A review of the components of brown seaweeds as potential candidates in cancer therapy

Abstract

Finding novel anticancer agents is very important for the treatment of cancer, and marine organisms are a valuable source for developing novel agents for clinical application. Therefore, the isolation and identification of novel anticancer components from brown seaweeds and a study of their mode of action is very attractive in current scenarios to assess their potential as an unexplored source for pharmacological applications. This review will reveal the active components of brown algae, together with their antitumor potential toward cancer treatment according to their structure. This should provide useful information for medicinal chemists in their attempts to develop potent anticancer agents.

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Ejaz Hussain

Ejaz Hussain received his B.S 4 year degree in Botany from Bahauddin Zakariya University Multan, Pakistan, and his M.Phil. degree in Botany from the Government College University, Lahore, Pakistan. In September 2015, he joined Prof. Da-yong Shi's group for his doctoral degree (PhD) at the Institute of Oceanology, the Chinese Academy of Sciences, CAS. His current research interests are in the isolation, purification and biological potential of natural products with anti-diabetic or antitumor activities.

Da-Yong Shi

Prof. Da-yong Shi received his B.Sc. degree in Chemistry from the Fermentation Engineering, Shandong Institute of Light Industry, his M.Sc. degree in Biochemistry from Qingdao University of Science and Technology, and his PhD degree in Medicinal Chemistry from the Institute of Oceanology, the Chinese Academy of Sciences (CAS). From 2005 to 2006, he was a postdoctoral fellow at the Natural Products Research & Infection Biology-Hans Knöll Institute (Jena, Germany). From 2006, he worked at the Institute of Oceanology, CAS. His research interests are in the isolation and synthesis of natural products with anti-diabetes mellitus or antitumor activities.

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1 Introduction

Cancer is known as a malignant tumor and is part of a group of diseases involving abnormal cell growth with the potential to kill normal cells and to spread rapidly to all parts of the body. Cancers can be classified on the basis of the type of cell such as carcinoma (cancers derived from the epithelial cells, which are the most common in the aged group of people), sarcoma (cancers originating from connective tissues), lymphoma and leukemia (both classes of cancer derived from hematopoietic cells such as blood cancer), germ cell tumor (cancers arising from pluripotent cells such as dysgerminoma and seminoma), and blastoma (cancer originating from immature embryos, which is the most common type in children).¹ There are about 100 known kinds of cancer so far that have been found to affect humans. There are many causes of cancer; for instance, tobacco contributes 25–30%, obesity, poor diet and excessive, and the use of alcohol 30–35%, genetic defects 15–20%, and 10% is following radiation.² Chemotherapy or CTX is considered a novel strategy to treat cancer cells today, and is defined as the use of chemical substances, namely, anticancer drugs, especially one or more chemotherapeutic agents (alone or combined), to stop the growth of cancer cells. There has also been a tremendous increase in the use of herbal drugs by cancer patients all around the world, which are chosen due to their potential effects against cancer diagnosis and easy access^3–6 and which people mostly take as part of a regime comprising multiple complementary and alternative medicine modalities.^7,8

Natural products from marine sources that have a strong medicinal potential have attracted much interest in the field of cancer research and in the development of novel anticancer drugs.⁹ So far, 15 000 novel compounds have been discovered from seaweed, and several antitumor compounds are currently being investigated through clinical trials.^10,11 Seaweed consumption and its health benefits are correlated and seaweed is considered a potential source for the development of anticancer drugs, functional foods, and pharmacological products.^12–17 In the current scenario, pharmaceutical companies are gaining interest in those compounds (sulfated polysaccharides, halogenated furanones, kahalalide F, lectins, kainoidsfucoidans, and aplysiatoxins) and are utilizing them in drug development after isolation from marine algae, especially phaeophyta.¹² The phyto-chemical constituents of brown seaweeds, such as carbohydrates, flavonoid, phenols, alkaloids, and proteins, play a key role against pathogens. These compounds also have significant potential as antitumor, antioxidants, and anticoagulants, and due to their immunomodulating activities.^18–22 In this review, we discuss the detailed structural composition of different components of brown algae, together with their antitumor potential toward cancer treatment.

