Keywords

9.1 Background

Among all life-threatening diseases of modern world, cancer has stirred enormous difficulties for the fields of medicine and immunology. Discovery and development of novel and efficient compounds from natural sources have been the key aspect of concern for researches, especially in the pharmaceutical field. Nature contains a broad variety of organisms including microbial inhabitants and lithosphere, atmosphere and hydrosphere altogether present an excellent source of distinctive chemical compounds with great potential to be used as therapeutic agents. Present trends credit drugs derived from natural sources to have notable impact on the antitumor agent discovery approach [1]. Natural products are considered to possess this giant potential due to their bioavailability, specific and strong binding to drug targets , ability to bind proteins with minimal entropy loss. In addition, it has been reported that compounds of natural origin are known to be adoptive to diverse conformations in aqueous and lipophilic environments [2].

The utilization of organisms present in folk medicine is being widely investigated worldwide. Among all traditional medicinal organisms, plant materials occupy a large part of natural products which are being recognized for their renowned bioactivities such as anticancer , antiviral, antioxidant and antibacterial. Starting from ancient times, folk medicines use marina algae intensely, and in this regard several species, especially brown algae have emerged as abundant source of nutrition, hence consumed as a kind of seasoned vegetable in various coastal areas worldwide [3–5]. Moreover, it has been treated as a source of natural marine product due to its biological activity in a broad range. Marine algae already reported to contain various phlorotannin derivates, which have been regarded as potential pharmacological polyphenols [6–7]. Phlorotannins are oligomeric form of phloroglucinol and have been revealed to have antioxidant, antibacterial, anti-inflammation, anti-allergy, anti-matrix metalloproteinase (MMP), apoptosis-induction, and so on [8–10].

9.2 Phlorotannins

Phlorotannins are natural compounds which are formed by the polymerization of 1,3,5-trihydroxybenzene (phloroglucinol) monomer units and are known to be biosynthesized through acetate–malonate pathway. Highly hydrophilic phlorotannins are found to be between 126 Da and 650 kDa molecular weight [11]. Phlorotannins of different molecular weights are mainly accumulated in marine brown algae which contains a wide range of phloroglucinol-based polyphenols. There four main types of phlorotannins based on linkage of monomers, namely fuhalols (phlorotannins with an ether linkage), fucols (with a phenyl linkage), fucophloroethols (with an ether and phenyl linkage) and eckols (with a dibenzodioxin linkage). Reports indicate several isolated and elucidated phlorotannins from marine sources such as phloroglucinol, eckol, fucodiphloroethol G, phlorofucofuroeckol A, 7-phloroeckol, dieckol, and 6,6′-bieckol [12]. In addition, triphloroethol A, 8,8’-bieckol, and 8,4’”-dieckol have been isolated. Marine brown alga Ecklonia cava is extensively studied and promoted to be a rich and dependable source of phenolic compounds in comparison to other brown algae [13]. Stressful conditions of marine environments and herbivore danger are considered to be battled by phlorotannins in case of brown algae. Owing to the health beneficial various biological activities of marine brown algae, phlorotannins are reported to be important compounds for future development and discovery of therapeutic agents .

The bioavailability of plant polyphenols have already been studied and discussed in vivo [14–16]. According to these reports it could be said that around 70 % out of consumed polyphenolics amount has been shown potent bioavailability. However, these reports mostly direct the issues through mouse models systems which present a need for further researches that investigates phlorotannin bioavailability in human subjects .

9.3 Anti-cancer Effect of Marine Algal Polyphenols

Harada and Kamei [17] showed that phlorotannins exhibit anticarcinogenic effects. Study presented that brown alga Laminaria japonica fractionated phlorotannin extract (PE) has shown considerable anti-proliferative activity in the hepatocellular carcinoma cells (BEL-7402) and also on leukemic cell lines (P388) with the IC50 values of 120 and > 200 μg/ml, respectively. Microscopic observations have revealed that the morphologic features of tumor cells treated with PE and 5-fluorouracil (a commercial chemotherapy drug) are markedly different from the normal control group suggesting the anti-proliferative effect of PE [18]. Moreover, dioxinodehydroeckol which was isolated from E. cava has shown to possess a notable anti-proliferative effect on human breast cancer cells (MCF-7). Dioxinodehydroeckol inhibited the proliferation of MCF-7 cells with rates of approximately 25, 40, 53, 56 and 64 % at concentrations of 1, 5, 10, 50 and 100 μM, respectively, compared to the control group. Study credited the potential anti-proliferative activity of dioxinodehydroeckol to its ability to induce of apoptosis through nuclear factor kappa-light-chain-enhanced activated B cells (NF-κB) family and NF-κB dependent pathway [19]. In another research, E. cava has been subjected to enzymatic extraction along crude polyphenolic and polysaccharide fractions. All aforementioned fractions of E. cava have been evidently shown to possess antiproliferative and antiradical activities. Especially the CphF at an IC50 of 5.1 μg/ml has inhibited cell proliferation in murine colon cancer cell line (CT-26) significantly. A nuclear cell staining assay suggested that this anti-proliferative effect of CphF is associated with apoptotic cell demise in CT-26 [20]. The direct correlation between the anti-proliferative effect of the algae and their polyphenolic content is evidently documented. In this context, the anti-proliferative effects of red alga, Palmaria palmate and three kelp Laminaria setchellii, Macrocystis integrifolia, Nereocystis leutkeana extracts has been studied on human cervical adenocarcinoma cell line (HeLa cells) . HeLa cell proliferation was inhibited between 0 and 78 % by P. palmate; 0 and 55 % by L. setchellii and 0 and 69 % by M. integrifolia and N. leutkeana at 0.5–5 μg/ml algal extract concentration range. This investigation suggests the effectiveness of polyphenolic compounds in controlling tumor growth and brings front a fact that marine algae could serve beneficial for anticancer properties [21]. In addition, in vivo tests also presented valuable data regarding antitumor effects of polyphenols. Dietary inclusion of brown algal polyphenols in pre-tumor bearing mouse feeding at the rates of 0.1 and 0.5 % has notably reduced tumor proliferation by 45 and 56 % and tumor mass by 54 and 65 %, respectively, for each application rate. Moreover, the topical application of polyphenols at 3 and 6 mg has significantly decreased tumor proliferation by 60 and 46 % and tumor mass by 66 and 57 %, respectively. In case of action mechanism, it is believed that brown algal polyphenols inhibit the cyclooxygenase-2 activity and cell proliferation hence preventing the tumor progression [22].

