Antioxidant, anti-inflammatory and anticancer potential of natural bioactive compounds from seaweeds

Chapter 5

Antioxidant, anti-inflammatory and anticancer potential of natural bioactive compounds from seaweeds Ravi Sakthivel and Kasi Pandima Devi* Department of Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India * Corresponding author: e-mail: [email protected]

Chapter Outline Introduction A short history of cancer Cancer: Old disease, new or something in between? Natural products for the treatment of cancer

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Marine natural products as a source of anticancer agents Conclusion Acknowledgments References

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Introduction In this 21st century, cancer which is endangering the health and life of humans is becoming the leading cause of death worldwide. It is caused by one of the following three ways such as unhealthy lifestyle (incorrect diet), environmental contamination and genetic predisposition [1]. Cancer is mainly characterized by a sequence of changes occurring at the cellular and genetic level, which reprograms a cell to undergo uncontrolled division resulting in the formation of malignant mass [2]. In the past few years, due to the advancement in cellular and molecular biology, several efforts have been made to fight against cancer [1]. According to the IARC (International Agency for Research on Cancer) and ACS (American Cancer Society) [3,4], the term “cancer” refers to a group of diseases and it is also understood as a major genetic disease. The two main characteristic features of cancer cells are uncontrolled proliferation and spread of abnormal cells from the primary location to the distant parts of the body (Metastasis). The uncontrolled spread of abnormal cells ultimately results in death of the patients [5,6]. Studies in Natural Products Chemistry, Vol. 63. https://doi.org/10.1016/B978-0-12-817901-7.00005-8 Copyright © 2019 Elsevier B.V. All rights reserved.

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A short history of cancer Gaining a better knowledge on history of cancer and its epidemiology in the past plays a significant role to further investigate and understand the underlying mechanisms leading to cancer [7]. The popular Greek physician Hippocrates (460–370 BC), who is considered as the “Father of Medicine” said, “Ars longa, vita brevis” or “The art of medicine is long and life is short.” This famous quote is mainly applicable to the people struggling from dreadful disease like cancer. The details of cancer appeared as early as 1600 BC in the ancient Egyptian medical text Edwin Smith papyrus, which quotes that there is no treatment for this disease. At first, Hippocrates used the term karkinos (Greek: Crab) and karkinoma for nonhealing ulcerous formation and swelling, after which the Roman physician, Celsus (28–50 BC) translated the Greek term into cancer. In ancient days, physicians used plasters for local treatment of tumors and also tried cauterization. During 2nd century, Galen (130–200 AD) made a detailed categorization about abnormal growth. He used the name “Onco” to describe tumors. He believed that cancer may arise in any part of the body, which is mainly caused by the accumulation of “residues of black bile” produced in the liver. Moreover, the Hippocratic physicians mentioned that, cancer is incurable and the patients live long if any interference does not occur, otherwise it causes death of the patient [8,9]. Recently Binder et al. [7] reported the archaeological record of young-adult individual from the archaeological site of Amara West in northern Sudan (Buried around 1200 BC), displaying multiple, mainly osteolytic, lesions on the vertebrae, ribs and all other bones present in the body. The radiographic, microscopic and SEM imaging of lesions positively suggested the diagnosis of secondary malignant neoplasm which was mainly produced by carcinoma of the prostate gland. In addition, the investigation on Ptolemaic Egyptian mummy strongly suggested that prostate cancer was present since antiquity [10]. Several physicians and researchers proposed various theories on the causes of cancer. In 17th–18th centuries, Zacutus Lusitani (1575–1642) and Nicholas Tulp (1593–1674) proposed “Infectious disease theory.” They proposed that cancer is a contagious disease and the cancer patients should be isolated to prevent the spread of cancer [11]. According to the report of American Cancer Society (ACS), in 1761, Giovanni Morgagni did an autopsy and related patient’s illness to pathologic findings after death, which served as the basis for scientific oncology to study of cancer. These reports positively suggest that cancer is not a modern phenomenon; it has a long history and is a disease of considerable antiquity [7]. In 1911 Peyton Rous, at the Rockefeller Institute described a type of sarcoma in chickens caused by Rous sarcoma virus for which he was awarded Nobel Prize in 1968. The use of chemotherapy started in early 20th century for the treatment of cancer when surgery and radiotherapy dominated the field of cancer therapy [11]. The research on cancer rapidly evolved due to various

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technical advances, and the oncology is one of the rapidly evolving fields in modern medicine. In 2014 World Health Organization and IARC identified and reported more than 100 physical, chemical and biological carcinogens. Recent research on cancer led to the discovery of new carcinogens and its mechanism of action, which provided new insight for the prevention of cancer. Serota [12] and Yuppa [13] mentioned the statements of Dr. Mukherjee in their book review that, “really cancer is genetic entropy; people will continue to surrender to this disease in its many forms.” It is also pointed out that “We must focus on prolonging life rather than eliminating death.” In addition, new discoveries occur daily and the search for cure will continue in laboratory all around the world as the race is long and the history of cancer is evolving. The interesting fact is that “the immortality of a cell line can lead to the mortality of the organism, but so goes the malady of cancer.” Compared to our normal cells, cancer cells grow faster, adapt better and they are more perfect version of us.

Cancer: Old disease, new or something in between? The previous section clearly depicts that cancer is an old disease, but archaeological evidence collected worldwide are much limited. Until now only around 200 skeletons and mummified individuals from all around the world have been reported with diverse primary and secondary malignancies [7]. The research on paleopathology mainly contributes to elucidate the pathogenesis of cancer. The chronological assessment of occurrence of cancer in ancient fossil clearly demonstrated that cancer is rare in antiquity and the reason for this might be diet, age at death and environmental factors. But the main reason for this rarity is undisputed due to the lack of evidences and limitations of the diagnostic methods used by the early investigators. Moreover, the evidence of scrotal cancer, nasal cancer and Hodgkin’s disease was reported in 1775, 1761 and 1832, respectively. It indicates that the reports on several tumors in scientific literature occurred only over the past 200 years. The available paleopathological and literary evidence strongly suggested the rarity of cancer in antiquity [14].

Natural products for the treatment of cancer Currently, several research activities have been engendered to identify potent chemopreventive agents with strong cellular cytotoxicity. This indicates that formulation of strong anticancer drugs with minimal side effects needs to be developed [15]. Significant numbers of chemical diversities are present in millions of plants, animals, microorganisms and marine organisms, which can be used for the treatment of 87% of the human diseases [16]. Several medicinal herbs from plant origin have also received great attention due to their wide range of pharmacological effects [16]. Recently WHO reported that