2 Categorization of anticancer compounds isolated from brown seaweeds

2.1 Polysaccharides

Polysaccharides are the main components of brown algae rather than green and red algae, and are composed of alginate 1 (Fig. 1), laminarin 2 (Fig. 1), fucoidan 3 (Fig. 1), and their derivatives. Some constituents of porphyran 4 (Fig. 1) and alginic acid 5 (Fig. 1), have also been reported in some species of brown algae.²³ The polysaccharides regulate the primary functions of brown algae, like strength and flexibility of the cell wall, prevent desiccation, and keep the ionic equilibrium. The polysaccharide content in brown algae, their structural composition, and functional and anticancer properties have been reported.^24–33 Polysaccharides are extensively studied as novel antitumor agents, especially those found in brown seaweeds, such as 8 to 12% of compound 3 (Fig. 1) present in Sargassum sp. and Fucus sp. on a dry weight basis.³⁴ Compound 3 (Fig. 1) comprise complex sulfated polysaccharides and account for 10–20% Dw in brown algae, and are considered as a unique polymer with a heterogeneous composition and structure, mainly composed of sulfated L-fucose and small fractions of mannose, rhamnose, xylose, and glucose.^35,36 The polysaccharides isolated from brown seaweeds contain similar repeating sugars but these are different in terms of sulphation and molecular weights, probably due to the different isolation techniques and geographical locations.^37–40 Compound 3 (Fig. 1) isolated from five different brown seaweeds consists of 13 to 36% fucose and an 8 to 25% variation in the degree of sulfation.⁴¹ Several studies have been carried out about how the sulfation variation in the polysaccharides of brown seaweeds affects their antitumor activity.^42,43 Marine algae phaeophyta possess sulfated polysaccharides as the major components of their cell wall and are considered as a valuable bioactive compound with several beneficial biological activities, such as antitumor,⁴⁴ anticoagulant,⁴⁵ antiviral,^46,47 and antiinflammatory,^48,49 as well as immunomodulating activities.⁵⁰ Marine macro algae, especially phaeophyceae – a class of brown seaweeds – contain fucoidan complex polysaccharides (FCSPs), and their specific biological activities depend on the source of the seaweed, the method of extraction, and their compositional and structural traits.³⁴ Ye et al. isolated highly sulfated polysaccharide fractions, SP-1, SP-2, and SP-3, from Sargassum pallidum and the in vitro results showed significant cytotoxicity against A549 cells, HepG2 cells, and MGC-803 cells.⁵¹ Compound 3 (Fig. 1) fractions from Dictyopteris delicatula and Dictyopteris polypodioides induced 60–90% and 28% tumor growth inhibition for Hela and RPMI-7951 cancer cells, respectively.^52,53 The polysaccharides extracted from Quebec's Ascophyllum nodosum, Fucus vesiculosus, and Saccharina longicruris contain significant constituents of sulfates, total sugars and uronic acids that have diverse industrial and pharmacological applications.⁵⁴ Compound 3 (Fig. 1) increased IFN gama T cells production and showed a significant increase in NK cells activity when applied to mice inoculated with P-388 tumor cells.⁵⁵ Compound 3 (Fig. 1) fractions isolated from Sargassum hornery, Eclonia cava, and Costaria costata induced the inhibition of colony formation in human melanoma and colon cancer cells, and might potentially be effective antitumor agents.⁵⁶ Compound 3 (Fig. 1) and fucose isolated from brown seaweeds are rich in sulfated polysaccharides and have potential biomedical properties in immunostimulatory,⁵⁷ immunomodulation, anti-inflammatory, anticoagulant,⁵⁸ antithrombotic, anticancer, and antiproliferative activities.⁵⁹ Compound 3 (Fig. 1) isolated from Undaria pinnatifida has the potential to repress the differentiation of adipose cells by inhabiting inflammatory cytokines and is considered as a potent therapeutic agent against obesity and diabetes.^60–63 There are authentic reports that low molecular weight compound 3 (Fig. 1) has better antitumor activity than high molecular weight compound 1 (Fig. 1).⁶⁴ O-Acetylated sulfated galactofucan polysaccharide isolated from the brown seaweed Undaria pinnatifida suppresses the proliferation of PC-3 (prostate cancer), A549 (alveolar carcinoma), and Hela (cervical cancer) and HepG2 (heptacellular carcinoma) cells in a similar way to that of commercial fucoidan.⁶⁵ Ascophyllan (6, Fig. 1), extracted from the brown alga Ascophyllum nodosum reduced the growth of U937 cells and also induced apoptosis and DNA fragmentation.^66,67 Compound 3 (Fig. 1) isolated from the brown seaweed Undaria pinnatifida was tested against AGS stomach cancer cells and it was found that the low molecular fraction was more effective i.e. <30 kDa compared to the >30 kDa fraction.⁶⁸ Compound 3 (Fig. 1) from Laminaria brasiliensis was found to be cytotoxic to Hela cells at doses of 2.5–40 μg mL⁻¹.⁶⁹ Polysaccharide fractions extracted from the brown alga Coccophora langsdorfii, with a similar linear backbone to compound 3 (Fig. 1), exhibited a significant colony formation of SK-ML-5 and SK-ML-28 melanoma cells (the percentage of inhibition was 28 and 76%, respectively).⁷⁰ In vitro and in vivo studies of polysaccharides and sulfated polysaccharides proved their significance as a novel source of anticancer agents and are hence the most studied group of macromolecules, but still none of the agents have entered into clinical trials, which may be due to issues around purifying and identifying their specific structure. Polysaccharides are a diverse group of molecules, where even pure fractions contain a diversity of sugar units, and it is difficult to find a specific administrative route. Polysaccharides from brown seaweeds have provided promising results but still identifying and formulating their molecular structures and determining the mechanism of their administration route is required and is an essential step in the development of anticancer drugs for human deadly diseases (Table 1).

Fig. 1 Structures of compounds 1–10.

Table 1 Anticancer components and their efficacy against cancer cells isolated from brown algae