9.4 Marine Algal Polyphenols as MMP Inhibitors

Matrix metalloproteinase enzymes (MMPs) play a significant role in the digestion of extra cellular matrix components, hence directly associated with chronic inflammation , wrinkle formation, arthritis, osteoporosis, periodontal diseases, tumor invasion, and metastasis in pathological conditions. During current decade, a detailed presentation of MMP inhibitory effects of phlorotannins derived from E. cava has been documented for the first time [23]. In this report, a novel gelatin digestion assay was able to visualize complete inhibition of bacterial collagenase-1 activity with introduction of 20 μg/ml of E. cava extract during preliminary screening assays. In addition, a sensitive fluorometric assay has been carried out and it showed that phlorotannin content of E. cava can specifically inhibit both MMP-2 and MMP-9 activities (p < 0.001) at 10 μg/ml. Also, artificially induced activities of MMP-2 and MMP-9 in human dermal fibroblast and HT 1080 cells have been successfully suppressed by E. cava extract in a comparable manner to that of positive control doxycycline. More interestingly, EC extract did not exert any cytotoxic effect even at 100 μg/ml, anticipating, its potential use as a safe MMP inhibitor. Therefore, it can easily be suggested that phlorotannins would be a potent natural source for the development of therapeutic agents against MMP and cancer.

In another research, 3-(3, 4-dihydroxy-phenyl)-acrylic acid phenethyl ester (caffeic acid phenethyl ester, CAPE) has also been isolated and characterized as biologically active compound with health benefits from methanol extracts prepared from roots of Rhodiola sacra and quadrifida [24, 25]. In this regard, Lee et al. evidently proposed that these active compounds can down regulate artificially enhanced MMP-9 activities, indicating a notable antitumor effect [26].

Comparison of 29 seaweed extracts in regard to their inhibitory efficiencies on transcriptional activities of MMP-1 expression has been performed by Joe et al. [27]. Research has concluded that the eckol and dieckol from Ecklonia species have showed strong inhibition of both NF-κB and AP-1 reporter activity, which were well related with their abilities to inhibit MMP-1 expression. In addition, MMP-1 expression was dramatically attenuated by treatment with the eckol or dieckol.

It has been also known that matrix metalloproteinases (MMPs) are crucial components in photoaging of the skin, especially due to high and long exposure to ultraviolet A. Reports indicate that enhanced activity of MMPs and increased photoaging appear to be stimulated by UV-irradiation-associated generation of reactive oxygen species (ROS). Ryu et al. demonstrates that the alga Corallina pilulifera methanol extract which has been shown a high phenolic content, reduced the expression of UV-induced MMP-2 and -9 of human dermal fibroblasts in a dose dependent fashion, and has also exhibited strong antioxidant activity by scavenging free radicals [28].

In a murine asthma model, it has been documented that MMP-9 expression was significantly reduced by the administration of E. cava extracts. And it has been presented that E. cava extracts were able to notable suppress the cytokine signaling-3 (SOCS-3) expression and reduce the increased eosinophil peroxidase (EPO) activities [29].

Also aforementioned phlorotannins, namely eckol, dieckol, 6,6′-bieckol and 1-(3′,5′-dihydroxyphenoxy)-7-(2″,4″,6″-trihydroxy-phenoxy)-2,4,9-trihydroxydibenzo-1,4,-dioxin were also extracted from brown alga, E. cava, and in regard it has been reported that these compounds were able to inhibit the expression of MMP-1, -3 and -13 induced by proinflammatory cytokines [30].

In short, polyphenols, especially from marine sources, have excellent MMP inhibitory activities; however potent cytotoxicity of polyphenols come front as a major drawback. Therefore, the pharmaceutical applications of these MMP inhibitors are usually limited.

In this regard, future researches should turn their attention to reduce their toxicity levels by altering the chemical structure in a way to preserves bioactivity while converting the compound to be biologically safe. Following these improvements, MMP inhibitor polyphenols will gain a huge potential to be used in clinical applications.

9.5 Conclusions

In conclusion, due to the abundant presence and distinctive chemical distribution of polyphenols among marine sources, especially algae, future focus should be directed to biological and pharmacological of novel polyphenols from marine sources with higher efficiency against cancer and less cytotoxicity to non-cancer cells. It is recommended to screen phlorotannins from other marine macro algae and evaluate their anticancer activities as a comparative study. With the latest advancements in the fields of molecular biology and biochemistry, a sophisticated approach to study the interactions of polyphenols with human cellular systems could prove beneficial in understanding and altering parameters like bioavailability and cytotoxicity of these compounds. Also, detailed studies on molecular interactions of phenolic compounds involved in the management of various human diseases would pave the way for development of novel therapeutic agents with superior efficiency. On the other hand, broadening the ways and studies that are developed to screen more biologically efficient polyphenols will definitely provide promising drug candidates for pharmaceutical purposes.