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more than 21,000 plant species have been used for herbal medicine worldwide [17]. For cancer treatment, natural products offer a new hope because many bioactive compounds isolated from plants, vegetables and fruits have been reported to have a significant role in cancer therapy and prevention. These compounds mainly induce apoptosis in neoplastic cells without causing any side effects to normal cells [18]. Several plant-derived anticancer agents such as vincristine, vinblastine, taxol, topotecan, irinotecan, etoposide and camptothecin derivatives are in clinical use worldwide. Vinca alkaloids from the plant Catharanthus roseus are the second most used class of anticancer drugs which were primarily used in combination with cancer chemotherapeutic drugs for the treatment of various types of cancers, including Kaposi’s sarcoma, advanced testicular cancer, lymphoma, leukemia, lung and breast cancers [19,20]. Currently, there are four major vinca alkaloids in clinical use such as vinorelbine, vincristine, vinblastine and vindesine [21]. Vinca alkaloids are classified as cell cycle-specific cytotoxic drugs. These antimitotic and anti-microtubule alkaloids develop synergy with tubulin and disrupt the microtubule function which leads to cell death. Currently, vinflunine a new synthetic vinca alkaloid has been approved in Europe for the treatment of cancer [19]. In addition, vinca alkaloids have the potential to inhibit malignant angiogenesis in vitro. It has been reported that low doses of vinblastine in combination with antibodies increase the antitumor response against drugresistant tumors. Vinblastine is used to treat Non-Hodgkin Lymphoma, Hodgkin Lymphoma and testicular carcinoma. Similarly, vincristine is used to treat neuroblastoma, rhabdomyosarcoma, Hodgkin’s disease, acute leukemia, Wilm’s tumor and also used to treat various non-malignant hematologic disorders [19]. The first-generation taxanes such as Docetaxel and Paclitaxel are the strong anticancer agents which possess different molecular targets and mainly act by inducing apoptotic cell death, microtubules stabilization and mitotic arrest. The anticancer agent Paclitaxel (Taxol) was first extracted from the leaf and bark of Taxus canadensis and Taxus baccata. It specifically binds with β-tubulin in the lumen of microtubules which play a major role in cell division leading to decrease in microtubule dynamics and cell cycle arrest at M phase. In addition to that, taxol blocks cancer initiation and progression process by increasing the level of CD80, 86, cytokines, Bax and MHCII molecules. It is widely used to treat a wide range of cancers including breast, lung and ovarian cancer. There are several analogs of Paclitaxel such as milataxel, ortataxel, larotaxel and tesetaxel which are currently undergoing clinical trials [22]. Podophyllotoxin is a most abundant polycyclic lignan primarily isolated from the rhizome of Podophyllum peltatum. It is mainly used as an antiviral agent. It has been reported that podophyllotoxin has the potential to inhibit replication of herpes simplex type I and measles virus. In addition, it is reported to possess potent antitumor activity. Podophyllotoxin is an antimitotic agent which mainly interacts with tubulin to inhibit polymerization of

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microtubules and arresting the cell cycle in the metaphase. This natural anticancer agent is mainly used for the treatment of different types of genital tumors, Wilms tumors, lung cancer, non-Hodgkin and other lymphomas [23]. Apart from this, several other bioactive agents such as Colchicine isolated from Colchicum autumnale (Colchicaceae); Cephalotaxus alkaloids such as Harringtonine and isoharringtonine isolated from Cephalotaxus harringtonia; Berberine isolated from the rhizome and root of Tinospora cordifolia; an antiangiogenic agent Combretastatins isolated from Combretum caffrum; Capsaicin isolated from red pepper were reported to possesses potent anticancer activity with different molecular targets against various types of cancer [22]. Several plant-derived flavonoids were successfully used for cancer treatment. It has been reported that around 8000 distinct flavonoids have been identified in plants, fruits and vegetables, which have the potential to reduce the risk of cancer [22,24,25]. In addition, Cyanidin glycosides isolated from apples, Gingerol isolated from the fresh rhizome of Zingiber officinale, Lycopene isolated from tomatoes, red carrots and watermelons, Resveratrol identified in grapes, peanuts and mulberries play a significant role in targeting various cancer signaling pathways and proven as potent anticancer agents against various cancer types [22]. The chemical structures of some of the successful anticancer agents are shown in Fig. 5.1. These reports positively suggest that development of alternative therapeutic agent from the natural products is an effective approach for the treatment of cancer.

Marine natural products as a source of anticancer agents The marine environment is one of the richest sources of several bioactive compounds [25]. About 70% of the earth’s surface is covered by world’s ocean, which has an enormous resource for the discovery of potent chemotherapeutic agents. It has been reported that biological diversity of marine ecosystem (deep sea floor and coral reef ) is higher than tropical rain forests [26]. The vast number of species coexisting in these limited extent habitats makes them highly complex and competitive. As a result of this heavy competition, a huge percentage of species have evolved chemical means to protect them against the detrimental threats present in the environment. These chemical means of adaptations generally take the form known as secondary metabolites, which include various chemical classes like alkaloids, terpenoids, steroids, polyketides, sugars and peptides [27]. The study on marine natural products is still in its infancy when compared to the study of terrestrial natural products [28]. The use of marine organisms in the traditional medicine does not have a long history, but in ancient days seaweeds have been used to fertilize the soil [29]. About 1003 new bioactive agents from various marine organisms have been listed in the publications of the year 2010 [29]. The marine natural products which have been playing a vital role in the area of

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FIG. 5.1 Chemical structure of some of the successful anticancer agents from plants. (A) Vincristine (PubChem CID: 5978), (B) Vinblastine (PubChem CID: 13342), (C) Paclitaxel (PubChem CID: 36314), and (D) Podophyllotoxin (PubChem CID: 10607).

drug discovery since 1950s, first began with the isolation of the bioactive nucleosides such as spongouridine and spongothymidine from the sponge Tectitethya crypta Laubenfels. This further inspired the synthesis of antiviral and anticancer drugs such as Vidarabine and Cytarabine for the treatment of herpes virus infection and acute myeloid leukemia, respectively. Various benthic species including Cnidarians, Bryozoans, Tunicates, Porifera and marine algae synthesize several bioactive molecules which can be used for the treatment of various human diseases. It has been reported that a tetrahydroisoquinoline alkaloid, Trabectedin (Yondelis), isolated from the ascidia Ecteinascidia turbinata Herdman was approved by Europe for the treatment of advanced soft tissue sarcoma [30]. Several marine natural products are in various phases of clinical development, mainly in the area of cancer research. For example, Bryostatin-1 a unique PKC activator, isolated from the marine bryozoans Bugula neritina is currently in clinical trials for the treatment of cancer. Similarly, the first marine-derived compound Didemnin B (a cyclic depsipeptide) isolated from tunicate Trididemnum solidum, has entered phases I and II clinical trials but dropped from further study due to its cardiotoxicity. Ecteinascidins, the second family of tunicate derived antitumor agent isolated

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from the mangrove tunicate Ecteinascidia turbinata were reported to have potent antitumor activity and also in phase II clinical trials [31]. The bioactive halogenated compound laurenditerpenol isolated from the red alga Laurencia intricata J.V. Lamouroux inhibited the hypoxia-inducible transcription factor which plays a vital role in anticancer drug development. Another marine natural product, (5S)-5-acetoxycaespitol isolated from the Brazilian red algae Laurencia catarinensis demonstrated cytotoxic activity against various tumor cells lines. It is assumed that the green alga Bryopsis sp. is the main source of the most remarkable bioactive metabolite Kahalalide F. This metabolite was initially obtained from the herbivorous sea slug Elysia rufescens. It is a potent antitumor drug candidate which causes cell membrane permeabilization and oncosis in cancer cells by lysosomal induction and is in phase II clinical trials. Other metabolites, diterpene halimedatrial isolated from Udotea flabellum and Halimeda sp., bromophenolic compound isorawsonol isolated from Avrainvillea rawsonii (Dickie), a new sterol compound, 24-R-stigmasta4,25-diene-3β,6β-diol isolated from Codium divaricatum Holmes were reported to possess anticancer potential. Apart from this, the metabolites isolated from the endophytes of marine green algae are also reported to have potent cytotoxicity, antibacterial and anti-protozoa activities [30]. The anticancer compounds isolated from various marine organisms and their mechanisms of action are shown in Table 5.1. These active compounds have been reported to have potent cytotoxic activity against various tumors [25]. Generally, the marine-derived anticancer agents exhibit their activity through several mechanisms of action on a wide range of biological targets. Mitosis, apoptosis, cell cycle, DNA synthesis, signal transduction, angiogenesis, multidrug efflux and mitochondrial respiration are the most common anticancer drug targets [28]. More than thousands of novel bioactive metabolites with wide biological activities have been reported in the past 20 years. Approximately 150 compounds were found to be cytotoxic against various tumor cells [34]. Though 35 compounds were known for its mechanism of action of antitumor activity, the remaining 124 compounds were yet to be studied for their detailed mechanism of action [26,35]. These reports positively reveal that marine environment is one of the excellent reservoirs for bioactive natural products [36]. Chemical structures of bioactive compounds isolated from the marine natural products are shown in Fig. 5.2.