Seaweed	Active agent(s)	Activity	Test type(s)	References
Esenia bicycles	Laminarin, EBL 1 : 3 : 1 : 6 B. D-Glucan (2, Fig. 1)	Anticancer activity at 200 μg mL^−1, human melanoma SK-MEL-28 cells and colon cancer DLD1-cells	In vitro	58
Coccophoa langsdorfii	α-L-Fucoidan (3, Fig. 1)	28% and 78% anticancer activity at 100 μg mL^−1 on SK-ML-5 and SK-ML-28 melanoma cells	In vitro	70
Ishigeo kamurae	Diphlorethohydroxycarmalol (DPHC) (50, Fig. 5)	75% anticancer activity at 100 μg mL^−1 on HL60 cancer cells	In vitro	143
Saccharina gurjanovae	Sulfated galactofucan SgF (MW 123 kDa) (3, Fig. 1)	21% anticancer activity at 800 μg mL^−1 on colon cancer DLD-1 cells	In vitro	144
Turbinaria conoides	Fucoidan (3, Fig. 1)	73.5% anticancer activity at 500 μg mL^−1 on A549 cell line	In vitro	145
Fucus evanescens	Fucoidan (3, Fig. 1)	70%, 63% anticancer activity at 400 μg mL^−1 on SK-MEL-28 and SK-MEL-5 cells	In vitro	146
Alaria angusta	Fucoidan AaF3 (3, Fig. 1) laminaran AaL (2, Fig. 1)	29% and 22% anticancer activity at 400 μg mL^−1 on HT29 cells, respectively	In vitro	58
Ecklonia cava	8,8-Bieckol (11, Fig. 2) (phlorotannins)	Anti-inflammatory	In vivo	147
Ecklonia cava	Phloroglucinol (PG) (14, Fig. 2)	Decreased CD44+ cancer cell population and expression of CSC regulators, such as Sox2, CD44, Oct4, Notch2 and β-catenin	In vitro and in vivo	90
Stoechospermum marginatum	Spatane derivatives compounds 4 (51, Fig. 5), 1b (52, Fig. 5) 2a (53, Fig. 5), and 4a (54, Fig. 5)	Anticancer activity on B16F10 cancer cell line with IC50 values of 3.28, 3.45, 3.62, and 4.11 μg mL^−1, respectively, as compared to the standard drug etoposide IC50 = 4.12 μg mL^−1	In vitro	148
Sargassum cichorioides	Fucoidan ScF2, (55, Fig. 5)	26% anti-proliferation activity at 200 μg mL^−1 on DLD-1 cells	In vitro	59
F. evanescens	Fucoidan FeF2 (56, Fig. 6),	46% anti-proliferation activity at 200 μg mL^−1 on RPMI-7951 cells
U. pinnatifida	Galactofucan UpF2 (57, Fig. 6)	60% inhibition activity at 200 μg mL^−1 on T-47D cells
Fucus vesiculosus	Fucoidan (3, Fig. 1)	Inhibit growth and apoptosis of HT-29 and HCT116 cells	In vitro	149
Ecklonia cava	Dieckol (9, Fig. 1)	50% anticancer activity at 84.3 μg mL^−1 and 99.6 μg mL^−1 on A2780 and SKOV3 cells	In vitro	91
Laminaria japonica	Phlorotannins (7, Fig. 1)	30% and 43% anti-proliferation activity at 100 μg mL^−1 on BEL-7402 and P388 cells	In vitro	92
Lobophora variegata	Fraction rich in fucans (FRF) (3, Fig. 1)	54% anticancer activity at 25 μg mL^−1 on HepG2 cells	In vitro	150
Sargassum heterophyllum	Sargaquinoic acid (SQA) (28, Fig. 3)	SQA displayed an IC50 of 67.4 ± 5.9 μM against MDA-MB-231cells via caspase-3 activity and the down-regulation of the Bcl-2, cell cycle arrest in the G1 phase	In vitro	151
Sargassum wightii	Methanolic extract	29% and 41% anticancer activity at 200 μg mL^−1 on HeLa and MDA-MB 231 cell lines	In vitro	152
Pylaiella littoralis	PLE extract	67.9%, 37%, 21.9%, and 20.2% antiproliferative activity at 100 μg mL^−1 on HT-29, AGS, SK-HEP, NCI-H1299 cell lines	In vitro	153
Laminaria japonica	Fucoidan (3, Fig. 1)	2% osteoblast differentiation at 10 μg mL^−1 in hABM-MSCs	In vitro	154
Sargassum macrocarpum	Sargafuran (58, Fig. 6)	At 15 μg mL^−1 kills completely P. acnes	In vitro	155
D. polypodioides and Sargassum sp.	Fucoidan (3, Fig. 1)	44% and 28% anticancer activity at 200 μg mL^−1 on RPMI-7951 cells	In vitro	53
Fucus serratus, Laminaria digitata, Ascophyllmnodosum, Pelvetia canaliculata	Astaxanthin (59, Fig. 6), β-carotene (25, Fig. 3), zeaxanthin (22, Fig. 3)	Improves immune system, protects against eye diseases and anticancer effects	In vivo	156 and 157
Leathesia difformes	Methanolic extract	IC50 of 12.6 μg mL^−1 and 40.6 μg mL^−1 against KB and HT-29 cells	In vitro	158
Turbinaria ornata	Sulfated fucan-like polysaccharide (3, Fig. 1)	50% antiproliferative effect at 6.7 μg mL^−1 on NSCLC-N6 cell line	In vitro	61
Leathesia nana	Six bromophenol derivatives 6-(2,3-dibromo-4,5-dihydroxybenzyl)-2,3-dibromo-4,5-dihydroxybenzyl methyl ether (16, Fig. 2), (+)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-4-bromo-5,6-dihydroxy-1,3-dihydroisobenzofuran (17, Fig. 2), 3-bromo-4-(2,3-dibromo-4,5-dihydroxybenzyl)-5-methoxymethyl-pyrocatechol (18, Fig. 2), 2,3,3-tetrabromo-4,4,5,5-tetrahydroxy-diphenylmethane (19, Fig. 2), bis(2,3-dibromo-4,5-dihydroxybenzyl)ether (20, Fig. 3), 2,2,3-tribromo-3,4,4,5-tetrahydroxy-6-ethyloxymethyldiphenylmethane (21, Fig. 3) 17, 19, 20 (Fig. 2 and 3) compounds ethanolic extract of Leathesia nana (EELN)	All six exhibited 50% anticancer activity at 10 μg mL^−1 on A549, BGC-823, MCF-7, B16-BL6, HT-1080, A2780, Bel7402 and HCT-8 cell lines 77.5%, 80.1%, and 71.4% protein tyrosine kinase (PTK) inhibition activity. Inhibit the growth of sarcoma 180 tumor cells and increase the indices of thymus and spleen to improve the immune system	In vitro, in vivo, in vivo	98
Sargassum vulgare C. Agardh, Laminaria digitata	Alginates (SVHV and SVLV) (1, Fig. 1)	51.8%, 74.8%, 66.2%, and 88.8% inhibition of sarcoma 180 cells in mice at the doses of 50 and 100 mg per m^2 per day for SVLV and SVHV, respectively	In vivo	30 and 31
Sargassum fulvellum	Pheophytin a (26, Fig. 3)	Enhances the neuro differentiation of PC12 cells at 3.9 μg mL^−1 concentration	In vivo	159
Undaria pinnatifida and Hijikia fusiformis	Fucoxanthin, 5,6-epoxy-3′-ethanoyloxy-3,5′-dihydroxy-6′,7′-didehydro-5,6,7,8,5′,6′-hexahydro-β,β-caroten-8-one (23, Fig. 3)	Regulates the white adipose tissue (WAT) weight gain and hyperglycemia in diabetic/obese KK-Ay mice	In vivo	62
Eisenia bicyclis	Pyropheophytin a (60, Fig. 6)	Antioxidant activity	In vitro	111
Undaria pinnatifida	Fucoxanthin and its metabolite, fucoxanthinol (23, Fig. 3)	Inhibits adipocyte differentiation in 3T3-L1 cells	In vitro	160
Undaria pinnatifida	Fucoidan (3, Fig. 1)	15.2%, 29.8%, 39.3%; 45.1% inhibited growth of PC-3 cells and induced apoptosis at 10 μg mL^−1 50 μg mL^−1, 100 μg mL^−1, and 200 μg mL^−1, respectively	In vivo	161
Fucus vesiculosus	Fucoidan-sulfated polysaccharides (3, Fig. 1)	80% anticancer activity at 100 μg mL^−1 on DC cells and it has dose-dependent cytoprotective activity	In vitro	63
Sargassum mcclurei	Fucoidan polysaccharides SmF1, SmF2, SmF3, and SmF3-DS (3, Fig. 1)	17%, 48%, 20%, and 18% inhibited the colony formation of DLD-1 colon cancer cells at 100 μg mL^−1 respectively	In vitro	162
Sargassum sp., Fucus vesiculosus	Crude fucoidan MTA and SIG (3, Fig. 1)	40% and 36% reduction in viability of LLC and B16 cells at 1 μg mL^−1 in a dose-dependent manner, respectively	In vitro	34
Sargassum filipendula	SF-0.7v fucoidan (3, Fig. 1)	38.1% and 31.0%, growth inhibition at 2.0 mg mL^−1 on HepG2 and PC3, respectively	In vitro	163
Dictyopterispolypodioides	Fucoidan (3, Fig. 1)	44% and 28% growth inhibition at 200 μg mL^−1 on RPMI-7951 cells, respectively	In vitro	53
Ecklonia cava, Sargassum horneri, Costaria costata	Fucoidan (3, Fig. 1)	8–55% anticancer activity at 1–200 μg mL^−1 on SK-ML-28, DLD-1 cells	In vitro	56
Undaria pinnatifida	Fucoidan of sporophyll (3, Fig. 1)	10–20% antitumor activity at 0–0.8 mg mL^−1 on PC-3, Hela, A549, HepG2 cancer cells	In vitro	65
Dictyopterisdelicatula	Fucoidan (3, Fig. 1)	60–90% inhibition in tumor growth at 2 mg mL^−1 on Hela cancer cells	In vitro	52
Sargassum stenophyllum	Sarg A fucoidan polysaccharides (3, Fig. 1)	40% and 80% decrease in B16F10 melanoma cell tumors with the dose of 1.5 or 150 μg per animal per day for 3 days	In vivo	164
Laminaria digitata	Fucoidan (3, Fig. 1)	Inhibited inflammation and heterotypic tumor cell adhesions on MDA-MB-231 tumor cells at a significant level	In vitro	165
Sargassum thunbergii	Fucoidan fractions (3, Fig. 1)	Injection of 20 mg kg per day for 10 days increases the survival of Ehrlich carcinoma implanted IP in ICR/Slc mice as compared to control	In vivo	166
Alaria esculenta	Crude extract	Crude extract reduced viability of Caco-2 cancer cells	In vivo	167
Laminaria digitata	Laminarin (2, Fig. 1)	Induced tumor growth HT-29 Bcl-2 cells by the decrease in cytochrome c expression and the increase in Bad and Bax, restricted phosphorylation of ErbB2 and accumulation of cells in sub-G1 and G2-M phase	In vivo	93
Ascophyllumnodosum	Ascophyllan (6, Fig. 1)	Reduced the growth of U937 cells and also induced apoptosis and DNA fragmentation	In vivo	66
Ascophyllumnodosum	Ascophyllan (6, Fig. 1)	Inhibited tumor growth of Vero and XC cells and increased the growth of MDCK cells at concentrations 0–1000 μg mL^−1	In vivo	67
Leathesia nana	Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (20, Fig. 3)	Induced apoptosis in mouse breast cancer by a mitochondrial-mediated pathway and ROS generation. Inhibited topoisomerase I and cell cycle activity in the S phase	In vivo	168
Undaria pinnatifida	Fucoidan extract (3, Fig. 1)	Inhibited the angiogenesis by human umbilical vein endothelial cells	In vivo	116
Fucus vesiculosus	Fucoidan (3, Fig. 1)	Induced apoptosis of human lymphoma HS-sultan cancer cells by the down-regulation of ERK and activation of caspase-3 pathways	In vivo	169
Cladosiphon okamuranus	Fucoidan (3, Fig. 1)	Inhibited cell growth in MKN-45 cancer cells at 1 mg mL^−1	In vitro	170
Sargassum hemiphyllum	Hedaol A, B, and C (61, 62, 63, Fig. 6)	50% anticancer activity at 50 μg mL^−1 to P-388 cells for Heladaol A, B and C, respectively	In vitro	171
Hizikia fusiforme	Ethanolic extract	50–60% inhibition in tumor growth with doses of 30–50 μg mL^−1. Increased caspase-3, 8,9 PARP and decreased IAP-2, Bcl-2, IAP-1 and XIAP	In vivo	172
Ecklonia cava	Dieckol (9, Fig. 1)	Induced SK-Hep1 human hepatoma cell motility through the suppression of matrix metalloproteinase-9 pathways	In vivo	85
Sargassum fulvellum	Sodium alginate (8, Fig. 1)	Inhibited the tumor growth of S-180 in mice	In vivo	83
Stypopodim flabelliforme	Stypodiol (38, Fig. 4)	Induced anti-proliferation activity to SH-SY5Y cells with an IC value of ≤50 μM and was nontoxic to V79 normal cells	In vitro	123
Stypopodim flabelliforme	Two mero-diterpenoids derivatives 2β,3α-epitaondiol (41, Fig. 4), and flabellinol (42, Fig. 4)	All three showed cytotoxic to neuro-2a cells at 2–11 μM and 9–24 μM to NCI-H460 cells, respectively	In vivo	122
Bifurcaria bifurcata	Elaganolone (64, Fig. 6)	Strong antiprotozoal activity against T. bruceirhodesiense and a selective SI of 12.4 in LC6 cells	In vitro	173

