Review Article

Bioactive Compounds of Seaweeds and Their Effects on Certain Types of Cancer

Background

Cancer, which is the world’s second-largest cause of mortality, is the unregulated proliferation of cells and is related to significant pathological changes (1). Approximately 1.8 million people were diagnosed with cancer in the United States in 2020 (2). Further, about 140 690 cancer cases were detected and about 103 250 deaths of cancer were among the elderly in the United States (2). In addition to other types of cancer that can be metastasized into other tissues, more than 200 different types of malignant tumors are identified resulting in lethal metastasis tumors. Lung cancer was the most common and caused death among males, followed by prostate and colorectal cancer, as well as liver and stomach cancer. Among females, breast cancer, accompanied by colorectal and cervical and lung cancer, was the widely diagnosed cancer and caused deaths (3). Owing to this high degree of cancer effect, the removal of cancer has been given considerable attention (4).

However, various developed anticancer drugs can prolong the survival time of patients. The intrinsic side effects of these drugs seriously affect the quality of the patient’s life (5).

Carcinogenesis Process and Certain Types of Cancer

Carcinogenesis is a multi-stage complex process controlled by processes such as inflammation, growth and cell differentiation, and metastasis (6). It has been described as a three-stage process including initiation, promotion, and progression (7).

Cancers are categorized relative to the type of tissue and the cell they originate from (8). Carcinomas are epithelial cell-derived cancers and the most common human cancer. Sarcomas originate from muscle cells or the connective tissue. Different types of leukemia and lymphomas coming from white blood cells and their precursor cells are cancers that do not fall into any of these two large categories.

Breast cancer is one of the leading public health challenges worldwide. It is the most prevalent among women and is the world’s second type of cancer with 2 088 849 new cases in 2018 (3,9). Patients with breast cancer live extremely longer as early warning programs develop and improvements in the treatment of breast cancer contribute to ever-better survival results. The survival rate for five years increased from 75% in 1976 to 91% in 2017 (10).

Liver cancer is the world’s sixth most frequent form of cancer and occupies the second position in mortality after lung cancer (11). According to (12), two million people are annually died due to liver diseases, half of which are because of cirrhosis complications, and the other half is due to viral hepatitis and hepatocellular carcinoma (HCC). HCC is the main type of liver pathology and accounts for about 80% of cases of liver cancer (13). Despite continuing developments in chronic liver disease management, tumor identification, and oncological diagnosis, HCC prognosis remains lower compared to other tumor entities )3). HCC carcinogenesis includes angiogenesis, chronic inflammation, and macro-and micro-environmental tumors (13). Regrettably, a large number of patients lose the chance for resection due to delayed diagnosis (14).

Approximately 13 430 new cases of larynx cancer have been detected, with around 3620 patients who are dying from the disease (15). Laryngeal cancer occurs more frequently in males than in females (16). This type of cancer is regrettably one of the oncology conditions for which the lifetime risk has decreased from 66% to 63% over the past 40 years whereas the overall prevalence is decreasing (10).

The pathogenesis of laryngeal cancer includes a variety of risk factors (17). Tobacco and alcohol intake is the most important of these factors. The use of tobacco is strongly associated with the incidence of laryngeal cancer, with a 10-15 significantly greater threat for smokers compared to non-smokers and a risk 30 times higher for voracious smokers (18,19).

Treatment of Cancer

Invasive cancer care is primarily dictated by the histology of the tumor, the stage of cancer, patient preference, and success status (2). The primary treatment modalities are surgery, chemotherapy, and radiation therapy (20). For the majority of solid tumors, surgery remains the best therapy. Surgery could be possible in only a small subset of patients depending on the type of cancer (21). Some modalities including chemotherapy and radiation therapy are probably paired with surgery. However, major side effects such as fatigue, diarrhea, xerostomia, and secondary malignancies may be associated with these therapies (22).

Radiation therapy is the use of ionizing radiation for directly treating the cancerous tumor rather than the whole body. Chemotherapy is used to cure the whole body and applies to chemical treatment which quickly destroys all dividing cells (23).

Depending on the method of procedure, two types of procedures are commonly used in combination with each other, including neoadjuvant (pre-surgery), adjuvant (post-surgery), and concomitant treatment where radiotherapy and chemotherapy are employed with each other without operation (24). The integration of chemotherapy and radiation treatment helps many approaches to attack tumors and thus can help avoid the immunity of cancer cells to either therapy (25,26). The general course of therapy during neoadjuvant therapy includes radiation treatment accompanied by chemotherapy. It could be used to minimize tumor dimension. It has been shown that this method of treatment increases the survival rate of many cancer patients (24).

Adjuvant therapy is often used after surgery as there is a possibility that some cancer cells in the patient will still be present. There are five main types of adjuvant therapy for the treatment of cancer, including chemotherapy, hormonal, radiation, immune, and targeted therapy. The type of user is dictated by the type and level of cancer, as well as hormone tolerance and involvement of the lymph node (27).

Multidrug Resistance

A major issue in cancer clinical practice is the multidrug resistance (MDR) of tumor cells to chemotherapeutic agents. The enhanced expression of a membrane-associated transport protein such as P-glycoprotein (Pgp) is an important mechanism for acquiring the MDR phenotype in mammalian cells. Pgp is part of the highly conserved adenosine triphosphate cassette-binding (ABC) protein superfamily, which is one of the major groups in the animal kingdom (28).

The functional objective of Pgp in the organs via specialized excretory, secretory, and barrier functions is to afford defense against toxic insults (29). Pgp is commonly expressed in the stomach, liver, and kidney epithelial cells, as well as the brain and placenta endothelial cells.