Seaweeds Seaweeds or marine macroalgae are the primitive types of plants lacking leaves, true stems and roots. According to the information on marine algae in the seaweed site, currently there are about 6500 red seaweeds (Rhodophyta) 1500 species of green seaweed (Chlorophyta), and 1800 brown species (Phaeophyta) found in nature (Fig. 5.3) [37]. The brown and red seaweeds contribute to 0.2% and 27.0%, respectively, and others contribute 72.8% [38].

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TABLE 5.1 List of few important anticancer bioactive compounds isolated from marine natural products. Bioactive compound

Source

Mechanism of action

References

Cytarabine

Sponge

DNA synthesis inhibition

[25,32]

Bryostatin

Bryozoa

PKC activation

[25]

Dolastatin 10

Sea hare

Pro-apoptotic effects and inhibition of microtubules

[25,32]

Ecteinascidin 743

Tunicate

Alkylation of DNA

[25,32]

Aplidine

Tunicate

Inhibits cell cycle progression

[25,32]

Halichondrin B

Sponge

Interaction with tubulin

[25,32]

Discodermolide

Sponge

Stabilization with tubulin

[25,32]

Spirulan

Alga

Inhibition of heparanase

[33]

Tolyporphin

Alga

Inhibition of acyl CoA: cholesterol-O-acyl transferase

[33]

Stypodiol

Alga

Promotion of tubulin polymerization

[33]

Approximately more than 150,000 seaweeds were found to be present in the intertidal zones and tropical waters of the oceans. It can be consumed directly or used as ingredients in many dishes. Seaweed products are mainly utilized in the food industry, as components of fertilizers, in animal feed supplements and also as additives for human food. Seaweeds are one of the principle sources of chemical compounds like alginates, agar–agar and carrageenan which are also known as phytochemicals mainly used for animal feed, manure and human consumption in many countries. In addition, seaweed extracts are one of the main components of bio-stimulate products which are rich sources of minerals, vitamins and polysaccharides. Apart from this, the extract contains high levels of plant growth hormones like cytokines, auxin and gibberellins. It has been reported that the extract from the brown seaweed Ascophyllum nodosum is considered as one of the best seaweeds extract which is mainly harvested from the minerals-rich water. It is also estimated that about 50% of the global photosynthesis is contributed by marine algae. Around 35 countries cultivate seaweeds, of which people of Republic of China are the principal producers, followed by Japan and the Republic of Korea [38–41].

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FIG. 5.2 Chemical structure of some of the successful anticancer agents from marine natural products. (A) Aplidine (PubChem CID: 9812534), (B) Cytarabine (PubChem CID: 6253), (C) Bryostatin (PubChem CID: 5280757), (D) Trabectedin (PubChem CID: 108150), (D) Laurenditerpenol (PubChem CID: 11174259), (F) Halichondrin B (PubChem CID: 129628181), and (G) Kahalalide F (PubChem CID: 56928091).

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FIG. 5.3 Different types of marine algae based on pigmentation.

In India, approximately 841 species of seaweeds were found in both intertidal and deepwater regions. In Asian and Pacific cultures, the green, red and brown algae are widely being used in the diets [42]. It has been reported that around 15,000 novel compounds have been isolated from the seaweeds and several antitumor compounds are also being investigated through clinical trials [43]. Several bioactive compounds such as fatty acids, sterols, carotenoids, polysaccharide, dietary fibers, agar, carrageenan, alginate and phycocolloids are found to be present in seaweeds. Sterols are the most important and major nutritional component present in seaweeds. It plays a vital role in cellular function and is also involved in developmental signaling as a secondary messenger. It has been reported that the brown seaweeds Undaria and Laminaria contain 83–97% of fucosterol [38]. Similarly, the red seaweeds Palmaria and Porphyra contain 87–93% of desmosterol in total sterol content. Agar is the sulfated polysaccharide mainly extracted from the red seaweeds such as Gracilaria sp. and Gelidium sp. This seaweeds galactans contains β-9(1–3)-Dgalactose residues and α-(1–4)-3,6-anhydro-L-galactose. It has been reported that the agar-oligosaccharide has the potential to suppress the production of pro-inflammatory cytokine and also suppresses the enzyme involved in the

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production of nitric oxide. In addition, the cold water extraction of agar type polysaccharide from Gracilaria sp. was reported to possess potent antitumor activity and targets cancer cells by inducing apoptosis. Similarly, carrageenan present in seaweed was reported to possess potent antiviral, antitumor, immunomodulatory and anticoagulant activity [38]. Seaweeds have provided a great biological diversity for sampling in the phase of drug discovery and development. Seaweeds contain several polyphenols (catechin, epicatechin, epigallocatechin gallate and gallic acid), polysaccharides, sterols, terpenoids and fatty acids with potent antibacterial, antiviral, antioxidant, antitumor and immunostimulatory activity [44,45]. Seaweeds contain a huge amount of polysaccharides mainly in cell wall structure and also as storage polysaccharides and mucopolysaccharides. The seaweeds Ulva, Ascophyllum, Porphyra and Palmaria contain a high amount of polysaccharide. Ulva contains 65% of polysaccharide in total dry weight. The green seaweeds contain sulfuric acid polysaccharide and sulfated galactans whereas red seaweeds contain floridean starch, carrageenans, mucopolysaccharide and water-soluble sulfated galactans. The brown seaweeds contain fucoidan or sulfated fucose, laminarian or β-1,3-glucan and alginic acid. It has been reported that the seaweed polysaccharide shows antiherpetic bioactivity, antiviral activity, anticoagulant, antitumor, prevent from large intestine cancer, diabetes, obesity and also decrease low-density lipid-cholesterol (LDL) in rats [38]. The sulfated polysaccharides isolated from the brown alga Sargassum was found to possess potent free radical scavenging activity and anticancer activity [44]. It has been reported that the extract of brown seaweed Hydroclathrus clathratus and its purified polysaccharide fractions possess higher growth inhibitory activity against HL-60 and MCF-7 cell lines with low toxicity to the normal cells. In addition, the fraction of Hydroclathrus clathratus was reported to have in vivo antitumor activity against the Sarcoma 180 tumor in BALB/c mice [46]. Moreover, several seaweeds like Gracilaria corticata, Palmaria palmata, Laminaria setchellii, Macrocystis integrifolia, Nereocystis luetkeana, Sargassum pallidum have been reported for their in vitro antitumor and antiproliferative activity. The red algae Pyropia tenera and Gelidium amansii inhibit the growth of gastric cancer (AGS) and colon cancer cells (HT-29) in a dose-dependent manner. In addition, the red alga was found to possess more reducing power than brown kelps [47]. Several studies have reported the anticarcinogenic, anti-inflammatory and antiproliferative activity of various red algae, which positively reveal that the red algae contain potent anticancer bioactive compounds [48]. Fig. 5.4 shows the possible mechanisms of action of bioactive agents isolated from seaweeds.

Anticancer potential of seaweeds—combined beneficial effect Increasing number of evidence has revealed the strong relationship between oxidative stress, inflammation and cancer. Hence the new strategy for treatment of cancer is to design the anticancer drugs which could exhibit

FIG. 5.4 A possible mechanism of action of anticancer potential of seaweeds. The seaweed bioactive agents exert anticancer activity by inducing apoptosis, cell cycle arrest, decreasing ROS generation by modulating antioxidant enzymes level, inactivating Akt signaling pathway, suppress the expression of proinflammatory mediators and nuclear translocation of NF-kB.

