits tumor growth (volume and weight) without evident toxic effects on C57BL/6 mice bearing B16F10 melanoma. | Velatooru et al., 2016 |
| Not identified by the authors | MSP | Sulfated polysaccharide | Exhibits anti-metastatic ability, both in vitro and in vivo. Induces regulatory effects on Actin dynamics in an FAK/ERK1/2-dependent manner, which might be further attributed to its binding to FN and, consequently, FN-induced tumor adhesion, and migration. | Tang et al., 2006 |
| Not identified by the authors | Not defined | Sulfated polysaccharide | Induces apoptosis and cell arrest at G2/M phase of MKN45 cells via ROS/JNK signaling pathway. In addition, it promotes ROS production and mediate the phosphorylation of several proteins, including Jun N-terminal kinase (JNK), p53, Caspase-9, and -3. | Xie et al., 2016 |
| RHODOPHYTA (RED ALGAE) | ||||
| Lophocladia sp. | Lophocladines B | Alkaloid | Cell cycle analysis on MDA-MB-435 cells showed arrest at G2/M phase and induction of microtubule depolymerization on A-10 cells. | Gross et al., 2006 |
| Laurencia viridis | Polyether triterpenoid dehydrothyrsiferol | Terpenoid | Induces apoptosis on breast cancer cells by estrogen-depend and independent pathways. | Pec et al., 2003 |
| Eucheuma serra | Eucheuma serra agglutinin (ESA) | Lectin | Increases Caspase-3 expression and translocation of phosphatidylserine in lectin-treated colon26 cells, suggesting that cell death is mediated by apoptosis. In vivo is observed a significant growth inhibition of Colon26-induced tumors on BALB/c mice. DNA fragmentation in tumor cells after intravenous injection with ESA is also detected. | Fukuda et al., 2006 |
| Gracilaria verrucosa | (E)-9- oxooctadec-10-enoic acid (C10) | Enone fatty acid | Angiogenesis and NF-κB activation in HUVECs cells stimulated by VEGF are blocked as well as their proliferation and migration. This is also observed in vivo model of angiogenesis using mouse cornea. Moreover, the neovascularization induced by VEGF is significantly suppressed. | Furuno et al., 2011 |
| Grateloupia filicina | GFP08 | Sulfated polysaccharide | In the chicken chorioallantoic membrane assay, reduced new vessel formation. In mice decreases the weight of sarcoma-180 cells-induced tumor in a dose-dependent manner. Also decreased Tissue Factor (TF) expression without affecting the activities of MMP-2 and−9. | Yu et al., 2012 |
| Laurencia intricata | Laurenditerpenol | Diterpene | Inhibits hypoxia-inducible factor-1 (HIF-1) mediated hypoxic signaling in breast tumor cells. | Mohammed et al., 2004 |
| Laurencia papillosa | Sulfated carrageenan (ESC) | Sulfated polysaccharide | Inhibits MDA-MB-231 cell proliferation and induces cell death through nuclear condensation and DNA fragmentation. Cell death is induced by apoptosis as result of activation of the extrinsic apoptotic Caspase-8 gene. The apoptotic signaling pathway is regulated through the Caspase-3, Caspase-9, p53, Bax, and Bcl-2 proteins. | Murad et al., 2015 |
| Laurencia majuscula | Hexadecyl-1- O-α-l-arabinopyranoside | Arabinopyranoside | Decreases significantly CDK1 and Cyclin A expression, with slight changes in Cyclin B1; arrests cell cycle at G2/M. | Du et al., 2010 |
| Callophycus serratus | Bromophycolide A | Diterpene–benzoate macrolides | Induces apoptosis on A2780 human ovarian cells; arrests G1 phase of the cell cycle, consistent with decreased number of cells from the S and G2/M phases. | Kubanek et al., 2005 |
| Chondrus ocellatus | λ-Carrageenan | Sulfated galactan | Conjugation with 5-Fluorouracil (5-FU) enhanced antitumor activity and mitigated immunocompetence damage of 5-FU. | Zhou et al., 2006 |
| Laurencia microcladia | Elatol | Sesquiterpene | Induces cell cycle arrest at G1 and sub-G1 phases, leading cells to undergo apoptosis. Reduces the expressions of Cyclin-D1, Cyclin-E, Cyclin-dependent kinase (Cdk)2 and Cdk4. It is also observed increases in Bak, Caspase-9 and p53 expressions and a decrease in Bcl-xl expression. In vivo elatol treatment reduces tumor growth on C57Bl6 mice. | Campos et al., 2012 |
| Laurencia thyrsifera | Thyrsiferol | Triterpene | Supresses HIF-1 activation on T47D human breast tumor cells and blocks mitochondrial respiration at complex I. | Mahdi et al., 2011 |
| Champia feldmannii | Cf-PLS | Sulfated polysaccharide | In vivo antitumor activity without marked toxicity. Enhances the efficacy of 5-FU, while preventing immunocompetence hindrance by 5-FU. | Lins et al., 2009 |
| Porphyra haitanensis | Porphyran | Sulfated galactan | Conjugation with 5-FU enhanced its antitumor activity and mitigated immunocompetence damage. | Wang and Zhang, 2014 |