Generally, the drug aggregation defect present in MDR cells is altered by agents used to antagonize MDR. Although several agents have been tested to inhibit MDR in the hunt for chemo-sensitizers, no chemotherapy user agent exists to date. The modulators of the first generation were not designed specifically for MDR inhibition. Instead, they were discovered by chance, including verapamil, cyclosporine A, reserpine, and the like (30). The undesirable toxicity characteristics of first-generation molecules have been removed in second-generation agents designed after the chemical modification of earlier agents. Such modulators have greater tolerability although they experience volatile pharmacokinetic interactions (i.e., verapamil R isomer, valspodar, cyclosporine D analog, biricodar, and the like) (31). The compounds of the third generation (i.e., tariquidar, zosuquidar, laniquidar, and the like) have been engineered to be devoid of other therapeutic actions and to give Pgp greater selectivity and specificity. Clinical trials are being performed on many compounds from this group (32).

Biomedical Compounds of Seaweeds and Their Uses

Benthic marine algae or seaweeds are plants that exist either in fresh or brackish water. They are a large group of autotrophic organisms which for oxygen photosynthesis contain chlorophyll. Adaptive osmoregulation processes have been established to retain their osmotic internal pressure and to escape the effects of the resultant turgidity and hypoplasia from changes in their habitat’s salinity (33). Marine algae are micro- or macro-algae vegetative organisms, which differ in scale, morphology, and size ranging from 2 µm to 30 m. They are the predominant aquatic vegetation and are directly involved in habitat complexity, primary ocean development and retention of nutrients, and coastal ecosystems (34).

There have been more records of different natural antimicrobial products in the aquatic compared to the terrestrial environment. A previous study evaluated the source of structurally distinct natural substances with pharmacological and biological activities in marine organisms such as algae (35). As a source of medicinal compounds, marine algae dominate a special position among marine organisms (36) as the possible sources of antibiotic substances. An indication of the existence of antimicrobial active compounds is the synthesis of various metabolites from the seaweed. Macroalgae such as antibacterial active compounds (37) have derived a broad variety of bioactive compounds. Seaweeds have several distinct secondary metabolites with a large variety of biological activities. Compounds with cytostatic, antiviral, anthelmintic, antifungal, and antibacterial activity have been found in orange, brown, and red algae (38).

The seaweed is considered to be the primary source of bioactive compounds with a broad range of biological functions, including antioxidants, antibiotics, and anti-inflammatory compounds (39). Some bio-active materials of macroalgae act against those of pathogenic bacteria in their germination (40). Tüney et al (41) discovered that several species of crude marine algal extracts inhibit pathogenic bacteria. Seaweeds have various medicinal and pharmacotherapy substances while some of the isolated compounds have bacteriostatic and bactericidal characterization (42). Antibiotics have been used to treat different pathogens originating from terrestrial sources and used as therapeutic agents. New compounds have been discovered in the oceans and have economic potential (43).

Efficient cancer care is still missing despite decades of studies (44). In addition, there is a growing demand for new cell-selective anticancer agents with fewer negative impacts, increasing the quality of life of patients (44). Natural products provide a reliable choice when searching for drugs that can aid in the prevention of cancer (45).

Previous research (46) has concentrated on natural products from marine organisms throughout the past several decades primarily because of their broad environment (covering ~70% of the Earth’s surface), high biodiversity (95% of the world’s biodiversity), and the specific conditions in which these species are present (e.g., at extreme levels of temperature, salinity, and pressure). Among the studied marine compounds, the anticancer potential of extracts and compounds derived from marine algae is particularly exciting. Seaweeds are abundant in bioactive materials which are not found in food sources and terrestrial plants (39). Novel compounds such as fucoidan, alginate, fucoxanthin, polyphenols, and the like can possess unique health-promoting characteristics, including cancer therapy, that can be used in human health applications (47). For their anti-tumor activities, several extract-obtained or slightly distilled products have been examined from various red, green, and brown seaweeds (48). Gutiérrez-Rodríguez et al (49) reported that several seaweed compounds can be effective anticancer agents.

In response to a variety of evolving pressures in the atmosphere (e.g., salinity, temperature, UV exposure, and light) seaweeds may generate several novel secondary metabolites, which make them the most effective reservoirs of new human treatment materials (50). It has been shown that different compounds derived from a variety of marine algae eradicate or delay the development of cancer. The seaweed has a powerful curing effect on colon and breast cancers, which are the major causes of death rates associated with cancer in women and men (51). Apoptosis was found in cancer cells that were treated with seaweed extracts. Many amassing examples indicate that bioactive compounds derived from seaweeds generate antitumor effects through various modes of action, including the inhibition of tumor cell development, invasion and metastasis, and apoptosis induction in cancer cells (52,53).

In the field of cancer prevention, the ingestion of various types of seaweeds has been recognized to be responsible for the decreased incidence of cancer in Asian countries whose inhabitants traditionally intake a significant amount of seaweeds (51). Based on the findings of a cohort study in Japan, lower lung cancer mortality in males and females and lower pancreatic cancer mortality in males were correlated with seaweed intake in a joint cancer evaluation (54). However, in the above-mentioned analysis, no positive relation was observed between the consumption of the seaweed and prostate cancer, a finding supported by a prospective study of 18,115 Japanese men (55).

Seaweed’s Polysaccharides and Cancer Prevention

Polysaccharides seem to be the most commonly studied seaweed-derived cytotoxic compounds (56), and brown seaweeds containing alginate, fucoidan, and laminaran, among others, are the most common source of these bioactive polysaccharides. Sulfated galactans such as agar and carrageenans, which have many promising medicinal properties including antitumor activities are present in red seaweeds (57).

