It comes from the sea: macroalgae-derived bioactive compounds with anti-cancer potential

Figures & data

Table 1. Anti-cancer potential of brown, red, and green macroalgae.

Macroalgae	Cancer type	Specimen (compound)	Research model	Concentration and duration	Results	References
Brown macroalgae	Pancreatic	Fucus vesiculosus (purified acetonic extract)	In vitro: PANC-1, PancTu1, Panc89, Colo357	Up to 72 h EC50 determination for each pancreatic cell line	Strong inhibition of viability due to upregulation of cell cycle inhibitors with cells dying in a Cas-independent manner. Low cytotoxicity against terminally differentiated cells and non-malignant resting T cells. Accelerated apoptotic effects in combination with inhibitors of autophagy.	Geisen et al. [21]
		Turbinaria conoides (fucoidan, water extract)	In vitro: MiaPaCa-2, PANC-1	6.25, 12.5, 25, 50, 100 μg/mL for 24, 48, and 72 h	At lower concentrations than 100 μg/mL: significant inhibition of cell proliferation and induction of apoptosis as well as angiogenic potential. MMP-2 and -9 activities inhibition. At 100 μg/mL: induction of cytotoxicity in both cell lines increases with time in culture.	Delma et al. [22]
			In vitro: PANC-1, MiaPaCa-2, Panc-3.27, BxPC-3	3.125, 6.25, 12.5, 25, and 50 μg/mL for 24 and 72 h	Consistent and significant dose-dependent inhibition of cell survival, with maximal inhibition at 50 μg/mL. Induction of apoptosis, activation of Cas-3, -8, and -9, and cleavage of PARP. Inhibition of 57 and 38 pathway molecules with fucoidan-F5 in MiaPaCa-2 and PANC-1 cells, respectively. Fucoidans may target p53–NFκB crosstalk and dictate apoptosis in pancreatic cancer cells.	Delma et al. [23]
		Ecklonia cava (dieckol, commercial Sigma‐Aldrich, St. Louis, MO)	In vitro: PANC-1	0, 5, 10, 15, 20, 25, and 30 μM/mL for 24 h	Induction of apoptosis and increased ROS levels. Decreased expression of tumor cell progression inducers (cyclin D1 and PCNA). Decreased expression of Bcl-2 family proteins. Reduction of the antioxidant defense system in cancer cells without increasing inflammatory cytokine levels.	Xu et al. [24]
	Lung	Ecklonia cava (dieckol, commercial AKos Consulting & Solutions, Steinen, Germany)	In vitro: A549	25 and 50 μg/mL for 24 h	Inhibition of invasive and migratory properties of A549 cells. Induction of apoptosis via Pi3K/AKT/mTOR inhibition signaling. Tumor suppressor protein E‐cadherin activation.	Wang et al. [25]
		Ecklodia Cava (fucosterol, commercial Sigma‐Aldrich, St. Louis, MO)	In vitro: HCC827, A549, SK-LU-1, A427	0, 1.55, 3.12, 6.25, 12.5, 25, 50, and 100 μM for 24 h	Growth inhibition is more effective against A549 and SK-LU-1 cells. Induction of apoptosis and cell cycle arrest of A549 and SK-LU-1 cells.	Mao et al. [26]
		Sargassum crassifolium (native and degraded fucoidans, water extract)	In vitro: A549	0, 50, 100, 200, 300, 400, and 500 μg/mL for 48 h	Induction of apoptosis by native and degraded fucoidans. Decreased Bcl-2 expression, loss of mitochondrial membrane potential, increased CYC release, active Cas-9 and -3, and late apoptosis were observed. The signaling pathway mTOR is involved in native fucoidan and respective degradation products induced apoptosis of A549 cells.	Wu et al. [27]
Brown macroalgae		Sargassum aquifolium (oversulfated fucoidans)	In vitro: A549	200 μg/mL for 48 h	Fucoidan oversulfation leads to improved apoptosis of lung cancer cells. Sulfate content appears to play a key role in apoptotic cell death. Akt/mTOR/S6 pathway could be related to fucoidans induced apoptosis.	Hsiao et al. [28]