| Porphyra yezoensis | PY-D2 | Polysaccharide | Blocks cell cycle at G0/G1 or G2/M check-points on different cell lines (SMMC-7721, HO-8910, MCF-7, K562 cells). | Zhang et al., 2011 |
| Porphyra yezoensis | Sulfoquinovosyldiacylglycerol (SQDG) | Sulfolipids | Inhibits significantly telomerase activity. | Eitsuka et al., 2004 |
| Grateloupia elliptica | Pheophorbide a (Pa) | Chlorophyll | Induces cytostatic activity on glioblastoma cells (U87 MG). The cell cycle distribution showed that U87 MG cells are arrested at G0/G1 phase. | Nguyen et al., 2014 |
| Grateloupia longifolia | GLP | Polysaccharide | Prevents the proliferation of HMEC-1 and HUVEC cells, suppresses the formation of intact tube networks and decreases migration. Decreases vessels density and new vessels formation in the chick chorioallantoic membrane assay and also, by intravenous administration decreases tumor weight and vascular density without showing toxicity in mice bearing sarcoma-180-cells-induced tumors. | Zhang et al., 2006 |
| Rhodomelaceae confervoides | Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) | Bromophenol | Inhibits several biological processes associated with angiogenesis, including endothelial cell sprouting, migration, proliferation, and tube formation. | Wang B. et al., 2015 |
| Symphyacladia latiuscula | 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB) | Bromophenol | Inhibits MCF-7 breast cancer cells growth and induces DNA fragmentation by apoptosis, accompanied by a downregulation of Bcl-2 protein expression and PARP cleavage by Caspase-3. This treatment increases the level of p21 WAF1/CIP1 protein in a p53-dependent manner. | Lee et al., 2007 |
| Pterocladiella capillacea | Mertensene | Halogenated monoterpene | Induces apoptosis on HT-29 cells accompanied by Caspase-3 activation and PARP cleavage. Decreases the phosphorylated forms of several proteins (p53, Rb, Ccd2, Chkp2) and the levels of cyclin-dependent kinases CDK2 and CDK4, and increases the levels of death receptor-associated protein TRADD. In addition it seems to promote the activation of MAPK ERK-1/-2, Akt and NF-κB pathways. | Tarhouni-Jabberi et al., 2017 |
| CHLOROPHYTA (GREEN ALGAE) | ||||
| Avrainvillea nigricans | Nigricanosides A (NA) | Glycolipid | Arrests MCF-7 breast cancer cells in mitosis. Cells exhibit disorganized microtubule spindles. In vitro induces polymerization of Tubulin and inhibition of both MCF-7 and HCT-116 cells proliferation. | Williams et al., 2007 |
| Caulerpa spp. | Caulerpin | Alkaloid | Acts as an inhibitor of the transportation of electrons to mitochondrial complex III, interfering with the mitochondrial ROS-regulated HIF-1 activation and HIF-1 downstream target genes expression. | Liu et al., 2009 |
| Caulerpa taxifolia | Caulerpenyne | Sesquiterpenoid | An early shift into synthesis phase (S) along with a blockade at G2/M phase is observed on colorectal cancer cells. | Fischel et al., 1994 |
| Codium fragile | Siphonaxanthin | Carotenoid | Induces apoptosis on HeLa cells accompanied by a decrease of Bcl-2 expression and subsequently activation of Caspase-3 and increase of the expression of GADD45α and the Death Receptor 5 (DR5). | Ganesan et al., 2011 |
| Ulva intestinalis | EI-SP | Sulfated polysaccharide | Induces apoptosis on HepG2 cells accompanied by changes in mitochondrial membrane potential, release of cytochrome c to the cytosol, decrease and increase of Bcl-2 and Bax expression, respectively and cleavage of Caspase-3 and Caspase-9, as well as cleavage of PARP. | Wang et al., 2014 |
| Ulva intestinalis | DAEB | Sulfated polysaccharide | Exhibits low toxicity in vitro. In vivo DAEB reduces tumor mass and increases thymus and spleen mass. Tumor growth inhibition is ascribed to increase levels of TNF- α, NO, and ROS. | Jiao et al., 2009 |
| Capsosiphon fulvescens | Cf-GP | Glycoprotein | Inhibits AGS cells proliferation and migration by a decrease of Integrin expression via the TGF-β 1-activated FAK/PI3K/AKT pathways. | Boo et al., 2013 |
| Capsosiphon fulvescens | Cf-PS | Polysaccharide | Inhibits cell proliferation and induces apoptosis by inhibiting IGF-IR signaling and the PI3K/Akt pathway. | Kwon and Nam, 2007 |
| Codium fragile | Clerosterol | Sterol | Induces apoptosis accompanied by changes in mitochondrial membrane potential, an increase and a decrease of Bax and Bcl-2 expression, respectively, and activation of Caspase-3 and Caspase-9. | Kim et al., 2013 |
| Codium decorticatum | GLP | Glycoprotein | GLP induces apoptosis on MDA-MB-231 breast cancer cells by mitochondria-mediated intrinsic pathway promoting changes in the mitochondrial membrane potential and Bax/Bcl-2 ratio, cytochrome c release, and Caspases-3 and 9 activation. | Thangam et al., 2014 |