The results of a previous study revealed that alginate, laminaran, fucoidan, and other seaweed polysaccharides have apparent antitumor activities with the ingestion of dietary seaweed fibers capable of preventing cancer development and proliferation in the digestive tract (58). Alginate can cleanse the intestinal tract, increase the level of immunity and the protection of the intestinal tract, and decrease cancer risk. To prevent cancer, laminaran can induce apoptosis, and for several cancers, sulfated polysaccharides such as fucoidan have a wide range of antitumor activities. Direct or indirect antitumor effects are also demonstrated by certain unidentified seaweed polysaccharides (59). The action of an unspecified polysaccharide from Sargassum confusum was evaluated in S-180 tumors grown in mice. The improved immune function was found as measured by boosted the superoxide dismutase and glutathione peroxidase activities and developed thymocytes and splenocytes, as well as declined level of malondialdehyde (60,61).

Alginate is the main polysaccharide from the brown seaweed (62,63). It has a wide variety of bioactivities, including anticoagulants (64), antitumors (65), antivirals, antihypertension, and antioxidants (66). Alginate can also guard against carcinogens by protecting the stomach and intestinal surface membranes from the effects of carcinogenic substances (67). It is impossible for human intestinal enzymes to digest alginate, and therefore, alginic acid in the bowels chelates or makes insoluble heavy metal ions and cannot be absorbed into the body (68). A previous medical trial represented that alginate stimulates the development of the stomach mucous membranes, inhibits inflammation, and removes the mucous membrane colonies of Helicobacter pylori (69). Moreover, alginate allows for the restoration of intestinal biogenesis (70,71). Other studies have shown the effects of alginate on fecal microbial fauna, changes in compound and acid concentrations, and health-promoting prebiotic properties, specifically in the prevention of cancer (72,73).

In brown-seaweeds, laminaran is a storage glucan (74) that can serve as prebiotics in addition to its position as a dietary fiber (68). By affecting the composition of mucus, intestinal pH, and the production of short-chain fatty acids, it can also modulate intestinal metabolism. Ecological factors influence the structure and biological activities of laminaran (75).

Furthermore, stronger bioactivities were demonstrated to have sulfated laminaran (75). It was found to inhibit heparanase activity in mouse B16-BL6 melanoma cells and rat 13762 MAT mammary cancer cells. As a result, the ability of the tumor cells to deteriorate heparin sulfate in their extracellular matrixes decreased and an anti-metastatic effect was produced as well. Laminaran sulfate has had an impact on tumor cell proliferation and primary tumor growth in vivo at effective concentrations (76). Treatment with Laminaria sp has been reported to inhibit the proliferation of colon cancer cells by Fas and insulin-like growth factor I receptor signaling via the intrinsic apoptotic and ErbB pathways, respectively (77).

It also reduced the Bcl-2 family protein, which consists of members that stimulate and control apoptosis by regulating the mitochondrial permeabilization of the outer membrane. By regulating the ErbB-signaling pathway, it is a key step in the intrinsic path of apoptosis, as well as expression and inhibited cell cycle progression (77).

Fucoidan is a sulfated seaweed polysaccharide primarily consisting of l-fucose and sulfate units in addition to small quantities of d-galactose, d-mannose, d-xylose, and uronic acid (52,78). Its biological activities have been investigated as anticancer (79). Some investigations have shown that it can inhibit growth (80) and induce the apoptosis of cancer cells (81). It can reduce the metastasis (80) and inhibit the angiogenesis of cancer cells (82). It was found that fucoidan can induce apoptosis in a dose-dependent manner in HT-29 and HCT116 colon cancer cells (83). Data from in vitro and in vivo studies showed direct and inhibitory activity against some cancer cell lines, respectively (84).

Fucoidan can inhibit angiogenesis around cancer cells (85). Proangiogenic cytokine and vascular endothelial growth factor (VEGF) have also been shown to decrease and this has been associated with a substantial decrease in angiogenesis and tumor size in 4T1 tumors in vivo. The chick chorioallantoic membrane assay and the gel foam plug assay in mice demonstrated that fucoidan isolated from Sargassum stenophyllum has antiangiogenic activity (50). It has been shown that the production of VEGF-A reduced in human umbilical vein endothelial cells exposed to fucoidan isolated from Undaria pinnatifida (86).

Seaweed’s Polyphenols and Cancer Prevention

Seaweeds include several forms of phenolic compounds because their bioactive components act against grazers, parasites, and epiphytes while for photoprotection (87). The bioactive seaweed polyphenols have a strong antioxidant ability (88) which gives them a role in preventing degenerative diseases such as cancers. Many polyphenolic compounds have been isolated from brown algal organisms (89).

Other Seaweed-Derived Compounds and Antitumor Activities

Carotenoids are tetraterpenoids and expressed by more than 600 recognized natural structural variants of a specific linear C40 molecular backbone (90). They are colorful pigments that can be synthesized in certain non-photosynthetic bacteria. They are involved in photosynthesis, hormonal synthesis, photoprotection, and photomorphogenesis (91). Typically, carotenoids are classified into two classes of carotenes containing only the atoms of carbon and hydrogen and xanthophylls including at least one atom of oxygen (92). B-carotene is the most popular carotene, but the xanthophyll class includes lutein, fucoxanthin, and violaxanthin (93).