		Fucus vesiculosus and Laminaria japonica (fucoidan, commercial Sigma-Aldrich, St. Louis, MO)	In vitro: A549, CL1-5 In vivo: Oral administration to healthy mice for 14 days. LLC1-xenograft mouse model orally fed with fucoidan for 3 weeks	200 and 400 μg/mL for 48 h 24 mg/kg/daily for 14 days	Induction of endoplasmic reticulum stress response by activation of PERK–ATF4–CHOP pathway, leading to apoptotic cell death in vivo and in vitro. Prevention of tumorigenesis and tumor size reduction in vivo.	Hsu et al. [29]
		Unspecified Brown Algae (alginic acid, commercial Sigma-Aldrich, St. Louis, MO)	In vitro: A549, H1155	0.0, 0.2, 0.5, and 1.0 μg/mL for 48 h	In vitro inhibition of non‑small cell lung cancer‑induced angiogenesis. Downregulation of VEGF-A expression in a dose-dependent manner.	Wang et al. [30]
			In vivo: BALB/c xenograft mouse model	100 mg/kg body weight for 19 days.	Attenuated non‑small cell lung cancer‑induced angiogenesis in vivo via miR-506/STAT3/VEGF-A axis.
	Leukemia	Sargassum thunbergia (halosmysin A, ethanolic extract)	In vitro: P388, HL-60, L1210	2, 20, and 200 M for 72 h	Strong cytotoxicity against all leukemia cell lines, with IC50 values ranging from 2.2 ± 3.1 to 11.7 ± 2.8 μM for P388, HL-60, and L1210 cell lines, respectively.	Yamada et al. [31]
	Leukemia Breast	Sargassum polycystum (fucoidan, enzymatic extract)	In vitro: HL-60, MCF-7	12.5, 25, 50, and 100 μg/mL for 24 h	Antiproliferative effect on both tested cell lines. Increased DNA damage, apoptotic body formation, and arrested cell cycle of both cell lines. Effects proceed via the mitochondria-mediated apoptosis pathway.	Priyan et al. [32]
	Breast	Undaria pinnatifida (fucoxanthin, commercial Wuhan Heli)	In vitro: HLEC, MDA‐MB‐231 In vivo: MDA‐MB‐231 xenograft mouse model	25, 50, and 100 μmol/L for 12, 24, or 48 h 100 and 500 μmol/L injected at the tumor periphery every day, for 26 days	Inhibition of growth, proliferation, migration, tube formation, and suppression of PI3K/Akt/NF‐κB signaling of HLEC. Decrease of migration, invasion, and secretion of VEGF‐C of MDA‐MB‐231. Inhibition of tumor‐induced lymphangiogenesis in vitro. Inhibition of tumor growth and lymphangiogenesis.	Wang et al. [33]
		Undaria pinnatifida (fucoidan, Maritech extraction process)	Clinical trial: Co-administration of fucoidan with letrozole and tamoxifen (used hormonal therapies), breast cancer patients	500 mg twice daily for 3 weeks	No significant changes in the pharmacokinetics of letrozole, tamoxifen, or tamoxifen metabolites after co-administration with fucoidan were observed. No adverse effects or toxicity of fucoidan intake were reported. Fucoidan could be taken concomitantly with letrozole and tamoxifen without risk of significant clinical interactions.	Tocaciu et al. [34]
Brown macroalgae		Bifurcaria bifurcata (oxygenated acyclic diterpenes, n-hexanes and chloroform subextracts)	In vitro: MDA-MB-231	0–100 µg/mL for 72 h to determine the IC50 values	Moderate inhibition of MDA-MB-231 cells growth with IC50 values ranging from 11.6 to 32.0 µg/mL.	Smyrniotopoulos et al. [35]
	Cervical, colorectal, breast	Halopteris scoparia (n-hexane, chloroform, and methanol extracts)	In vitro: HeLa, CaCo-2, and MCF-7	0.5, 5, and 50 μg/mL of each extract for 48 h	Reduction in cell viability, especially against cervical adenocarcinoma cells (HeLa). Increased expression of many pro-apoptotic genes in both Cas-dependent and Cas-independent intrinsic and extrinsic pathways increased.	Güner et al. [36]
			In vivo: LD50 acute toxicity test (competent mice) and HET-CAM assay	LD50 acute toxicity test: a limit dose of 2000 mg/kg body weight HET-CAM: 0.5 and 1 mg/mL	No irritation or toxicity was observed for any extract.