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antioxidant and anti-inflammatory activity, as the combined beneficial effect. This review describes the antioxidant, anti-inflammatory and the anticancer properties of seaweeds. Antioxidant potential of seaweeds Reactive oxygen species (ROS), composed of free radicals such as hydroxyl (HO
) radicals, superoxide anion (O2  ) and non-free radical species such as singlet oxygen (1O2) and H2O2 are the different forms of activated oxygen [49]. Several evidences suggest that ROS and RNS play a major role in chronic inflammation and cancer [50]. ROS can easily react with most of the biological molecules including lipids, lipoproteins, proteins and DNA. It exhibits both positive and negative effect toward biological systems. Generally ROS play a vital role in various biological functions. They regulate many signal transduction pathways; modulate their functions by directly reacting with and modifying the structure of proteins, transcription factors and genes. Moreover, it is involved in signaling cell growth and differentiation, regulating the activity of enzymes (such as ribonucleotide reductase), mediating inflammation by stimulating cytokine production and eliminating pathogens and foreign particles [51]. On the other hand, these ROS cause irreversible oxidative damage in the biomolecules, which results in a variety of pathophysiological disorders [49]. Formation of ROS in human cells occurs through endogenous metabolism, results in extensive oxidative damage, which in turn leads to geriatric degenerative disorders, carcinogenesis and other human diseases [52,53]. An increased ROS disrupts the redox homeostasis causing elevation of ROS production or decline of ROS scavenging capacity, which is termed as oxidative stress. The elevated ROS can promote cellular proliferation and differentiation resulting in cancer cell growth [54]. In addition, occupational exposure to the metals apparently induces ROS productions which are mainly associated with carcinogenesis [53]. Moreover, ROS can modulate the expression of many transcription factors and signaling proteins, which are mainly involved in stress response and cell survival mechanisms [55]. The occurrence of gene mutation causes genetic instability, which facilitates the further metabolic malfunction leading to tumor progression [51]. In order to prevent this, cells develop various protective mechanisms to prevent ROS formation or detoxify the ROS with the help of antioxidants. Antioxidants neutralize the excess oxidant production and converts oxidants into less damaging or harmless species [56]. Hence it is necessary to isolate compounds that possess antioxidant activity. The bioactive compounds have the potential of free radical scavenging or inducing antioxidant enzymes and also have the potential to inhibit mutation. Terrestrial plants, fruits and vegetables are the main sources of antioxidants, apart from this various compounds with antioxidant potential have also been isolated from seaweeds [57]. Recently, the bioactive agents such as fucoxanthin and phloroglucinol from the brown

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seaweeds were found to possess antioxidant and anticancer activity in in vitro and in vivo models without causing an adverse effect to the normal cells [58]. Similarly, a cell wall sulfated polysaccharide (Fucoidans) extracted from the marine brown algae such as Dictyota ciliolata, Padina sanctae-crucis, and Sargassum fluitans were reported to have highest ROS scavenging activity and also possess protective effect against various oxidant-induced oxidative stress in HepG2 cells through regulation of glutathione and catalase activity [57]. In addition, several studies evidenced that, fucoidan induces cytotoxicity against various cancer cells by inhibiting cell invasion, angiogenesis, metastasis, cell cycle arrest and regulating growth signaling molecules involved in various cellular regulatory mechanisms and inducing apoptosis [59]. The ethanol extracts of the red algae Callophyllis japonica and Gracilaria tenuistipitata were reported to possess antioxidant activity. Also, the aqueous extract of G. tenuistipitata increased the recovery of H1299 cells from H2O2-induced DNA damage, induced G2/M arrest and counteracted cellular proliferation [53,60]. The seaweed-derived bioactive agents modulate cellular antioxidant status and ROS generation which play a vital role in the carcinogenesis process [53]. Table 5.2 demonstrates the antioxidant potential of various seaweed species, which are reported recently. Anti-inflammatory potential of seaweeds Inflammation is one of the most complex processes, initiated by several factors such as environmental pollution, chemical injury and bacterial infection, which leads to injury or death of cells [89]. Moreover, formation of free radicals leads to oxidative stress-mediated damage of the complex cellular molecules that can cause inflammatory diseases. It has been estimated that approximately 20% of all human cancers are caused due to chronic inflammation [50]. Apart from the other factors, inflammation also has molecular links to carcinogenesis [53]. Previously it has been observed that expression of proinflammatory mediators induce cell progression and aggressiveness in various malignancies. The tumor cells were found to express phenotype similar to the inflammatory cells. Increased level of various cytokines like IL-6, IL-8, G-CSF, IFN-γ and MIP-1β were observed in breast carcinoma [90]. IL-8 acts as an essential regulator of chemotaxis, neutrophil activation and also an activator of NF-κB [90]. Inflammatory cells activate pro-carcinogens into DNA damaging species and may increase the DNA damage. For example neutrophils activate aflatoxins, aromatic amines, phenols, oestrogens, and polycyclic aromatic hydrocarbons [91]. Activation of pro-carcinogens results in initiation, promotion and progression of tumors [56]. Marine natural products, especially several seaweeds were reported to possess anti-inflammatory activity. Apart from the brown and green algae, various species of red algae were found to possess anti-inflammatory activity. The seaweed-derived antiinflammatory agents inhibit the production of cellular reactive oxygen species

TABLE 5.2 List of some of the recently reported seaweeds with antioxidant potential. Name of the seaweed

Family

Active component/extract

Biological activity

References

Column chromatography purified ethyl acetate sub-fraction

Highest DPPH and lipid peroxidation scavenging activity (97.7%)

[61]

Sargassaceae

Aqueous extract

Preserving normal antioxidant enzyme activity by inhibiting lipid peroxidation in gastric mucosa

[62]

Fucaceae

Methanolic extract

l

Protective effect against H2O2 mediated DNA damage Highest FRAP activity Preventing β-carotene bleaching Scavenging DPPH radicals and highest FRAP activity Most effective to prevent H2O2-mediated SOD depletion in Caco-2 cells

[63]

ABTS [2,20 -azinobis (3ethylbenzothizoline-6-sulfonic acid)] radical scavenging activity Hydroxyl and Peroxyl radical scavenging activity Inhibition of hemoglobin-induced linoleic acid oxidation

[64]

Himanthalia elongata Himanthaliaceae Sargassum pallidum

Fucus serratus

Fucus vesiculosus

l l

Fucaceae

l

Pelvetia canaliculata Fucaceae

Methanolic extract

Padina tetrastromatica Dictyotaceae

l

l

Butanol and ethyl acetate extract l

Turbinaria conoides

l

Sargassaceae

Butanol and ethyl acetate extract

Continued

TABLE 5.2 List of some of the recently reported seaweeds with antioxidant potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

Gracilariaceae

Hexane extract

l

Sargassaceae

Ethyl acetate fraction

l

References

Gracilaria corticata Singlet oxygen quenching activity

[64]

ABTS [2,20 -azinobis (3ethylbenzothizoline-6-sulfonic acid)] radical scavenging activity Fe2+ chelating, H2O2 scavenging and lipid peroxidation inhibitory activity

[65]

Turbinaria ornata

l

Sargassum muticum Sargassaceae Dictyopteris australis Dictyotaceae Spatoglossum aspermum Dictyotaceae Spatoglossum variabile Dictyotaceae Sargassum marginatum Sargassaceae

Methanolic extract

More FRAP reducing activity

Methanolic extract

l l

Metal ion chelating properties Reducing power activity

[66] [67]

Dictyopteris delicatula Dictyotaceae

Fucans

High ferric chelating activity and reducing power activity

[68]