In marine algae, carotenoid profiles are used to distinguish gray, brown, and red seaweeds (94). The structure of carotenoids greatly influences their activity as the antioxidant potential enhances by the inclusion of functional groups in the terminal rings. Carotenoids have an antioxidant function that is attributed to their capacity of singlet oxygen to quench and free radicals to scavenge. The mechanism by which oxidative stress-related diseases, including cancer, along with cardiovascular and neurodegenerative diseases are prevented is their antioxidant properties (95). According to Stahl and Sies, there are many forms of cancer that carotenoids can protect against. This is consistent with epidemiological evidence showing an inverse association between the risk of cancerand the intake diet rich with carotenoids (96).

Fucoxanthin is a carotenoid with a unique property in the hydrocarbon polyene chain, along with the functional groups of allergic bonds and oxygen, including epoxy, hydroxyl, carbonyl, and carboxyl groups (97). It is found in brown seaweeds such as microalgae and macroalgae and has defensive and photosynthetic roles (98). Although its content varies throughout the seaweed season and life cycle, it is the most abundant of all carotenoids found in the brown seaweed (91). The anti-inflammatory, anti-cancer, and antioxidant roles of fucoxanthin have been reported in several studies (99,100). The antioxidant activity of fucoxanthin involves free radical scavenging that is one of the mechanisms behind its anti-cancer effect (93).

In conclusion, the human body had resistance against the traditional treatments of the tumor. Thus, investigators should use the bioactive ingredient of natural products as the seaweed in the treatment. Therefore, our future study will focus on using the brown seaweed extract as an antitumor in vitro.

Authors’ Contributions

All authors equally contributed to this research.

Conflict of Interest Disclosures

There is no conflict of interests.

Ethical Issues

Not applicable.

Funding

None.

