Marine Natural Products: A Source of Novel Anticancer Drugs

Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.


Nature and Cancer Chemotherapy
Over the past 50 years, emerging evidence has shown that many natural products derived from plants and microbes of marine origin (Table 1), exhibit beneficial effects in the prevention and treatment of cancer i.e., cytarabine, eribulin mesylate, brentuximab vedotin, and trabectidine are marine-based drugs used against leukemia, metastatic breast cancer, soft tissue sarcoma and ovarian cancer [20,21]. Not only the marines represent the main source for anticancer drugs but also there are other vital sources like as plants, animals, invertebrates and terrestrial microbes, for example Taxol; is an antineoplastic drug obtained from the bark of the Western Yew tree (Taxus brevifolia L., Taxaceae), proved to be useful in the treatment of breast cancer [22], in addition to the active complex alkaloid compounds such as Vincristine and Vinblastine which are present in Vinca herb. They have proven effective agents against childhood leukemia and Hodgkinʼs disease (a cancer of the lymph nodes), choriocarcinoma, respectively [23].
Although the National Cancer Institute provides researchers with the resources needed to better elucidate the role of food and nutrients in cancer prevention, cancer chemoprevention using marine natural compounds [16,24] has not been investigated in-depth and the preclinical and clinical data for this strategy remain scant, in spite of the robust chemical rationale [16]. Many other compounds with anticancer properties have been isolated and developed from various biological resources, such as plants, microbes and marine organisms ( Figure 2). Consequently, a large number of natural products are in preclinical investigations, and 13 natural products isolated from marine organisms are being tested in different phases of clinical trials, highlighting the potential of marine natural compounds [25]. A focused, combinatorial approach would has been suggested to accelerate the development of new anti-cancer drugs from marine resources with increased efficiency and fewer side effects [26].

Nature and Cancer Chemotherapy
Over the past 50 years, emerging evidence has shown that many natural products derived from plants and microbes of marine origin (Table 1), exhibit beneficial effects in the prevention and treatment of cancer, i.e., cytarabine, eribulin mesylate, brentuximab vedotin, and trabectidine are marine-based drugs used against leukemia, metastatic breast cancer, soft tissue sarcoma and ovarian cancer [20,21]. Not only the marines represent the main source for anticancer drugs but also there are other vital sources like as plants, animals, invertebrates and terrestrial microbes, for example Taxol; is an antineoplastic drug obtained from the bark of the Western Yew tree (Taxus brevifolia L., Taxaceae), proved to be useful in the treatment of breast cancer [22], in addition to the active complex alkaloid compounds such as Vincristine and Vinblastine which are present in Vinca herb. They have proven effective agents against childhood leukemia and Hodgkin's disease (a cancer of the lymph nodes), choriocarcinoma, respectively [23].
Although the National Cancer Institute provides researchers with the resources needed to better elucidate the role of food and nutrients in cancer prevention, cancer chemoprevention using marine natural compounds [16,24] has not been investigated in-depth and the preclinical and clinical data for this strategy remain scant, in spite of the robust chemical rationale [16]. Many other compounds with anticancer properties have been isolated and developed from various biological resources, such as plants, microbes and marine organisms ( Figure 2). Consequently, a large number of natural products are in preclinical investigations, and 13 natural products isolated from marine organisms are being tested in different phases of clinical trials, highlighting the potential of marine natural compounds [25]. A focused, combinatorial approach would has been suggested to accelerate the development of new anti-cancer drugs from marine resources with increased efficiency and fewer side effects [26].

Marine Organisms and Cancer Chemotherapy
Oceans cover over 70% of the earth. The total global biodiversity is estimated to include ca. 500 × 10 6 species of prokaryotic and eukaryotic organisms. The marine environment is indeed an exceptionally diverse reservoir of life, containing nearly 250,000 described species [27,28]. Among marine organisms, 3.7 × 10 30 microorganisms have been discovered in marine environments [29], 99% of all bacteria cannot be cultured but can synthesize many fascinating natural products that are potential drug leads [30]. This extraordinary chemical and pharmacological scope of marine organisms could be attributed for the necessity to produce secondary metabolites as defense tools to survive in extreme environments; of temperatures, salinity, pressure and to resist predators.
Since ancient times, marine flora has been used for medicinal purposes worldwide: in India, China, the Near East, and Europe [31]. From then till now, less than 5% of the deep sea has been explored, and less than 0.01% of the deep-sea floor has been sampled in detail [32]. The Caribbean sponge (Cryptotethya crypta) was the first marine organism to be investigated in detail chemically [33], and extensive phytochemical studies on pure compounds from this organism were performed from 1950 to 1960, before the identification of cytosine arabinoside (ara-C) [34][35][36]. Furthermore, some marine organisms, such as microflora (bacteria, actinobacteria, cyanobacteria and fungi), microalgae, macroalgae (seaweeds) [31], invertebrate animals [37,38] sponges, soft corals, sea fans, sea hares, nudibranchs, bryozoans, tunicates, etc. [2], have been investigated for cancer control [39,40]. The bioactive molecules impact has been evaluated against various cancer types in clinical trials [41][42][43][44][45],. Additionally, with the ongoing advancement in marine chemistry, new tools have been employed, e.g., metabolomics, to examine marine products from different perspectives [31].