Ulvaceae

Methanolic extract

l

Methanolic extract

Scavenging activity against nitric oxide, hydrogen peroxide, hydroxyl radicals, free radical scavenging (DPPH), FRAP and reducing power

[70]

Ethanol extracts

Suppresses H2O2-induced cellular apoptosis and activates cellular antioxidant enzymes

[71]

Aqueous extract

Enhance the recovery of H1299 cells from H2O2induced DNA damage

[71]

Polysaccharides (Fucans)

l

Ulva clathrata

Enteromorpha antenna Ulvaceae

High DPPH radical scavenging activity

[69]

Enteromorpha linza Ulvaceae Gracilaria corticata Gracilariaceae Callophyllis japonica Kallymeniaceae Gracilaria tenuistipitata Gracilariaceae Canistrocarpus cervicornis Dictyotaceae

l

Low hydroxyl radical scavenging activity Good superoxide radical scavenging and ferrous chelating ability

[72]

Continued

TABLE 5.2 List of some of the recently reported seaweeds with antioxidant potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

Heterofucans

l

References

Sargassum filipendula Sargassaceae

Highest antioxidant activity with ascorbic acid equivalents

[73]

More reducing power activity Sargassum graminifolium Sargassaceae

Polysaccharides

l l l

Superoxide anion scavenging activity DPPH radical scavenging ability Reducing power activity

[74]

Turbinaria ornata Sargassaceae Gayralia oxysperma

Methanol extract

Highest antioxidant activity and ferric reducing power

[75]

Methanol extract

Significant antioxidant activity and ferric reducing activity

[75]

Purified phlorotannin extracts

Strongest lipid peroxidation inhibitory activity and superoxide radical scavenging activity

[76]

More superoxide radical scavenging activity

[76]

Gayraliaceae Chaetomorpha antennina Cladophoraceae Fucus spiralis Fucaceae Cystoseira nodicaulis Sargassaceae

Gracilaria gracilis Gracilariaceae

Ethyl acetate extract

l l

Highest antioxidant and ferric-reducing activity DPPH radical scavenging activity

[77]

Prevents reactive oxygen radicals formation Total antioxidant capacity and ferrous chelating activity

[78]

Protective effect against H2O2 induced oxidative stress Strong radical scavenging activity

[79,80]

Greater reducing power activity DPPH radical scavenging activity

[81]

Caulerpa cupressoides Caulerpaceae

Sulfated polysaccharides

l l

Ulva rigida Ulvaceae

Crude extract and ethanol precipitate

l

l

Halimeda monile Aqueous extract and free phenolic acid fraction

l

Ulvaceae

Sulfates polysaccharides extract

Ameliorate hepatic antioxidant enzymes (catalase, glutathione peroxidase and superoxide dismutase) and non-enzymatic (reduced glutathione and total thiol) antioxidant defenses

[82]

Ulvaceae

Derivatives of sulfated polysaccharide

l

Strong hydroxyl radical and superoxide radical scavenging activity Strong DPPH radical scavenging activity

[83]

Halimedaceae

l

Ulva lactuca

Enteromorpha linza

l

Continued

TABLE 5.2 List of some of the recently reported seaweeds with antioxidant potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

Ulvaceae

Sulfated polysaccharides

l

References

Ulva fasciata l

l l

Superoxide radical scavenging activity Dose-dependent hydroxyl radical scavenging activity ABTS radical scavenging activity Strong reducing power activity

[84]

Porphyra yezoensis Bangiaceae

Dc-Porphyran

l

Greater superoxide anion and hydroxyl radical scavenging activity

[85]

Methanol, acetone/water extract

l

Highest inhibition of TEAC (Trolox equivalent antioxidant capacity) and DPPH Highest values of reducing power

[86]

Porphyra columbina Bangiaceae

l

Gracilaria biridiae Gracilariaceae

Sulfated polysaccharide

l

Moderate hydroxyl and DPPH radical scavenging activity

[87]

Endocladiaceae

Supercritical carbon dioxide fluid extract

l

DPPH radical scavenging activity Inhibition of lipid peroxidation Hydroxyl radical scavenging activity

[88]

Gloiopeltis tenax l l

Antioxidant, anti-inflammatory and anticancer potential Chapter

5 133

(ROS), H2O2-induced lipid peroxidation, and inducible nitric oxide synthase. For example, two enone fatty acids such as (E)-10-Oxooctadec-8-enoic acid and (E)-9-Oxooctadec-10-enoic acid derived from the red alga Gracilaria verrucosa inhibited the generation of the inflammatory markers such as TNF-α, IL-6 and nitric oxide [53]. Table 5.3 demonstrates the anti-inflammatory potential and its mechanism of action of seaweeds. Anticancer potential of seaweeds Nowadays seaweeds are of immense interest since it has a broad range of biological activities such as antibacterial, antiviral, antifungal, anti-inflammatory, antitumor, antioxidant activities and also has potent therapeutic effects against dreadful diseases like cancer and AIDS [113,114]. Apart from the secondary metabolites, seaweeds are a rich source of sulfated polysaccharides, which are reported to have antitumor, antiangiogenesis, cytotoxic, antimetastatic, and immunostimulating properties [115]. Moreover, polysaccharides such as fucoidan, alginate, agarose and carrageenan represent a very interesting class of macromolecules that are widespread in nature and have recently attracted more attention in the biochemical and medical areas due to their immunomodulatory and anticancer effects [116]. Fucoidan, a sulfated polysaccharide also called as fucan, fucosan or sulfated fucan, isolated from the seaweed have potent antiproliferative activity against human lung adenocarcinoma cell line A549 [117]. Fucoidan is a heparin-like molecule with a considerable percentage of L-fucose, sulfated ester groups, as well as small proportions of glucuronic acid, D-xylose, D-mannose and D-galactose. The structures and compositions of fucoidan vary among different species of brown algae. Similarly, the pharmacological effects of fucoidans also vary with their molecular weight. It has wide pharmacological activities including antitumor and antimetastatic activities. It has been reported that fucoidan isolated from the seaweed Fucus evanescens showed antitumor and antimetastatic activity in C57Bl/6 mice transplanted with Lewis lung adenocarcinoma. In another study, the low molecular weight fucoidan was found to induce mitochondrial-mediated apoptosis pathway in MDA-MB-231 breast cancer cells and also play a vital role in mitochondrial dysfunction, Ca2+ homeostasis and caspase activation [28,31]. The bioactive compounds such as Fucoxanthin and Phloroglucinol isolated from brown seaweeds showed chemotherapeutic and chemopreventive activity against breast cancer. The mechanism of its anticancer activity against breast cancer cells was found to be cell cycle arrest, inhibition of metastasis, antiangiogenic and antioxidant activity [118]. Previously, it has been reported that fucoxanthin inhibited the growth of human gastric adenocarcinoma cells MGC-803 in a dose-dependent manner by inducing G2/M phase arrest and apoptosis. In addition, fucoxanthin significantly decreased the expression of survivin, STAT3, CyclinB1 and also play a possible role in JAK/STAT signal pathway in the induction of antitumor activity. Besides the anticancer activity,

TABLE 5.3 List of some of the recently reported seaweeds with anti-inflammatory activity. Name of the seaweed

Family

Active component/ extract

Biological activity

Bangiaceae

Dc-porphyran

l

Inhibits nitric oxide (NO) production in LPS-stimulated RAW264.7 cells by preventing the expression of inducible NO synthase

[85]

Bangiaceae

Aqueous and alcoholic fractions

l

Significantly reduced the carrageenan-induced paw edema in a dose-dependent manner

[92]

Lessoniaceae

8,8-Bieckol (phlorotannins)

In vivo anti-inflammatory activity

Ethanolic extract

l

References

Porphyra yezoensis

Porphyra vietnamensis

Ecklonia cava [43,93]