References

1. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog 2013; 18(1-2):43-73. doi: 10.1615/critrevoncog.v18.i1-2.40 [Crossref] [ Google Scholar]
2. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020; 70(3):145-64. doi: 10.3322/caac.21601 [Crossref] [ Google Scholar]
3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424. doi: 10.3322/caac.21492 [Crossref] [ Google Scholar]
4. Harorani M, Noruzi Zamenjani M, Golitaleb M, Davodabady F, Zahedi S, Jadidi A. Correction to: effects of relaxation on self-esteem of patients with cancer: a randomized clinical trial. Support Care Cancer 2020; 28(1):413. doi: 10.1007/s00520-019-05068-6 [Crossref] [ Google Scholar]
5. Kroschinsky F, Stölzel F, von Bonin S, Beutel G, Kochanek M, Kiehl M. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care 2017; 21(1):89. doi: 10.1186/s13054-017-1678-1 [Crossref] [ Google Scholar]
6. Weinstein IB. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 2000; 21(5):857-64. doi: 10.1093/carcin/21.5.857 [Crossref] [ Google Scholar]
7. Marjanovic ND, Weinberg RA, Chaffer CL. Cell plasticity and heterogeneity in cancer. Clin Chem 2013; 59(1):168-79. doi: 10.1373/clinchem.2012.184655 [Crossref] [ Google Scholar]
8. Martin TA, Ye L, Sanders AJ, Lane J, Jiang WG. Cancer invasion and metastasis: molecular and cellular perspective. In: Madame Curie Bioscience Database. Austin, TX: Landes Bioscience; 2013.
9. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69(1):7-34. doi: 10.3322/caac.21551 [Crossref] [ Google Scholar]
10. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017; 67(1):7-30. doi: 10.3322/caac.21387 [Crossref] [ Google Scholar]
11. Anwar MA, Tabassam S, Gulfraz M, Sheeraz Ahmad M, Raja GK, Arshad M. Isolation of oxyberberine and β-sitosterol from Berberis lycium Royle root bark extract and in vitro cytotoxicity against liver and lung cancer cell lines. Evid Based Complement Alternat Med 2020; 2020:2596082. doi: 10.1155/2020/2596082 [Crossref] [ Google Scholar]
12. Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W. Estimating the global prevalence, disease progression, and clinical outcome of hepatitis delta virus infection. J Infect Dis 2020; 221(10):1677-87. doi: 10.1093/infdis/jiz633 [Crossref] [ Google Scholar]
13. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 2017; 16:1. doi: 10.4103/jcar.JCar_9_16 [Crossref] [ Google Scholar]
14. Morise Z, Kawabe N, Tomishige H, Nagata H, Kawase J, Arakawa S. Recent advances in the surgical treatment of hepatocellular carcinoma. World J Gastroenterol 2014; 20(39):14381-92. doi: 10.3748/wjg.v20.i39.14381 [Crossref] [ Google Scholar]
15. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66(1):7-30. doi: 10.3322/caac.21332 [Crossref] [ Google Scholar]
16. Baselga J. Why the epidermal growth factor receptor? the rationale for cancer therapy. Oncologist 2002; 7 Suppl 4:2-8. doi: 10.1634/theoncologist.7-suppl_4-2 [Crossref] [ Google Scholar]
17. Markou K, Christoforidou A, Karasmanis I, Tsiropoulos G, Triaridis S, Constantinidis I. Laryngeal cancer: epidemiological data from Νorthern Greece and review of the literature. Hippokratia 2013; 17(4):313-8. [ Google Scholar]
18. Kuper H, Boffetta P, Adami HO. Tobacco use and cancer causation: association by tumour type. J Intern Med 2002; 252(3):206-24. doi: 10.1046/j.1365-2796.2002.01022.x [Crossref] [ Google Scholar]
19. Steuer CE, El-Deiry M, Parks JR, Higgins KA, Saba NF. An update on larynx cancer. CA Cancer J Clin 2017; 67(1):31-50. doi: 10.3322/caac.21386 [Crossref] [ Google Scholar]
20. Abbas Z, Rehman S. An overview of cancer treatment modalities. In: Neoplasm. London: IntechOpen; 2018. 10.5772/intechopen.76558
21. Berry MF. Esophageal cancer: staging system and guidelines for staging and treatment. J Thorac Dis 2014; 6 Suppl 3:S289-97. doi: 10.3978/j.issn.2072-1439.2014.03.11 [Crossref] [ Google Scholar]
22. Loh SY, McLeod RWJ, Elhassan HA. Trismus following different treatment modalities for head and neck cancer: a systematic review of subjective measures. Eur Arch Otorhinolaryngol 2017; 274(7):2695-707. doi: 10.1007/s00405-017-4519-6 [Crossref] [ Google Scholar]
23. Ma H, Li HQ, Zhang X. Cyclopamine, a naturally occurring alkaloid, and its analogues may find wide applications in cancer therapy. Curr Top Med Chem 2013; 13(17):2208-15. doi: 10.2174/15680266113139990153 [Crossref] [ Google Scholar]
24. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L. Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol Res 2007; 56(4):275-87. doi: 10.1016/j.phrs.2007.08.003 [Crossref] [ Google Scholar]
25. Arruebo M, Vilaboa N, Sáez-Gutierrez B, Lambea J, Tres A, Valladares M. Assessment of the evolution of cancer treatment therapies. Cancers (Basel) 2011; 3(3):3279-330. doi: 10.3390/cancers3033279 [Crossref] [ Google Scholar]
26. Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer 2020; 20(2):89-106. doi: 10.1038/s41568-019-0222-9 [Crossref] [ Google Scholar]
27. Mishra J, Drummond J, Quazi SH, Karanki SS, Shaw JJ, Chen B. Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. Crit Rev Oncol Hematol 2013; 86(3):232-50. doi: 10.1016/j.critrevonc.2012.09.014 [Crossref] [ Google Scholar]
28. Gameiro M, Silva R, Rocha-Pereira C, Carmo H, Carvalho F, Bastos ML. Cellular models and in vitro assays for the screening of modulators of P-gp, MRP1 and BCRP. Molecules 2017; 22(4):600. doi: 10.3390/molecules22040600 [Crossref] [ Google Scholar]
29. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53:615-27. doi: 10.1146/annurev.med.53.082901.103929 [Crossref] [ Google Scholar]
30. Ozben T. Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett 2006; 580(12):2903-9. doi: 10.1016/j.febslet.2006.02.020 [Crossref] [ Google Scholar]
31. Robey RW, Shukla S, Finley EM, Oldham RK, Barnett D, Ambudkar SV. Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)-mediated transport by the orally administered inhibitor, CBT-1((R)). Biochem Pharmacol 2008; 75(6):1302-12. doi: 10.1016/j.bcp.2007.12.001 [Crossref] [ Google Scholar]
32. Dash RP, Jayachandra Babu R, Srinivas NR. Therapeutic potential and utility of elacridar with respect to P-glycoprotein inhibition: an insight from the published in vitro, preclinical and clinical studies. Eur J Drug Metab Pharmacokinet 2017; 42(6):915-33. doi: 10.1007/s13318-017-0411-4 [Crossref] [ Google Scholar]
33. Monsur HA, Jaswir I, Simsek S, Amid A, Alam Z. Chemical structure of sulfated polysaccharides from brown seaweed (Turbinaria turbinata). Int J Food Prop 2017; 20(7):1457-69. doi: 10.1080/10942912.2016.1211144 [Crossref] [ Google Scholar]
34. Marbà N, Krause-Jensen D, Olesen B, Christensen PB, Merzouk A, Rodrigues J. Climate change stimulates the growth of the intertidal macroalgae Ascophyllum nodosum near the northern distribution limit. Ambio 2017; 46(Suppl 1):119-31. doi: 10.1007/s13280-016-0873-7 [Crossref] [ Google Scholar]
35. Alves C, Silva J, Pinteus S, Gaspar H, Alpoim MC, Botana LM. From marine origin to therapeutics: the antitumor potential of marine algae-derived compounds. Front Pharmacol 2018; 9:777. doi: 10.3389/fphar.2018.00777 [Crossref] [ Google Scholar]
36. Manilal A, Sujith S, Selvin J, Kiran GS, Shakir C, Lipton AP. Antimicrobial potential of marine organisms collected from the southwest coast of India against multiresistant human and shrimp pathogens. Sci Mar 2010; 74(2):287-96. doi: 10.3989/scimar.2010.74n2287 [Crossref] [ Google Scholar]
37. El Shafay SM, Ali SS, El-Sheekh MM. Antimicrobial activity of some seaweeds species from Red sea, against multidrug resistant bacteria. Egypt J Aquat Res 2016; 42(1):65-74. doi: 10.1016/j.ejar.2015.11.006 [Crossref] [ Google Scholar]
38. Barzkar N, Tamadoni Jahromi S, Poorsaheli HB, Vianello F. Metabolites from marine microorganisms, micro, and macroalgae: immense scope for pharmacology. Mar Drugs 2019; 17(8):464. doi: 10.3390/md17080464 [Crossref] [ Google Scholar]
39. Salehi B, Sharifi-Rad J, Seca AML, Pinto D, Michalak I, Trincone A. Current trends on seaweeds: looking at chemical composition, phytopharmacology, and cosmetic applications. Molecules 2019; 24(22):4182. doi: 10.3390/molecules24224182 [Crossref] [ Google Scholar]
40. Kolanjinathan K, Ganesh P, Govindarajan M. Antibacterial activity of ethanol extracts of seaweeds against fish bacterial pathogens. Eur Rev Med Pharmacol Sci 2009; 13(3):173-7. [ Google Scholar]
41. Tüney Kızılkaya İ, Cadirci Cadirci, BH BH, Ünal D, Sukatar A. Antimicrobial activities of the extracts of marine algae from the coast of Urla (Izmir, Turkey). Turk J Biol 2006; 30(3):171-5. [ Google Scholar]
42. Gorban EN, Kuprash LP, Gorban NE. [Spirulina: perspectives of the application in medicine]. Lik Sprava 2003(7):100-10.
43. Tortorella E, Tedesco P, Palma Esposito F, January GG, Fani R, Jaspars M. Antibiotics from deep-sea microorganisms: current discoveries and perspectives. Mar Drugs 2018; 16(10):355. doi: 10.3390/md16100355 [Crossref] [ Google Scholar]
44. Seca AML, Pinto D. Plant secondary metabolites as anticancer agents: successes in clinical trials and therapeutic application. Int J Mol Sci 2018; 19(1):263. doi: 10.3390/ijms19010263 [Crossref] [ Google Scholar]
45. Pádua D, Rocha E, Gargiulo D, Ramos AA. Bioactive compounds from brown seaweeds: phloroglucinol, fucoxanthin and fucoidan as promising therapeutic agents against breast cancer. Phytochem Lett 2015; 14:91-8. doi: 10.1016/j.phytol.2015.09.007 [Crossref] [ Google Scholar]
46. Appeltans W, Ahyong ST, Anderson G, Angel MV, Artois T, Bailly N. The magnitude of global marine species diversity. Curr Biol 2012; 22(23):2189-202. doi: 10.1016/j.cub.2012.09.036 [Crossref] [ Google Scholar]
47. Brown ES, Allsopp PJ, Magee PJ, Gill CI, Nitecki S, Strain CR. Seaweed and human health. Nutr Rev 2014; 72(3):205-16. doi: 10.1111/nure.12091 [Crossref] [ Google Scholar]
48. Ramberg JE, Nelson ED, Sinnott RA. Immunomodulatory dietary polysaccharides: a systematic review of the literature. Nutr J 2010; 9:54. doi: 10.1186/1475-2891-9-54 [Crossref] [ Google Scholar]
49. Gutiérrez-Rodríguez AG, Juárez-Portilla C, Olivares-Bañuelos T, Zepeda RC. Anticancer activity of seaweeds. Drug Discov Today 2018; 23(2):434-47. doi: 10.1016/j.drudis.2017.10.019 [Crossref] [ Google Scholar]
50. Murphy C, Hotchkiss S, Worthington J, McKeown SR. The potential of seaweed as a source of drugs for use in cancer chemotherapy. J Appl Phycol 2014; 26(5):2211-64. doi: 10.1007/s10811-014-0245-2 [Crossref] [ Google Scholar]
51. Moussavou G, Kwak DH, Obiang-Obonou BW, Maranguy CA, Dinzouna-Boutamba SD, Lee DH. Anticancer effects of different seaweeds on human colon and breast cancers. Mar Drugs 2014; 12(9):4898-911. doi: 10.3390/md12094898 [Crossref] [ Google Scholar]