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2.2 Phenolic compounds

Polyphenols act as antioxidants and have an ability to scavenge free radicals and up-regulate certain metal chelation reactions to improve the body's own antioxidant system.⁷¹ Phenolics are secondary metabolites of seaweeds and are composed of aromatic rings bearing one or more hydroxyl groups and include flavonoids, lignans, tannins, and phlorotannins and may have an in vivo affect in receptor sensitivity,^28,72 cell signaling pathways, and in gene regulation or inflammatory enzyme activity.⁷³ Phlorotannins (7, Fig. 1), are produced in abundance through secondary metabolism in phaeophyceae.^74–76 Compound 7 (Fig. 1) consists of different molecular sizes (400–400 000 Da) and accounts for 0.5–20% Dw in brown algae. The phenolic content quantitative analysis and comparative studies of Fucaceae, Sargassaceae, Cystoseiraceae, and Laminariaceae have been reported.^77–81 A flavonoid content of 88 μg mL⁻¹ have been isolated from a methanol extract of the brown alga Turbinaria ornate and exhibited significant anti-proliferation activity on A549, PC-3, HCT-15, and MG-63 tumor cells in vivo.⁸² Sodium alginate (8, Fig. 1), isolated from Sargassum fulvellum, inhibited the tumor growth of S-180 mice.^83,84 Dieckol (9, Fig. 1), from brown alga when applied to SK Hep-1 cells decreased TPA cell motility and MMP-9 activity associated with AP-1 in MAPK signaling pathways.⁸⁵ Methanol extracts of Sargassum fulvellum and Sargassum thunbergii inhibited by 79.1% and 72.1% an inflammatory symptom of mouse ear edema without any toxicity, respectively.⁷⁴ A polyphenolic crude ethanolic extract from Ecklonia cava induced the inhibition of MMP-2 and MMP-9 activity, and the link was thought to be associated with polyphenols and anticancer activity.⁸⁶