Myagropsis myagroides Sargassaceae

l

l

l l

Dose-dependent inhibition of production of PGE2, NO and proinflammatory cytokines Suppress the expression of iNOS and COX-2 in LPS-stimulated RAW 264.7 cells Strongly suppress nuclear translocation of NF-κB by preventing degradation of inhibitor of κB-α as well as by inhibiting phosphorylation of Akt and MAPKs Reduce ear edema in PMA-induced mice Inhibits the phosphorylation of extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases

[94,95]

Gracilaria changii Gracilariaceae

Methanolic extract

l

Significant inhibition of TNF-α response level and TNF-α and IL-6 gene expression

[96]

Ethanol extract

l

[97]

l

Concentration-dependent reduction of LPS-induced prostaglandin E2 production Suppresses the expression of inducible iNOS and COX-2 at the protein level in RAW 264.7 cells Reduced the release of TNF-α and IL-6 into the medium

Aqueous extract

l

Dose-dependent inhibition of mouse ear edema

[98]

Neorogioltriol

l

Significant reduction of carrageenan-induced rat edema Inhibition of LPS-induced NF-κB activity and TNF-α production Significant inhibition of release of nitric oxide and the expression of COX-2 in LPS-stimulated Raw264.7 cells

[99]

Dictyopteris divaricata Dictyotaceae Dictyopteris prolifera

l

Dictyotaceae Prionitis cornea Halymeniaceae Grateloupia lanceolata Halymeniaceae Grateloupia filicina Halymeniaceae Dichotomaria obtusata Galaxauraceae Laurencia glandulifera Rhodomelaceae

l l

Continued

TABLE 5.3 List of some of the recently reported seaweeds with anti-inflammatory activity.—Cont’d Name of the seaweed

Family

Active component/ extract

Biological activity

Caulerpaceae

Methanolic extracts

l

References

Caulerpa mexicana Decreased xylene-induced ear edema Reduction of cell migration to different sites

[100]

l

Bryothamnion triquetrum Rhodomelaceae

Crude methanolic extract

l

Inhibits migration of leucocytes in Swiss mice

[101]

Dictyoteae

Heterofucan

l

Binds to the surface of leucocytes and inhibits migration of leucocytes to the site of injury 100% inhibition of chemical-induced leukocyte migration into the peritoneal cavity

[102]

Profound inhibitory effects against nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells Inhibit NO and PGE2 production via the inhibition of iNOS and COX-2

[103]

Terpene compound reported for its strong anti-inflammatory activity

[104]

Dictyota menstrualis

l

Laurencia snackeyi Rhodomelaceae

Aplysistatin

l

l

Laurencia dendroidea Rhodomelaceae

Lupeol, β-amyrin

l

Palmaria palmata Palmariaceae

Lipid extracts

l

l

l

Inhibits the production of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 Downregulates the expression of 14 pro-inflammatory genes such as TLR1, TLR2, TLR4, TLR8, TRAF5, TRAF6, TNFSF18, IL6R, IL23, CCR1, CCR4, CCL17, STAT3, MAP3K1 Inhibits LPS-induced pro-inflammatory signaling pathways in human THP-1 macrophages

[105]

Inhibits leukocyte recruitment in rat Inhibits neutrophil adhesion to platelets

[106]

Significantly inhibits rat paw edema induced by carrageenan and dextran Inhibits histamine, compound 48/80 and L-arginine induced paw edema Downregulates IL-1β, TNF-α, and COX-2 mRNA and protein levels

[107]

Laminaria saccharina Laminariaceae

Sulfated polysaccharides

l

Sulfated polysaccharide fraction

l

l

Gracilaria cornea Gracilariaceae

l

l

Laurencia claviformis Rhodomelaceae

Pacifenol

l

Act as a COX inhibitor

[108]

Epitaondiol

l

Inhibits eicosanoids (LTB4 and TXB2) release and also modulates COX pathway

[108]

Stypopodium flabelliforme Dictyotaceae

Continued

TABLE 5.3 List of some of the recently reported seaweeds with anti-inflammatory activity.—Cont’d Name of the seaweed

Family

Active component/ extract

Biological activity

Dictyotaceae

Heterofucan

l

References

Lobophora variegata l

l

Reduction of edema and serum TNF-α level in rat Anti-inflammatory activity in acute zymosan-induced arthritis in rats Significantly inhibits cell influx and NO release in a zymosaninduced arthritis model

[109]

Decreasing neutrophils migration Strongly reduced the Carrageenan-induced rat paw edema

[110]

Significantly inhibits carrageenan-induced paw edema and neutrophil migration Reduce the concentration of neutrophil-specific enzyme myeloperoxidase in paw tissue Reduce the peritoneal leukocyte count Decrease the IL-1β concentration

[111]

Effectively inhibits LPS-induced nitric oxide (NO) production in the zebrafish embryo

[112]

Caulerpa cupressoides Caulerpaceae

Sulfated polysaccharides

l

Methanol extract

l

l

Spatoglossum schroederi Dictyotaceae

l

l l

Laurencia snackeyi Rhodomelaceae

5β-Hydroxypalisadin B

l

Antioxidant, anti-inflammatory and anticancer potential Chapter

5 139

fucoxanthin has potent antiangiogenic activity. It has been reported that fucoxanthin suppressed the blood vessel-like structures formation from CD31-positive cells and also showed “significant suppressive effect on the proliferation of human umbilical vein endothelial cells (HUVEC) and tube formation without any significant activity on HUVEC chemotaxis” [119]. Similarly, the brominated phenols and polyphenols isolated from various red seaweeds were found to possess anticancer activity against various cancer cell lines such as HCT-15, A549, PC-3, MG-63, HeLa and HL-60 [120]. Phlorotannins are natural compounds mainly accumulated in marine brown algae which are formed by the polymerization of 1,3,5-trihydroxybenzene (phloroglucinol) monomer units. Phlorotannins exhibit anticarcinogenic activity. It has been reported that Eckol, a Phlorotannin compound isolated from the brown algae Ecklonia cava possess potent antiproliferative activity against human breast cancer cells MCF-7. Moreover, Dioxinodehydroeckol a phloroglucinol derivative from Ecklonia cava have the ability to induce apoptosis through NF-κB-dependent pathway. In another study, Phloroglucinol decreased the expression of cancer stem-like cells regulators such as Sox2, CD44, Oct4, Notch2 and β-catenin and CD44+ cancer cell population. In addition, dietary inclusion of brown algal polyphenols significantly reduced the tumor proliferation in the pre-tumor bearing mouse. These brown algae polyphenols prevent the tumor progression in vivo by inhibiting the activity of cyclooxygenase-2 and cell proliferation [28,43]. Terpenes and polyketides are the linear chain to complex polycyclic molecules reported to be present in brown algae. The meroterpenoid metabolites such as sargaquinone, sargaquinoic acid, sargahydroquinoic acid, allahydroquinone, sargachromenol from the seaweed Sargassum fallax were reported to possess anticancer activity against p388 human cancer cells [43]. Recently, our group reported that the red alga Gracilaria edulis contains a diterpene compound with antiproliferative activity against human lung adenocarcinoma cell line A549 [121]. The details of anticancer potential of the seaweeds are shown in Table 5.4. Fig. 5.5 shows the chemical structures of some of the successful bioactive agents isolated from seaweeds.