52. Farooqi AA, Butt G, Razzaq Z. Algae extracts and methyl jasmonate anti-cancer activities in prostate cancer: choreographers of ‘the dance macabre’. Cancer Cell Int 2012; 12(1):50. doi: 10.1186/1475-2867-12-50 [Crossref] [ Google Scholar]
53. Liu Z, Gao T, Yang Y, Meng F, Zhan F, Jiang Q. Anti-cancer activity of porphyran and carrageenan from red seaweeds. Molecules 2019; 24(23):4286. doi: 10.3390/molecules24234286 [Crossref] [ Google Scholar]
54. Okada E, Nakamura K, Ukawa S, Wakai K, Date C, Iso H. The Japanese food score and risk of all-cause, CVD and cancer mortality: the Japan Collaborative Cohort Study. Br J Nutr 2018; 120(4):464-71. doi: 10.1017/s000711451800154x [Crossref] [ Google Scholar]
55. Zava TT, Zava DT. Assessment of Japanese iodine intake based on seaweed consumption in Japan: a literature-based analysis. Thyroid Res 2011; 4:14. doi: 10.1186/1756-6614-4-14 [Crossref] [ Google Scholar]
56. Namvar F, Mohamad R, Baharara J, Zafar-Balanejad S, Fargahi F, Rahman HS. Antioxidant, antiproliferative, and antiangiogenesis effects of polyphenol-rich seaweed (Sargassum muticum). Biomed Res Int 2013; 2013:604787. doi: 10.1155/2013/604787 [Crossref] [ Google Scholar]
57. Pangestuti R, Kim SK. Biological activities of carrageenan. Adv Food Nutr Res 2014; 72:113-24. doi: 10.1016/b978-0-12-800269-8.00007-5 [Crossref] [ Google Scholar]
58. Lopez-Santamarina A, Miranda JM, Mondragon ADC, Lamas A, Cardelle-Cobas A, Franco CM. Potential use of marine seaweeds as prebiotics: a review. Molecules 2020; 25(4):1004. doi: 10.3390/molecules25041004 [Crossref] [ Google Scholar]
59. Cunha L, Grenha A. Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applications. Mar Drugs 2016; 14(3):42. doi: 10.3390/md14030042 [Crossref] [ Google Scholar]
60. Liu QY, Meng QY. [In vivo anti-tumor effect of polysaccharide from Sargassum confusum and the mechanisms]. Di Yi Jun Yi Da Xue Xue Bao 2004; 24(4):434-6. [ Google Scholar]
61. Gautam N, Das S, Kar Mahapatra S, Chakraborty SP, Kundu PK, Roy S. Age associated oxidative damage in lymphocytes. Oxid Med Cell Longev 2010; 3(4):275-82. doi: 10.4161/oxim.3.4.12860 [Crossref] [ Google Scholar]
62. Rehm BHA. Alginates: Biology and Applications. Vol. 13. Berlin: Springer; 2009.
63. Dobrinčić A, Balbino S, Zorić Z, Pedisić S, Bursać Kovačević D, Elez Garofulić I. Advanced technologies for the extraction of marine brown algal polysaccharides. Mar Drugs 2020; 18(3):168. doi: 10.3390/md18030168 [Crossref] [ Google Scholar]
64. Yang JS, Xie YJ, He W. Research progress on chemical modification of alginate: a review. Carbohydr Polym 2011; 84(1):33-9. doi: 10.1016/j.carbpol.2010.11.048 [Crossref] [ Google Scholar]
65. Murata M, Nakazoe J. Production and use of marine aIgae in Japan. Jpn Agric Res Q 2001; 35(4):281-90. [ Google Scholar]
66. Wijesekara I, Pangestuti R, Kim SK. Biological activities and potential health benefits of sulfated polysaccharides derived from marine algae. Carbohydr Polym 2011; 84(1):14-21. doi: 10.1016/j.carbpol.2010.10.062 [Crossref] [ Google Scholar]
67. Nishibori N, Itoh M, Kashiwagi M, Arimochi H, Morita K. In vitro cytotoxic effect of ethanol extract prepared from sporophyll of Undaria pinnatifida on human colorectal cancer cells. Phytother Res 2012; 26(2):191-6. doi: 10.1002/ptr.3527 [Crossref] [ Google Scholar]
68. Holdt SL, Kraan S. Bioactive compounds in seaweed: functional food applications and legislation. J Appl Phycol 2011; 23(3):543-97. doi: 10.1007/s10811-010-9632-5 [Crossref] [ Google Scholar]
69. Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS PharmSciTech 2003; 4(4):E61. doi: 10.1208/pt040461 [Crossref] [ Google Scholar]
70. Aneiros A, Garateix A. Bioactive peptides from marine sources: pharmacological properties and isolation procedures. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 803(1):41-53. doi: 10.1016/j.jchromb.2003.11.005 [Crossref] [ Google Scholar]
71. Mackie AR, Macierzanka A, Aarak K, Rigby NM, Parker R, Channell GA. Sodium alginate decreases the permeability of intestinal mucus. Food Hydrocoll 2016; 52:749-55. doi: 10.1016/j.foodhyd.2015.08.004 [Crossref] [ Google Scholar]
72. Wang Y, Han F, Hu B, Li J, Yu W. In vivo prebiotic properties of alginate oligosaccharides prepared through enzymatic hydrolysis of alginate. Nutr Res 2006; 26(11):597-603. doi: 10.1016/j.nutres.2006.09.015 [Crossref] [ Google Scholar]
73. Han ZL, Yang M, Fu XD, Chen M, Su Q, Zhao YH. Evaluation of prebiotic potential of three marine algae oligosaccharides from enzymatic hydrolysis. Mar Drugs 2019; 17(3):173. doi: 10.3390/md17030173 [Crossref] [ Google Scholar]
74. Graiff A, Ruth W, Kragl U, Karsten U. Chemical characterization and quantification of the brown algal storage compound laminarin-a new methodological approach. J Appl Phycol 2016; 28(1):533-43. doi: 10.1007/s10811-015-0563-z [Crossref] [ Google Scholar]
75. Gupta S, Abu-Ghannam N. Bioactive potential and possible health effects of edible brown seaweeds. Trends Food Sci Technol 2011; 22(6):315-26. doi: 10.1016/j.tifs.2011.03.011 [Crossref] [ Google Scholar]
76. Elgundi Z, Papanicolaou M, Major G, Cox TR, Melrose J, Whitelock JM. Cancer metastasis: the role of the extracellular matrix and the heparan sulfate proteoglycan perlecan. Front Oncol 2019; 9:1482. doi: 10.3389/fonc.2019.01482 [Crossref] [ Google Scholar]
77. Park HK, Kim IH, Kim J, Nam TJ. Induction of apoptosis and the regulation of ErbB signaling by laminarin in HT-29 human colon cancer cells. Int J Mol Med 2013; 32(2):291-5. doi: 10.3892/ijmm.2013.1409 [Crossref] [ Google Scholar]