Sargassum muticum, Fucus vesiculosus, Gelidium sesquipedale, and Cystoseira compressa extracts were evaluated to find out the total flavonoid and phenolic contents in order to investigate the cytotoxic and mutagenic potential. Hexane extracts of these isolates had no significant cytotoxic and mutagenic activity against the human hepatocellular carcinoma Hep 3B cell line when applied as 5–50 μg mL⁻¹. The finding suggests that the phytochemical constituent of brown seaweeds might be a suitable agent for the control of human deadly diseases.^87–89 Phlorotannin compounds, such as eckol (10, Fig. 1), 8,8′-bieckol (11, Fig. 2), 6,6′-bieckol (12, Fig. 2), and 6,8′-bieckol (13, Fig. 2), have been isolated from several brown algae, namely Sargassum fulvellum, Sargassum thunbergii, Ecklonia cava, Hizikia fusiformis, Ishige okamurae, Ecklonia cava, Eisenia arborea, and Eisenia arborea.⁷⁴ Phloroglucinol (14, Fig. 2), isolated from Ecklonia cava, decreases the CD44+ cancer cell population and the expression of CSC regulators such as Sox2, CD44, Oct4, Notch2, and β-catenin.⁹⁰ Compound 9 (Fig. 1) from Ecklonia cava exhibited 50% anticancer activity at 84.3 μg mL⁻¹ and 99.6 μg mL⁻¹ on A2780 and SKOV3 cells, respectively.⁹¹ The growth of two tumor cell lines BEL-7402 and P388 cells was inhibited to 30 to 43% at 100 μg mL⁻¹ of compound 7 (Fig. 1)-rich extracts from Laminaria japonica and apoptosis was also observed.⁹² Compound 2 (Fig. 1), isolated from the brown alga Laminaria digitata, induced apoptosis in HT-29 Bcl-2 cells in a dose-dependent manner, via increasing the percentage of cells in the sub-G1, G2-M phase and inhibited the heregulin-stimulated phosphorylation of ErbB2.⁹³ Similarly, compound 1 (Fig. 1) was isolated from the brown alga Sargassum vulgare and studied in vivo and exhibited 27 to 88% inhibition of tumor growth in Swiss mice with S-180 implanted SC, supplemented at doses of 50 and 100 mg m² per day for 10 days.⁹⁴ Kimiya et al. studied various extracts of brown algae in vivo and in vitro, including Ecklonia cava, Codium fragile, Ulva japonica, Undarina pinnatifida, and P. binghamiae, against RBL-2H3 cells at 100 to 200 μg mL⁻¹; among these, P. binghamia exhibited the highest degranulation of both RBL-2H3 cells as well mouse esinophils.⁹⁵ A phlorotannin compound, dioxinodehydroeckol (15, Fig. 2), induced apoptosis in MCF-7, MDA-MB-231 cells and increased the activities of caspase-3 and -9, Bax, p53, and PARP pathways via the down-regulation of NF-kB and Bcl2.^20,28 Bromophenol compounds from marine organisms, especially from brown algae, have proven to be valuable characteristic natural products with a range of potential biological activities, including antioxidant, antidiabetic, anticancer, and as an α-glucosidase inhibitor. Leathesia nana, a marine brown seaweed, possess six unique bromophenols compounds (16–21, Fig. 2 and 3) and all six exhibited 50% anticancer activity at 10 μg mL⁻¹ on A549, BGC-823, MCF-7, B16-BL6, HT-1080, A2780, Bel7402, and HCT-8 cell lines, respectively.^96–99

Fig. 2 Structures of compounds 11–19.s

Fig. 3 Structures of compounds 20–28.

2.3 Carotenoids

Carotenoids are natural pigments and dietary fibers and contain functional compounds primarily found in both plants and animals. Brown seaweed's cell wall contains catatonic compounds, including lutein, zeaxanthin (22, Fig. 3), and fucoxanthin (23, Fig. 3).^100,101 Brown algae is considered to be a rich marine reservoir of secondary metabolites, especially carotenoids, and they possess a range of bioactivities, including, antioxidant, anticancer, anti-inflammatory, and antiviral.¹⁰² Epidemiological investigations have evidenced that there is a clear link between seaweed carotenoids diet and cancer risk, and considered that these have potential as important pharmaceutical compounds, which might be a promising anticancer marine drug.¹⁰³ Carotenoids are colored terpenes produced by a secondary metabolism in brown algae, and have an abundant structural variety, such as a-carotene (24, Fig. 3), and b-carotene (25, Fig. 3), chlorophyll a, phaeophytin a, (26, Fig. 3), lutein, zeaxanthin (22, Fig. 3), and fucoxanthin (23, Fig. 3). They play a key role in human nutrition, providing provitamin A, as well as acting in hormone synthesis, photomorphogenesis, photoprotection, and against cerebrovascular diseases.^104–107 Compound 23 (Fig. 3) content values in the range 1–6 mg g⁻¹,^15,18 structural variability,^108,109 and the bioactivity of some brown seaweeds have been reported up to 16 mg g⁻¹ for Turbinaria sp.,¹⁰⁶ and even higher for Laminaria sp. and Undaria pinnatifida.¹⁰⁵ Compound 23 (Fig. 3) and fucoxanthinol both have a reduced proliferation of HUVECs without affecting their chemotaxis and inhibit the growth in ex vivo rat aortic rings through the suppression of micro vessel (CD31+ve) formation.¹¹⁰ A compound 23 (Fig. 3) derivative from two brown algae Undaria pinnatifida and Hijikia fusiformis regulates the white adipose tissue (WAT) weight gain and hyperglycemia in diabetic/obese KK-Ay mice in vivo.⁶² Similarly, compound 23 (Fig. 3) and its metabolite, fucoxanthinol were isolated from the brown alga Undaria pinnatifida and exhibited significant inhibition to adipocyte differentiation in 3T3-L1cells.¹¹¹ Compound 23 (Fig. 3) induced apoptosis via the activation of caspase-3 and -9, and reduced the expression of Bax and Bcl-2 proteins, but not Bcl-X(L).¹¹² However, apoptosis, DNA fragmentation, a reduction in Bcl-2, Bax, and caspase-3 activation has been observed in DU145, PC-3 and LNCaP prostate cancer cell lines.^113,114 Compound 23 (Fig. 3) reduced cell viability and induced apoptosis via a decrease in Bcl-2 expression on HT-29 and DLD-1 cells.¹¹⁵ Compound 23 (Fig. 3) increased the NFκB-regulated Bax/Bcl-2 mRNA ratio, via the inhibition of ERCC1 and NF-kB expression through blocking the P13K/AKT pathways. It also induced cell inhibition of human hepatoma HepG2 cells and improved cisplatin treatment.¹¹⁶ Compound 23 (Fig. 3) induced the apoptosis G2/M1 cell cycle arrest via down-regulating the expression of CyclinB1, which was linked with the JAK/STAT pathway.¹¹⁷ Compound 23 (Fig. 3) induced apoptosis via the reduction of cell viability in EJ-1 cancer cells and increased hypodiploid cells, the DNA ladder, and caspase-3 activities.¹¹⁸