Conclusion Natural products from various sources are used for several decades for the treatment of various human diseases. Until now, several natural bioactive molecules are reported to possess extensive biological activities including anticancer properties. Similar to the terrestrial natural products, marine natural products also play a major role in the treatment of various diseases including cancer. Among all, seaweeds are one of the considerable marine renewable resources. The bioactive molecules isolated from the seaweeds were found to possess potent anticancer activity against various cancer cells in vitro and in vivo. The seaweed-derived active molecules can protect the cells from

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential. Name of the seaweed

Family

Active component/extract

Biological activity

References

Sargassaceae

Polysaccharides

Antitumor activity against human lung cancer cell A549

[122]

Gracilariaceae

Sulfated galactans

Retards the migration of cholangiocarcinoma cells (HuCCA-1) by inhibiting EGFR and ERK phosphorylation in EGFR/MAPK/ERK signaling pathway

[123]

Methanol extract

Highest anticancer activity against MCF-7 cells by inducing apoptosis

[124]

Sulfated laminaran

Inhibits human breast adenocarcinoma (MDAMB-231) cells migration in vitro through inhibition of MMP-2 and MMP-9 activity

[125]

Acetonic crude extract of the thallus

Significant antiproliferative activity against human pancreatic adenocarcinoma Panc89 and PancTU1 cells

[126]

Sargassum thunbergii

Gracilaria fisheri

Dictyota dichotoma Dictyotaceae Fucus evanescens Fucaceae

Fucus vesiculosus Fucaceae

Turbinaria conoides Sargassaceae

Ethyl acetate fraction of ethanol extract

Induces apoptosis in HepG2 cells

[127]

Fucoidan

Antiproliferative activity against A549 cells by induction of G0/G1 phase cell cycle arrest

[128,129]

Fucoidan

Antiangiogenic activity by inhibiting the tube formation and migration of human microvascular endothelial cells (HMEC-1)

[130]

Fucoidan

Antiproliferative activity against colon cancer cells HCT-15

[131]

α-L-fucoidan

Significantly inhibited the colony formation of human melanoma cells SK-MEL-5 and SK-MEL-28

[132]

Fucoidan

l

Turbinaria conoides Sargassaceae Sargassum fusiforme Sargassaceae

Sargassum cinereum Sargassaceae Coccophora langsdorfii Sargassaceae

Fucus evanescens Fucaceae

l

l

Inhibits epidermal growth factor-induced neoplastic transformation of JB6 Cl41 cells through TOPK/ERK1/2/MSK 1 pathway Suppressed HCT 116 colon tumor growth in xenograft animal model Inhibits the colony formation of colon cancer cells HCT 116 by inhibiting TOPK kinase activity

[133]

Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

Gracilariaceae

Phytol and ethyl acetate extract

l

References

Gracilaria edulis Antiproliferative activity against A549 cell line EA extract showing antiproliferative activity against HepG2, PC3 and A549 cell line

[121]

Sphaerodactylomelol

Inhibition of cell proliferation and cytotoxicity against HepG2 cells

[134]

Methanol extract

l

Antiproliferative activity against HeLa and SiHa cells Induces cell cycle arrest Induces mitochondria-dependent apoptosis

[135]

l

Sphaerococcus coronopifolius Sphaerococcaceae Dictyota cilliolata Dictyotaceae Dictyota menstrualis

l l

Dictyotaceae Saccharina gurjanovae Laminariaceae

Sulfated galactofucan

In vitro anticancer activity against colon cancer DLD-1 cells

[43,136]

Alariaceae

Fucoidan and laminaran

In vitro anticancer activity against HT29 cells

[43,137]

Alaria angusta

Ecklonia cava Lessoniaceae

Phloroglucinol

Decrease the CD44 + cancer cell population and expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and β-catenin in vitro and in vivo

[43,138]

Dictyotaceae

Spatane derivatives compounds

In vitro anticancer activity against B16F10 cancer cell line

[43,139]

Lessoniaceae

Dieckol

In vitro antiproliferative activity against A2780 and SKOV3 cells

[43,140]

Camptothecin

l

Stoechospermum marginatum

Ecklonia cava

Padina tetrastromatica Dictyotacea Caulerpa racemosa

l

Caulerpaceae

Lycodine

Sargassaceae

Pesudopelletierine

Time-dependent growth inhibition of breast carcinoma cell line MCF-7 Activation of apoptosis

[141]

Anticancer activity against HeLa, K-562 and MDA-MB-231 cells

[142]

Turbinaria ornata

Sargassum wightii Sargassaceae Ulva fasciata

Crude extract

l

Ulvaceae Gracillaria corticata Gracilariaceae Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

References

Hydroquinone diterpene mediterraneol

l

Inhibitor of mitotic cell divisions

[143]

Sargassaceae

Meroterpene, usneoidone E and Z

l

Antitumor activity

[143]

Dictyotacea

Diterpenes from methanol extract

l

Antitumor activities against lung carcinoma (H460) and liver carcinoma (HepG2)

[143,144]

Methanol extract

l

Antiproliferative activity against MCF-7, MDA-MB-231, HeLa, HepG2, and HT-29 in a dose-dependent manner Greatest growth inhibitory activity against MCF-7 cells Induces apoptosis

[145]

Cystoseira mediterranea Sargassaceae Cystoseira usneoides

Padina pavonia

Gracillaria corticata Gracilariaceae

l

l

Eisenia bicyclis Lessoniaceae

Laminarin

Growth Inhibitory activity against human melanoma SK-MEL-28 and colon cancer DLD-1 cells

[146]

Lobophora variegata Dictyotaceae

Fraction rich in fucans

In vitro anticancer activity against HepG2 cells

Bangiaceae

Sterol fraction

l

[43,147]

Porphyra dentata

l l

Cell growth inhibition by inducing apoptosis in 4T1 cancer cells in vitro In vivo antitumor activity Decrease the reactive oxygen species (ROS) and arginase activity of MDSCs in tumorbearing mice

[148,149]

Low cytotoxicity in lung cancer cell line A549 Concentration-dependent growth inhibition of colon cancer cells (HCT15) and breast cancer cells (MCF7)

[143]

Cystoseira crinite Sargassaceae

Crude aqueous extract

Cystoseira sedoides

l

l

Sargassaceae Cystoseira compressa Sargassaceae Gracilaria edulis Gracilariaceae

Ethanol extract

l

In vitro and in vivo antitumor activity against the Ehrlich ascites tumor by inducing apoptosis

[150]

Fucoidan

Inhibition of colony formation in human colon cancer cells DLD-1

[151]

Sargassum mcclurei Sargassaceae

Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

References

Sulfated polysaccharides

Antiproliferative activity against A549 and HepG2 cell line

[152]

Fucoidan

l

Sargassum plagiophyllum Sargassaceae Undaria pinnatifida Alariaceae

l l

Induce apoptosis in human hepatocellular carcinoma (SMMC-7721) cells via ROSmediated mitochondrial pathway Downregulates livin and XIAP mRNA In vitro anticancer activity, against PC-3 cells by inducing intrinsic and extrinsic apoptosis pathways via the activation of ERK1/2 MAPK, inactivation of p38 MAPK and PI3K/Akt signaling pathway, and the downregulation of Wnt/β-catenin signaling pathway

[43,153,154]

Dose- and time-dependent growth inhibition and induce apoptosis in human breast cancer cells Antiangiogenic activity

[66]

Reduce the proliferation of human colon cancer cell (HT-29)

[155,156]

Sargassum muticum Sargassaceae

Polyphenol

l

l

Laminaria sp. Laminariaceae

Laminarin

l

Enteromorpha intestinalis Ulvaceae

Methanolic extract

l

Cytotoxicity against HeLa cells

[157]

Hexane fraction

l

Dose-dependent inhibition of cell growth Induce apoptosis Inhibition of NF-κB Modulates EGFR-phosphorylation, kRas, AurKb and Stat3 in various cancer cells such as MiaPaCa-2, Panc-1, BXPC-3, Panc-3.27

[158]