78. Li B, Lu F, Wei X, Zhao R. Fucoidan: structure and bioactivity. Molecules 2008; 13(8):1671-95. doi: 10.3390/molecules13081671 [Crossref] [ Google Scholar]
79. Cumashi A, Ushakova NA, Preobrazhenskaya ME, D’Incecco A, Piccoli A, Totani L. A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Glycobiology 2007; 17(5):541-52. doi: 10.1093/glycob/cwm014 [Crossref] [ Google Scholar]
80. Alekseyenko TV, Zhanayeva SY, Venediktova AA, Zvyagintseva TN, Kuznetsova TA, Besednova NN. Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide isolated from the Okhotsk Sea Fucus evanescens brown alga. Bull Exp Biol Med 2007; 143(6):730-2. doi: 10.1007/s10517-007-0226-4 [Crossref] [ Google Scholar]
81. Kim EJ, Park SY, Lee JY, Park JH. Fucoidan present in brown algae induces apoptosis of human colon cancer cells. BMC Gastroenterol 2010; 10:96. doi: 10.1186/1471-230x-10-96 [Crossref] [ Google Scholar]
82. Ye J, Li Y, Teruya K, Katakura Y, Ichikawa A, Eto H. Enzyme-digested fucoidan extracts derived from seaweed Mozuku of Cladosiphon novae-caledoniae kylin inhibit invasion and angiogenesis of tumor cells. Cytotechnology 2005; 47(1-3):117-26. doi: 10.1007/s10616-005-3761-8 [Crossref] [ Google Scholar]
83. Boo HJ, Hyun JH, Kim SC, Kang JI, Kim MK, Kim SY. Fucoidan from Undaria pinnatifida induces apoptosis in A549 human lung carcinoma cells. Phytother Res 2011; 25(7):1082-6. doi: 10.1002/ptr.3489 [Crossref] [ Google Scholar]
84. Lowenthal RM, Fitton JH. Are seaweed-derived fucoidans possible future anti-cancer agents?. J Appl Phycol 2015; 27(5):2075-7. doi: 10.1007/s10811-014-0444-x [Crossref] [ Google Scholar]
85. Atashrazm F, Lowenthal RM, Woods GM, Holloway AF, Dickinson JL. Fucoidan and cancer: a multifunctional molecule with anti-tumor potential. Mar Drugs 2015; 13(4):2327-46. doi: 10.3390/md13042327 [Crossref] [ Google Scholar]
86. Liu F, Wang J, Chang AK, Liu B, Yang L, Li Q. Fucoidan extract derived from Undaria pinnatifida inhibits angiogenesis by human umbilical vein endothelial cells. Phytomedicine 2012; 19(8-9):797-803. doi: 10.1016/j.phymed.2012.03.015 [Crossref] [ Google Scholar]
87. Mannino AM, Micheli C. Ecological function of phenolic compounds from Mediterranean fucoid algae and seagrasses: An overview on the genus Cystoseira sensu lato and Posidonia oceanica (L) Delile. J Mar Sci Eng 2020; 8(1):19. doi: 10.3390/jmse8010019 [Crossref] [ Google Scholar]
88. Lee H, Kang C, Jung ES, Kim JS, Kim E. Antimetastatic activity of polyphenol-rich extract of Ecklonia cava through the inhibition of the Akt pathway in A549 human lung cancer cells. Food Chem 2011; 127(3):1229-36. doi: 10.1016/j.foodchem.2011.02.005 [Crossref] [ Google Scholar]
89. Kang HS, Chung HY, Kim JY, Son BW, Jung HA, Choi JS. Inhibitory phlorotannins from the edible brown alga Ecklonia stolonifera on total reactive oxygen species (ROS) generation. Arch Pharm Res 2004; 27(2):194-8. doi: 10.1007/bf02980106 [Crossref] [ Google Scholar]
90. Mikami K, Hosokawa M. Biosynthetic pathway and health benefits of fucoxanthin, an algae-specific xanthophyll in brown seaweeds. Int J Mol Sci 2013; 14(7):13763-81. doi: 10.3390/ijms140713763 [Crossref] [ Google Scholar]
91. Balboa EM, Conde E, Moure A, Falqué E, Domínguez H. In vitro antioxidant properties of crude extracts and compounds from brown algae. Food Chem 2013; 138(2-3):1764-85. doi: 10.1016/j.foodchem.2012.11.026 [Crossref] [ Google Scholar]
92. Krinsky NI, Johnson EJ. Carotenoid actions and their relation to health and disease. Mol Aspects Med 2005; 26(6):459-516. doi: 10.1016/j.mam.2005.10.001 [Crossref] [ Google Scholar]
93. Zorofchian Moghadamtousi S, Karimian H, Khanabdali R, Razavi M, Firoozinia M, Zandi K. Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae. ScientificWorldJournal 2014; 2014:768323. doi: 10.1155/2014/768323 [Crossref] [ Google Scholar]
94. Takaichi S. Carotenoids in algae: distributions, biosyntheses and functions. Mar Drugs 2011; 9(6):1101-18. doi: 10.3390/md9061101 [Crossref] [ Google Scholar]
95. Terao J, Minami Y, Bando N. Singlet molecular oxygen-quenching activity of carotenoids: relevance to protection of the skin from photoaging. J Clin Biochem Nutr 2011; 48(1):57-62. doi: 10.3164/jcbn.11-008FR [Crossref] [ Google Scholar]
96. Stahl W, Sies H. Bioactivity and protective effects of natural carotenoids. Biochim Biophys Acta 2005; 1740(2):101-7. doi: 10.1016/j.bbadis.2004.12.006 [Crossref] [ Google Scholar]
97. Zhang H, Tang Y, Zhang Y, Zhang S, Qu J, Wang X. Fucoxanthin: a promising medicinal and nutritional ingredient. Evid Based Complement Alternat Med 2015; 2015:723515. doi: 10.1155/2015/723515 [Crossref] [ Google Scholar]
98. Peng J, Yuan JP, Wu CF, Wang JH. Fucoxanthin, a marine carotenoid present in brown seaweeds and diatoms: metabolism and bioactivities relevant to human health. Mar Drugs 2011; 9(10):1806-28. doi: 10.3390/md9101806 [Crossref] [ Google Scholar]
99. Kumar SR, Hosokawa M, Miyashita K. Fucoxanthin: a marine carotenoid exerting anti-cancer effects by affecting multiple mechanisms. Mar Drugs 2013; 11(12):5130-47. doi: 10.3390/md11125130 [Crossref] [ Google Scholar]
100. Gammone MA, D’Orazio N. Anti-obesity activity of the marine carotenoid fucoxanthin. Mar Drugs 2015; 13(4):2196-214. doi: 10.3390/md13042196 [Crossref] [ Google Scholar]