	Colorectal	Eisenia bicyclis (phlorofucofuroeckol A, methanol extract)	In vitro: HCT116, SW480, LoVo, HT-29	0, 50, and 100 μM for 24 h	Increased concentrations of phlorofucofuroeckol A induced reduction of cell viability in all tested cell lines via ATF3-mediated pathway, which may be explained by the apoptosis through the cleavage level of PARP (a biomarker of apoptosis and apoptosis-dependent cell death) increased by phlorofucofuroeckol A treatment.	Eo et al. [37]
		Costaria costata (phlorethols fraction)	In vitro: normal and X-ray irradiated HCT116, HT-29	0–1000 μg/mL for 24 h – cell viability Determination of the sensitivity of the cells to radiation (X-ray at a dose rate from 2 to 10 Gy) Determination of the radiosensitizing activity of phlorethols on irradiated cells	Cytotoxic activity against HT-29 (IC50 =92 μg/mL) and HCT116 (IC50=94 μg/mL) cells. The non-toxic concentration of phlorethols lead to the inhibition of colony formation in colon cancer cells and enhanced their sensitivity to low non-toxic X-ray irradiation, which may indicate a beneficial combination of radiation and phlorethols.	Malyarenko et al. [38]
		Fucus vesiculosus (fucoidan, commercial Sigma-Aldrich, St. Louis, MO)	In vitro: p53^+/+ and p53^–^/^– HCT116	0, 10, 25, 50, 100, and 150 μg/mL for 48 h – cell viability	Concentrations of 150 μg/mL were considered less cytotoxic for both wild type and null cells. At this concentration, fucoidan induced apoptosis, cell damage, and induced G1 arrest in cell cycle progression.	Park et al. [39]
Brown macroalgae	Liver	Sargassum fusiforme (SFPS, water extract)	In vitro: HepG2	125, 250, 500, 1000, and 2000 mg/mL for 24, 48, and 72 h – cytotoxicity and apoptosis assays	Induced high dose dependent cytotoxicity to HepG2 cells in vitro and stimulated apoptosis of HepG2 cells, increased the expression of Bax, and decreased the expression of Bcl-2.	Fan et al. [40]
		Ecklonia cava (dieckol, commercial LESEN Phytochem & Herbs Extract Solution Provider)	In vivo: HCC model – induced in male Wistar rats by drinking water with 0.01 % of NDEA for 15 weeks	Oral administration of 10, 20, and 40 mg/kg body weight for 15 weeks	Administration of 40 mg/kg body weight was highly effective in comparison with smaller doses. It significantly reversed the activities of hepatic marker enzymes, decreased lipid peroxidative markers, increased antioxidant cascade, and decreased NDEA concentration in the liver.	Sadeeshkumar et al. [41]
		Sargassum (fucoidan, commercial Shaanxi Kang Yue Biological Technology, Xi'an, China)	In vitro: SMMC-7721, Huh7 and HCCLM3	0, 10, 20, 30, and 40 mg/mL for 24, 48, and 72 h – Migration, invasion, and wound healing assays	Dose-dependent inhibition of migration and invasion for the three tested cancer cell lines. Fucoidan prevents invadopodia formation in a dose-dependent manner by deactivating the integrin αVβ3/SRC/E2F1 signaling pathway.	Pan et al. [42]
			In vivo: HCCLM3 xenograft mouse model	Oral administration with 1 g/kg for 21 days.	Reduction of tumor size and decrease of the number of liver metastasis.