2.4 Terpenoids

Terpenes and polyketides, for example, account for most of the secondary metabolites and can be recognized as oligomers of the primary metabolites isoprene and acetate, respectively. Terpenes and polyketides in brown algae frequently occur as secondary metabolites and their structure ranges from acyclic entities with a linear chain to complex polycyclic molecules, which are considered to be the main components for cancer treatment.¹¹⁹ The antitumor activity of meroterpenoid metabolites isolated from Sargassum fallax against p388 human cancer cells were found to have IC₅₀ values of 17, 14, 32, and >27–29 μM when treated with 1 mg mL⁻¹ for sargaquinone (27, Fig. 3), sargaquinoic acid (28, Fig. 3), sargahydroquinoic acid (29, Fig. 4), and fallachromonoic acid (30, Fig. 4), fallahydroquinone (31, Fig. 4), fallaquinone (32, Fig. 4), and sargachromenol (33, Fig. 4), respectively.¹²⁰ Atomarianone A (34, Fig. 4), and B (35, Fig. 4), compounds were isolated from Taonia atomaria and both were found to be cytotoxic to NSCLC-N6, A549 cell lines with IC₅₀ values of <7.35 μM.¹²¹ Diterpenoid metabolites isolated from the brown alga Cystoseira mediterranea were tested in vivo against in mouse P388 leukemia cells and found to have significant cell inhibition activity.¹²² The isolated terpenoid derivatives sargaquinone (27, Fig. 4), taondiol (36, Fig. 4), isoepitaondiol (37, Fig. 4), stypodiol (38, Fig. 4), stypoldione (39, Fig. 4), and sargaol (40, Fig. 4) were found to have strong antioxidant potential, with specific biological activities, such as, compound 39 (Fig. 4) which inhibits the microtubule polymerization, compound 36 (Fig. 4) which exhibits anticancer activity, compound 37 (Fig. 4) related to insecticidal activity, and cytotoxicity against P-388 lymphocytic cells related to metabolites of compounds 27 and 40 (Fig. 4). Two mero-diterpenoids, including, 2β,3α-epitaondiol (41, Fig. 4) and flabellinol (42, Fig. 4), were isolated from Stypopodium flabelliforme, and in vivo studies showed that all three were cytotoxic to neuro-2a cells at 2–11 μM and 9–24 μM to NCI–H460 cells, respectively.¹²³ Compound 38 (Fig. 4) induced anti-proliferation activity to SH-SY5Y cells with an IC value of ≤50 μM and was also found to be nontoxic to V79 normal cells.¹²⁴

Fig. 4 Structures of compounds 29–42.

2.5 Proteins, lipids, sterols and quinones, vitamins, fatty acids, and amino acids

The protein structure of brown seaweeds and their biological potential are still poorly studied so far, but their amino acid composition has been well documented by several studies.¹²⁵ The protein contents in the brown seaweed are usually considered small and different from species to species, such as, Undaria sp., which has the highest ratio of 24% dry weight, followed by 17–21% for Fucus, Sargassum and Laminaria, while the lowest content of 10% is for Ascophyllum sp. Brown seaweed proteins generally contain the highest content of threonine, alanine, valine, glycine, leucine, and lysine, together with several amino acids, such as histidine, tryptophan, cysteine, methionine, and tyrosine with lower levels.^126,127 Combined glutamic acid and aspartic acid levels of 22–44%, 39–41%, and 18% wet weight of the total amino acid fraction are reported for Fucus sp., Sargassum sp. and Laminaria digitata, respectively.^128–130 Amino acids isolated from the brown seaweeds Sargassum vulgare (C. agardh) and Sargassum thunbergii extracts have been considered as potential sources of new treatments for parasitic diseases such as anti-helmintics.¹³¹ Ishihara et al. isolated two polyunsaturated fatty acids 18 : 4n − 3 and 16 : 4n − 3 from two brown marine algae Ulva pertusa and Ulva pinnatifida and extensively studied them in vivo, and they exhibited a strong inhibition on Leukotriene B4, 5-hydroxyeicosatetraenoic acid and leukotriene C4 in MC/9 mice mast cells.¹³² Deoxylapachol a 1,4-naphthoquinone (43, Fig. 5), derivative isolated from Landsburgia quercifolia induced apoptosis to p-388 human cancer cells (IC > 0.6 pg mL⁻¹).¹³³ Sargachromanol E (44, Fig. 5), from Sargassum siliquastrum, induced caspase-3-mediated apoptosis in HL-60 cancer cells.¹³⁴ Two steroidal compounds, named 3-keto-22-epi-28-nor-cathasterone and cholest-4-ene-3,6-dion, were isolated from Cystoseira myrica and induced cytotoxicity to HEPG-2 and HCT116 cells in the range of 12.38–1.16 μM in selective patterns.¹³⁵ Ergosterols (45, Fig. 5), isolated from the brown alga Lyengaria stellata, exhibited a noticeable hematopoietic effect when it was applied orally at the doses of 10 mg/200 g body weight to rabbits for 30 days.^136,137 Another compound, fucosterol (46, Fig. 5), isolated from the brown seaweeds Pelvetia siliquosa, Cystoseira foeniculacea, and Sargassum angustifolium, exhibited a significant cytotoxic effect to HT-29, Caco-2 and T47D cells.^138,139 Laminaria japonica glycoprotein (LJGP) induced apoptosis and cell cycle arrest in AGS, HepG2, and HT-29 cancer cells in a dose-dependent manner via mediation by a Fas signaling pathway, caspas-3 activation, and a mitochondrial pathway.¹⁴⁰ The PGE2 production and histamine release were lowered in the canine mastocytoma cell line C2 and RBL-2H3 cells treated with alpha-linolenic acid (47, Fig. 5), γ-linolenic acid (48, Fig. 5), and docosahexaenoic acid (49, Fig. 5), respectively.^141,142