Rizoclonium riparium Cladophoraceae Dictyota dichotoma Dictyotaceae

l

Hormophysa triquetra Sargassaceae

l

Dichloromethane fraction

l

Spatoglossum asperum Dictyotaceae

Ethyl acetate fraction

Stoechospermum marginatum Dictyotaceae

Methane fraction

Rhodomelaceae

Methanol extract and fractions

l

Cytotoxicity against A549, HCT15, MCF7

[159]

Sargassaceae

Methanol, chloroform, ethyl acetate and aqueous extracts. (Contains high polyphenolic content)

l

Potent antiproliferative activity against A549 and MG-63 cells

[160]

Laurencia obusta

Turbinaria ornata

Kappaphycus alvarezii Solieriaceae Acanthophora spicifera Rhodomelaceae Gracilaria corticata Gracilariaceae

Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

Bryopsidaceae

Kahalalide F (cyclic depsipeptide)

l

References

Bryopsis sp.

l

Phase I clinical trial, 106 patients with advanced solid tumors Recommended for further phase II studies

[161]

In vivo antitumor activity with no visible side effects for extract

[162]

Eucheuma cottonii Solieriaceae

Ethanol extract

l

Acinetosporaceae

Crude extract

In vitro antiproliferative activity against HT-29, AGS, SK-HEP, NCIH1299 cell lines

[43,163]

Laminarin

Induced apoptosis in HT-29 human colon cancer cells. Increased the percentage of cells in the sub-G1 and G2-M phase. Inhibited the heregulin-stimulated phosphorylation of ErbB2

[43,164]

Pylaiella littoralis

Laminaria digitata Laminariaceae

Saccharina cichorioides Laminariaceae

Fucoidan

In vitro antiproliferative activity against DLD-1 cells

Fucoidan

In vitro antiproliferative activity against RPMI-7951 cells

Galactofucan

In vitro growth inhibitory activity against T-47D cells

7-Hydroxycymopochromanone and 7-hydroxycymopolone

l

Elatol (Sesquiterpenoid)

l

[43,165]

Fucus evanescens Fucaceae Undaria pinnatifida Alariaceae Cymopolia barbata Dasycladaceae

l

Affect cell viability of colon cells (HT29) CYP1 inhibitors

[166]

In vitro cytotoxicity against, A549, B16F10, DU145, MCF-7 and L929 Cell cycle arrest and an increase in apoptosis In vivo antitumor activity

[167]

In vivo antitumor activity Reduces tumor volume in Ehrlich ascites carcinoma bearing Swiss albino mice Increases the level of antioxidant enzymes SOD and CAT

[168]

Induces apoptosis in HL-60 cells

[169]

Laurencia microcladia Rhodomelaceae

l l

Acanthophora spicifera Rhodomelaceae

Crude ethanol extract

l l

l

Hydroclathrus clathratus Scytosiphonaceae

Ethyl acetate portion of ethanol extract

l

Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

References

Methanol extract

l

Decreased MMP-9 and decreased cell invasion in T24 cells

[170]

Pepsin-digested extracts

l

Increased cytotoxicity and DNA damage in WEHI-3, HL-60 cells Low toxic effect in RAW 264.7 cells

[171]

Polyopes lancifolius Halymeniaceae Caulerpa microphysa Caulerpaceae

l

Gracilaria tenuistipitata Gracilariaceae

Crude aqueous extract

l

Protective effect against H2O2-induced cytotoxicity and oxidative stress-induced DNA damage in H1299 cells

[172]

Sargassaceae

Ethanol extract

l

Cytotoxicity against liver (Hep-2) and breast cancer (MCF-7) cells

[173]

Sargassaceae

Crude Fucoidan

l

Inhibit the growth of Lewis lung carcinoma (LCC) and melanoma B16 cells in vitro Enhance the NK cell activity in vivo Inhibits migration and invasion of lung cancer cell (A549) via the downregulation of ERK1/2 and Akt-mTOR as well as NF-kB signaling pathways

[174,175]

Sargassum sp.

Sargassum sp.

Fucus vesiculosus Fucaceae

l l

Fucus evanescens Fucaceae

Fucoidan

In vitro anticancer activity against SK-MEL-28 and SK-MEL-5 cells

[43,176]

Sargaquinoic acid

In vitro anticancer activity against MDA-MB231cells via caspase-3 activation and downregulation of Bcl-2, cell cycle arrest in G1 phase

[43,177]

Dictyotaceae

Meroditerpenoids

l

Anticancer activity against human colon adenocarcinoma (Caco-2), human neuroblastoma (SH-SY5Y), rat basophilic leukemia (RBL*-2H3), murine macrophages (RAW.267) and Chinese hamster fibroblasts (V79) cells

[178]

Udoteaceae

Crude extract

l

Cytotoxicity against HeLa, Hep-2, SiHa and KB

[179]

Codiaceae

Siphonaxanthin

l

Both induce apoptosis in HL-60 cells via activation of caspase-3 Siphonaxanthin is potent cytotoxic in nature, It induces GADD45α and DR5 and suppresses Bcl-2 expression

[180]

Sargassum heterophyllum Sargassaceae

Stypopodium flabelliforme

Udotea flabellum

Codium fragile

Undaria pinnatifida Alariaceae

l

Fucoxanthin

Continued

TABLE 5.4 List of some of the recently reported seaweeds with anticancer potential.—Cont’d Name of the seaweed

Family

Active component/extract

Biological activity

References

Fucoidan

In vitro anticancer activity against RPMI-7951 cells

[43,181]

Fucoidan extract

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[182]

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[183]

Fucoidans

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Inhibits colony formation of human melanoma (SK-MElL-28) and colon cancer (DLD-1) cells

[184]

Plocamium cornutum Plocamiaceae Ecklonia cava Lessoniaceae Sargassum hornery Sargassaceae Costaria costata Agaraceae

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FIG. 5.5 Chemical structure of some of the anticancer bioactive agents isolated from seaweeds. (A) Phloroglucinol (PubChem CID: 359), (B) Fucoxanthin (PubChem CID: 5281239), (C) Fucoidan (PubChem CID:92023653), (D) Alginate (PubChem CID: 131704328), (E) kappa-Carrageenan (PubChem CID: 11966249), (F) (E)-10-oxooctadec-8enoic acid (PubChem CID: 6443259), (G) (E)-9-oxooctadec-10-enoic acid (PubChem CID: 6443258), (H) Dieckol (PubChem CID: 3008868), and (I) Sargaquinoic acid (PubChem CID: 101145056).

154 Studies in Natural Products Chemistry

potent environmental carcinogenic substances by suppressing the action of carcinogens or restoring the level of the cellular antioxidant defense system. These bioactive agents can modulate EGFR and also have the potential to downregulate the expression of ERK1/2 and Akt-mTOR as well as NF-κB signaling pathways which leads to inhibition of cancer cell migration and invasion. These reports positively suggest that seaweeds are one of the promising sources of potent anticancer agents. Some of the compounds have been recommended for clinical trials but still, the research on anticancer potential of seaweedderived bioactive agents is at its infancy. Several anticancer active agents need to be explored from the seaweeds which are distributed throughout the world. Hence further studies on seaweeds compounds will be helpful to develop potent anticancer agents from the natural origin.

Acknowledgments R.S. wishes to thank UGC for the Research Fellowship provided through SAP (DRS-I) [Grant No. F.3-28/2011 (SAP-II)] program. The authors sincerely acknowledge the computational and bioinformatics facility provided by the Alagappa University Bioinformatics Infrastructure Facility (funded by DBT, GOI; File No. BT/BI/25/012/2012, BIF). The authors also thankfully acknowledge DST-FIST (Grant No. SR/FST/LSI-639/2015(C)), UGC-SAP (Grant No. F.5-1/2018/DRS-II (SAP-II)) and DST-PURSE (Grant No. SR/ PURSE Phase 2/38 (G)) for providing instrumentation facilities.

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