Green macroalgae	Lung	Caulerpa taxifolia (for synthesis of Ag NPs)	In vitro – A549	10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 mg/mL overnight	Biosynthesized Ag NPs exhibited cytotoxicity against A549 cells, with an IC50 of 40 mg/mL. Cell morphology was affected.	Zhang et al. [43]
	Breast	Chaetomorpha sp. (ethanol and aqueous extracts)	In vitro – MCF-7, MDA-MB-231	20–200 μg/mL for 72 h – cell viability	Ethanol extract of algae possessed higher antioxidant and anti-cancer activity compared to aqueous extract. MDA-MB-231 breast cancer cell lines were significantly affected by different concentrations of ethanol extracts of Chaetomorpha sp.	Haq et al. [44]
	Liver Breast	Ulva lactuca (phycocyanin, methanolic extract)	In vitro – HepG2, MCF-7	10, 20, and 40 μM – cell viability and apoptosis assays	Antiproliferative and pro-apoptotic activities on liver and breast cancer cell lines.	Al-Malki [45]
	Liver	Ulva lactuca (sulfated polysaccharides and aqueous extract)	In vivo: Hepatocarcinogenesis induced by injection of DENA in rats	Oral administration of 50 mg/kg daily for 2, 12, and 24 weeks	Marked chemoprevention of DENA-initiated hepatocarcinogenesis through inhibition of abnormal cell proliferation and induction of apoptosis. Modest inhibition of rat liver carcinogenesis was observed with the aqueous extract. Sulfated polysaccharides changed serum parameters of hepatic damage and modulated various components of the hepatic enzymatic and nonenzymatic antioxidant defense systems.	Hussein et al. [46]
Red macroalgae	Breast	Kappaphycus alvarezii (methanolic extract)	In vitro: MCF-7	1, 3, 7, 9, 12, and 15 mg/mL for 24 h – cell viability	Induction of cytotoxicity on MCF-7 cell line, with an IC50 value of 4.1 mg/mL.	Chang et al. [47]
			In vivo: Subchronic toxicity in healthy rats and mammary carcinogenesis induced by DMB rat model	Oral administration 2000 mg/kg body weight) daily – toxicity for 8 weeks Oral administration of 300 mg/kg for 11 weeks	No toxicity was observed for the sub-chronic toxicity test. Decreased the size of the tumors and the white blood cell level.
		Porphyridium sordidum (polysaccharides)	In vitro – Normal and electroporated MCF-7 and MDA-MB-231	10, 25, 50, 75, or 100 μg/mL for 48 h	Cell survival appeared to be dose and cell type dependent. Additional application of electroporation (200 V/cm) increased the effect of polysaccharide on cell proliferation: 75 μg/mL polysaccharide +200 V/cm electroporation led to a 40% decrease in viability and changes in cell morphology.	Nikolova et al. [48]
	Lung	Gelidiella acerosa (sequential extraction)	In vitro: A549	0.1–2 mg/mL for 24 h – cell viability and apoptotic assays	Inhibition of cell proliferation, migration, and colonization as well as induction of apoptosis.	Fazeela Mahaboob Begum et al. [49]
	Lung Gastric Melanoma	Gracilariopsis lemaneiformis (polysaccharides, water extract)	In vitro: A549, MKN28, and B16	5, 10, 20, 30, 40, 50, 60, 80, or 100 μg/mL for 24, 48, and 72 h – cell viability and apoptotic assays	Modulation of cell viability, apoptosis, morphology, and related Fas/FasL signaling pathway. Inhibition of cell proliferation by induction of apoptosis for all three tested cell lines.	Kang et al. [50]
			In vivo: A549-xenograft mouse model	Intraperitoneal injection at 20, 40, and 80 mg/kg body weight twice a week for 6 weeks.	Growth inhibition of xenografted tumors in mice in a concentration-dependent manner. The presence of cleaved Cas-3 and Ki67 are important indicators of apoptosis and proliferation, respectively.