Fig. 5 Structures of compounds 43–55.

3 Mechanisms of action and comparison of the toxicity of the compounds with other chemotherapeutic drugs

In recent decades, scientists have devoted much attention to investigating the nature of the initialization and progression of malignant tumors through the advancement of genetics and molecular biology. In some research papers, there are some mechanistic studies that prove the role of these compounds in regulating the biological and physiological processes of the cell, and this has research field has occupied many researchers around the chemotherapeutic world.^20,65,66,138 In some reports, researchers have identified specific inhibitory activities of natural compounds from brown seaweeds, in a number of key cellular processes, including, antimetastatic, antiangiogenic, telomerase, proapoptotic, tumor angiogenesis, and apoptosis pathways.^174,175 Compound 6 (Fig. 1) has been reported to induce cytokine release TNF and granulocyte colony-stimulating factor (GCSF) from macrophage-derived RAW264.7 cells though apoptosis and DNA fragmentation,⁶⁶ while a sulfated polysaccharide compound 3 (Fig. 1) extracted to Hydroclathrus clathratus was found to increase the tumor necrosis factor (TNF-α) in mouse serum.⁶⁴ Compound 14 (Fig. 2) has been evidenced to inhibit the epithelial-mesenchymal cell transition (EMT) process and to suppress the metastatic ability of breast cancer cells through a decrease in expression of SNAIL-related zinc-finger transcription factors and by the inhibition of PI3K/AKT and Ras/Raf-1/ERK signaling pathways.¹⁷⁶ Compound 22 (Fig. 3) proved its anti-carcinogenic activity was interrelated with mutagens such as 1-nitropyrene,¹⁷⁷ and aflatoxin B1 (AFB1),¹⁷⁸ by regulating specific genes involved in T-cell transformations.¹⁷⁹ Compound 23 (Fig. 3) has been evidenced to induce apoptosis through caspase-3, -7, -9 activation and to suppress Bax and Bcl-2 proteins expression through inhibition of the NF-kB pathway in several cancer cell lines, including the HL-60 cell line,¹¹⁴ MDA-MB-231,¹⁸⁰ MCF-7 breast cancer cells,¹⁸¹ Caco-2 colon cancer cells,¹⁸² Caco-2, HT-29, DLD-1 cells,¹¹⁵ prostate cancer cell line,¹¹² and the urinary bladder cancer EJ-1 cell line.¹¹⁸ Compound 25 (Fig. 3) prevents the carcinogenesis by preventing DNA damage,¹⁸³ the onset of cancers, especially lung cancer,¹⁸⁴ and regulates several biological functions, including the hormones, and tissue growth and differentiation, and is a mediator of cell signaling and a regulator of cells.¹⁰⁴ A compound 59 (Fig. 6)-rich algal extract, has been evidenced to provide potent protection against UVA-induced DNA damage to melanocytes, intestinal CaCo-2 cells,¹⁸⁵ and to inhibit the androgen-induced proliferation of human prostate cancer cells.^113,186 In the current scenario of chemotherapy, there are several studies that have proven the synergistic effects of natural bioactive compounds when in combination with complementary or conventional anticancer drugs.^187–189 These chemotherapeutics have been received promising results for the application of natural compounds when in combination with commonly used anticancer drugs, such as in the activation of different molecular mechanistic pathways, improved drug absorption, enhanced anticancer drug efficiency, and increased clinical responses.^27,175,190 A compound 7 (Fig. 1)-rich extract exhibited significant antiproliferative effect over that of 5-fluorouracil (a commercial chemotherapy drug), against P388 and BEL-7402 cancer cells at doses of 120 μg mL⁻¹ and >200 μg mL⁻¹, respectively.⁹² A recent finding for compound 22 (Fig. 3) has evidenced a significant antiproliferative effect against MCF-7 and MDA-MB-231 cells, through apoptosis and cell cycle arrest when co-treated with cisplatin, tamoxifen, and paclitaxel. The suppression of Bcl-2 proteins expression, ERK and AKT signaling pathway, the regulation of estrogen receptors, and the production of oxidative stress are possible mechanisms.²⁷ Compound 23 (Fig. 3) has been found to have promising results when combined in treatment with oxaliplatin/5-fluorouracil/leucovorin or irinotecan/fluorouracil/leucovorin, such as a decrease in fatigue and an increased survival rate of patients receiving the co-treatment.¹⁹¹ Compound 50 (Fig. 5) has been found to be more potent than acarbose, a commercial carbohydrate digestive enzyme inhibitor, against alpha-glucosidase and alpha-amylase with IC₅₀ values of 0.16 mM and 0.53 mM, respectively, and can be considered a potent chemotherapeutic drug for treating diabetes.¹⁴³ However, despite the strong potential of these studies, these natural compounds need more comprehensive studies carried out before they can be translated into useful modern chemotherapeutic drugs (Fig. 7 and 8).

Fig. 6 Structures of compounds 56–64.