			In vivo: HepG2-xenograft mouse model	Orally fed with SPFS 100, 200, and 400 mg/kg body weight for 28 days	Inhibition of tumor growth and induction of immunomodulatory activity in vivo.
			In vivo: adult male zebrafish model	Oral administration 15, 30, 45, and 60 μg/day for 10 days – Acute and chronic toxicity analysis in zebrafish	Inhibition of tumor growth in zebrafish.

PANC-1: human pancreatic cancer cell line from pancreatic ductal adenocarcinoma; PancTu1: human pancreatic cancer cell line from pancreatic ductal adenocarcinoma; Panc89: human pancreatic cancer cell line from ductal adenocarcinoma derived from metastatic site – lymph node; Colo357: human pancreatic cancer cell line from metastatic pancreatic adenocarcinoma; MiaPaCa-2: human pancreatic cancer cell line from pancreatic ductal adenocarcinoma; Panc-3.27: human pancreatic cancer cell line from pancreatic adenocarcinoma; BxPC-3: human pancreatic cancer cell line from pancreatic ductal adenocarcinoma; A549: human lung cancer cell line from lung adenocarcinoma; HCC827: human lung cancer cell line from lung adenocarcinoma; SK-LU-1: human lung cancer cell line from lung adenocarcinoma; A427: human lung cancer cell line from lung adenocarcinoma; CL1-5: human lung cancer cell line from lung adenocarcinoma; P388: Leukemia cancer cell line from mouse lymphoma; HL-60: human leukemia cancer cell line from adult acute myeloid leukemia; L1210: cancer cell line from mouse leukemia; MCF-7: human breast cancer cell line from invasive breast carcinoma of no special type; derived from metastatic site – pleural effusion; HLEC: human lymphatic endothelial cells; MDA-MB-231: human breast cancer cell line from breast adenocarcinoma; derived from metastatic site – pleural effusion; HeLa: human cancer cell line from papillomavirus-related endocervical adenocarcinoma; CaCo-2: human cancer cell line from colon adenocarcinoma; HCT116: human colorectal cancer cell line from colon carcinoma; SW480: human colorectal cancer cell line from colon adenocarcinoma; LoVo: human colorectal cancer cell line from colon adenocarcinoma; derived from metastatic site – left supraclavicular lymph node; HT-29: human colorectal cancer cell line from colon adenocarcinoma; HepG2: human liver cancer cell line from hepatoblastoma; SMMC-7721: human cancer cell line from papillomavirus-related endocervical adenocarcinoma; Huh7: human liver cancer cell line from hepatocellular carcinoma; HCCLM3: human liver cancer cell line from hepatocellular carcinoma; MKN28: human gastric cancer cell line from gastric tubular adenocarcinoma; derived from metastatic site-liver; B16: mouse melanoma cancer cell line; MMP: matrix metalloproteases; Cas: caspase; NFκB: nuclear factor κB; Bcl-2: B-cell leukemia-2; PARP: poly ADP ribose polymerase; ROS: reactive oxygen species; Pi3K/AKT/mTOR pathway: plays a key role in lung cancer cell survival, proliferation, and growth; mTOR: Akt/mammalian target of rapamycin pathway – related to several cell functions such as invasion, proliferation, migration, and survival; PERK–ATF4–CHOP pathway: plays a key role in inducing CHOP transcription; CYC: cytochrome C; Bax: Bcl-2 associated X protein; DENA: diethylnitrosamine; IC₅₀: the effective dose of the substance required to inhibit cell growth by 50%; HET-CAM: Hen’s egg test chorioallantoic membrane; LD50: determination the lethal dose of a substance that will kill 50% of the tested animals; SFPS: Sargassum fusiforme polysaccharide; HCC: hepatocellular carcinoma; NDEA: N-nitrosodiethylamine.

Figure 1. Mechanisms of action of macroalgae major bioactive compounds in cancer cells.

Figure 2. Brown, green, and red macroalgae species and targeted types of cancer.

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