Fig. 7 Molecular mechanisms and targets of phloroglucinol, fucoxanthin, and fucoidan mediating anticancer activity in breast cancer.¹⁹²

Fig. 8 Anticancer effects of fucoxanthin and fucoxanthinol on various types of cancer cells and their mechanism of action.¹⁹³

4 Conclusions and prospective

Cancer is a multi-faceted molecular disease that cannot be cured by drugs alone to date. Many academic and research institutes, even after their intensive efforts, are still unable to find potential antitumor compounds rather than just a few useful products.¹⁹⁴ Therefore, there is a growing trend for scientists to seek novel compounds to treat cancer. Although a few marine antitumor compounds are being tested and utilized to treat human deadly diseases such as cancer, they are known to have some side effects such as sleepiness, nervousness, tiredness, and drowsiness. To eliminate these side effects, researchers have paid great attention to finding potential drugs from marine sources with potent efficacy and specificity for the treatment of cancer. Brown seaweeds have a diversity of compounds and novel entities such as polysaccharides, polyphenolic contents, carotenoids, terpenoids, bromophenols, proteins, lipids, amino acids, vitamins, sterols, and quinines. Therefore, in vitro and in vivo studies of these compounds have proven their strong potential against cancer cells without toxicity problems. Considerably, there are still many issues that persist to develop a marine drug such as potential toxic side effects and large-scale production issues. However, biochemical combinatorial genetic and metabolic engineering can be helpful for the development of natural drugs by modification or by eliminating the toxic groups from these natural compounds to obtain a pure compound that is more specific and less cytotoxic. In addition, the anticancer activity and specificity of active compounds can be increased to determine the exact mechanism of action, structural activity relationship, synthetic methods, and drug metabolism. There is a need for extensive study to overcome the issues related to finding these desired compounds such as large-scale production issues that may be improved through new aquaculture and fermentation processes. The brown seaweeds studied to date have exhibited strong potential against various cancer cells without producing toxicity and therefore, there is a need to explore the marine brown algae for the development of new pharmaceutical products. Thus, this review might be useful for developing potential anticancer drugs from brown seaweeds.

Abbreviations

IFN	Interferon factor
NK	Natural killer
FCSPs	Fucoidan complex sulfated polysaccharides
AGS	Human stomach cancer cell line
RPMI-7951	Human malignant melanoma obtained
P-388	Murine leukemic cells
Pc-3	Prostate cancer
A549	Alveolar carcinoma
Hela	Cervical cancer
HepG2	Heptacellular carcinoma
U937	Human leukemic monocyte lymphoma
kDa	Kilo dalton
SK-ML-5	Human malignant melanoma
SK-ML-28	Human malignant melanoma
HCT-15	Human colon cancer cell line
MG-63	Human osteosarcoma
MCF-7	Breast cancer
Hep-2	Liver cancer
S-180	Sarcoma 180
Dw	Dry weight
MAPK	Mitogen-activated protein kinase
TPA	Tetradecanoylphorbol acetate
MMP-9	Matrix metalloproteinase-9
AP-1	Activator protein-1
Hep 3B	Human hepatoma cell line
BGC-823	Human gastric cancer cell line
B16-BL6	Murine melanoma
HT-1080	Human fibrosarcoma cells
A2780	Human ovarian cancer cell line
Bel7402	Human hepatocellular carcinoma
HCT-8	Human colon cancer cells
CSCs	Cancer stem-like cells
SKOV3	Human ovarian carcinoma cell line
P388	Human leukemia cells
HT-29	Human colon adenocarcinoma cells
RBL-2H3	Basophilic leukemia cell line
MDA-MB-231	Human mammary adenocarcinoma
WAT	White adipose tissues
HUVECs	Human umbilical vein endothelial cells
3T3-L1	Mouse adipose tissue cell line
DU145	Human prostate cancer cell line
LNCaP	Human prostate adenocarcinoma cell line
DLD-1	Human colorectal adenocarcinoma
ERCC1	Expression of excision repair cross complementation 1
PI3K/AKT	Phosphatidylinositol 3-kinase
NFκB	Nuclear transcription factor kappa B
EJ-1	Human bladder cancer cells
MGC-803	Human gastric adenocarcinoma cancer cells
JAK/STAT	Janus kinase/signal transducer and activator of transcription
Neuro-2a	Mouse neuroblastoma cell line
V79	Chinese hamster lung fibroblast cell line
MC/9	Mice mast cells
HCT116	Human colon cancer cells
Caco-2	Human epithelial colorectal
T47D	Breast cancer cell line
LJGP	Laminaria japonica glycoprotein
EBL	Eisenia bicyclis laminaran
SgF	Sulfated glactofucan
AaF	Alaria agusta fucoidan
AaL	Alaria agusta laminaran
ScF	Sargassum cichorioides fucoidan
FeF	Ficus evanescens fucoidan
UpF	Undaria pinnatifida galactofucan
FRF	Fraction rich in fucans
SQA	Sargaquinoic acid
PLE	Pylaiella littoralis extract
NCI-H1299	Human lung cancer cell line
hABM-MSCs	Human alveolar bone marrow-derived mesenchymal stem cells
ERK	Extracellular signal-related kinase
JNK	c-Jun N-terminal kinase
KB	Human leukemia-lymphoma cell line
NSCLC-N6	Human non-small cell bronchopulmonary carcinoma line
PTK	Protein tyrosine kinase
SVLV	Sargassum vulgare low viscosity
SVHV	Sargassum vulgare high viscosity
PC12	Clonal rat pheochromocytoma cell line
DC	Dendritic cells
SmF	Sargassum mcclurei fucoidan
LCC	Lewis lung carcinoma cells
MCB16	Melanoma cells B16
MDCK	Madine–Darby canine kidney
ROS	Reactive oxygen species
MKN-45	Human gastric adenocarcinoma
SK-Hep1	Human hepatoma cell line
LC6	Large cell lung cancer cell line
SH-SY5Y	Human neuroblastoma cell line
NCI-H460	Lung cancer cell line
EELN	Ethanolic extract of Leathesia nana
GCSF	Granulocyte colony-stimulating factor
EMT	Epithelial-mesenchymal cell transition

Acknowledgements

The study was supported by the National High-level personnel of special support program (“people plan”), Program for Talent of Aoshan, National Natural Science Foundation of China (No. 41276167, 41206066, 41506169 and 41306157), China Postdoctoral Science Foundation (No. 2015T80755 and 2014M551972), the National science and technology support project (2013BAB01B02-2), Focus on research and development plan in Shandong province (2015GGF01039), Science and Technology Development Program of Qingdao Shinan District (No. 2013-12-008-SW), and Basic Research Projects of Qingdao Science and Technology Plan (No. 14-2-4-35-jch).

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