Characterization of Marine Metabolites
The major obstacles for better understanding of marine metabolites chemistry and composition are sampling difficulties. Sufficiently large quantities are required for detailed analyzes and resolution of the instrumental and bioassay approaches used. For modern analytical methods in mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy [46], sub mg, or low micro

Marine Organisms and Cancer Chemotherapy
Oceans cover over 70% of the earth. The total global biodiversity is estimated to include ca. 500 × 10 6 species of prokaryotic and eukaryotic organisms. The marine environment is indeed an exceptionally diverse reservoir of life, containing nearly 250,000 described species [27,28]. Among marine organisms, 3.7 × 10 30 microorganisms have been discovered in marine environments [29], 99% of all bacteria cannot be cultured but can synthesize many fascinating natural products that are potential drug leads [30]. This extraordinary chemical and pharmacological scope of marine organisms could be attributed for the necessity to produce secondary metabolites as defense tools to survive in extreme environments; of temperatures, salinity, pressure and to resist predators.
Since ancient times, marine flora has been used for medicinal purposes worldwide: in India, China, the Near East, and Europe [31]. From then till now, less than 5% of the deep sea has been explored, and less than 0.01% of the deep-sea floor has been sampled in detail [32]. The Caribbean sponge (Cryptotethya crypta) was the first marine organism to be investigated in detail chemically [33], and extensive phytochemical studies on pure compounds from this organism were performed from 1950 to 1960, before the identification of cytosine arabinoside (ara-C) [34][35][36]. Furthermore, some marine organisms, such as microflora (bacteria, actinobacteria, cyanobacteria and fungi), microalgae, macroalgae (seaweeds) [31], invertebrate animals [37,38] sponges, soft corals, sea fans, sea hares, nudibranchs, bryozoans, tunicates, etc. [2], have been investigated for cancer control [39,40]. The bio-active molecules impact has been evaluated against various cancer types in clinical trials [41][42][43][44][45]. Additionally, with the ongoing advancement in marine chemistry, new tools have been employed, e.g., metabolomics, to examine marine products from different perspectives [31].

Characterization of Marine Metabolites
The major obstacles for better understanding of marine metabolites chemistry and composition are sampling difficulties. Sufficiently large quantities are required for detailed analyzes and resolution of the instrumental and bioassay approaches used. For modern analytical methods in mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopy [46], sub mg, or low micro gram, amounts may be enough for full structure elucidation. The marine community has used MS for the past three  [47][48][49][50]. MS has been mainly used in past studies for identifying and quantifying the specific fractions or trace components within the marine organisms, and identification is then aided by MS/MS analysis, as exemplified by the identification of hierridin B from a marine cyanobacterium Cyanobium spp. strain [51]. There is no doubt that NMR is the most widely used technique for structural characterization of molecules, i.e., acremines P was isolated from a marine-derived strain of Acremonium persicinum and identified using NMR techniques [52]. Nevertheless, the lower sensitivity level of NMR compared to MS hinders the identification of metabolites present at trace levels or low amounts. Although originally used for small, relatively simple organic compounds, it has gained widespread popularity as a method for marine´s metabolites fingerprinting organism [53,54]. However, although LC-HRMS is extremely sensitive and can detect compounds present at very low quantities, there are certain classes of compounds that cannot be detected by MS; they may not form ions at all, or ion formation may be suppressed or they are not able to be eluted from the column to be detected. NMR, on the other hand, has no separation step and therefore provides a snapshot of the metabolome of the sample. It is less sensitive than MS, but more robust and reproducible with universal feature in metabolites detection, all of which allowing for comparison of results from different datasets or running at different time periods. Also, coupling of metabolomics to other "omics" technologies, i.e., genomics could aid in better correlation of marine metabolome in relation to its genotype. [55]. These analytical techniques are also used to elucidate the function/mode of action of metabolites. For example, functional metabolomics was employed to reveal metabolic alterations associated in MCF-7 breast cancer cells exposed to the alkaloid ascididemin [56].

From Marine Organisms to Anticancer Drugs
There are more than 22,000 known microbial secondary metabolites, 70% of which are produced by actinomycetes, 20% by fungi, 7% by Bacillus spp. and 1-2% by other bacteria [57]. It should be noted that generally 10% of all currently known biologically active natural products are of microbial origin. There are few examples of marine antineoplastic agents that have reached clinical phase trials. For instance, bryostatin 1, ET-743 and dolastatin 10. The bryostatin 1 has recently entered phase II clinical trial against melanoma, non-Hodgkin's lymphoma, renal cancer and colorectal cancer [58][59][60]. The biological effect of bryostatin 1 is mediated via the promotion of normal growth of bone marrow progenitor cells [61]. Moreover, ET-743, a tetrahydroisoquinilone alkaloid isolated from tunicate Ecteinascidia turbinata entered phase I clinical trials [62], since it exerts anti-proliferative effects by selective alkylation of guanine residues in the DNA minor groove [63], whereas dolastatin 10, a member of a peptide family isolated from the mollusk Dolabella auricularia, reached phase II clinical trials [64], based on its inhibition of microtubule assembly, which eventually leads to metaphase arrest in the cell cycle [65,66], (Table 2, Figure 3).

Marine Plants
Marine plants have rarely been discussed in the literature as a distinct and self-contained group. These plants have traditionally been treated either as the poor relations of marine animals in courses and texts on marine biology or as examples of particular groups of algae, where the essential 'marine-ness' of marine plants tends to disappear among the taxonomic and morphological parallels with freshwater algae. Over 90% of marine plant species are algae [67]. Because there is great chemical diversity in marine plants, including marine algae and mangroves, products isolated from these plants have been shown to possess antibacterial, antifungal, analgesic, anti-inflammatory, cytotoxic, hypotensive, and spasmogenic activities [68,69].

Marine Plants
Marine plants have rarely been discussed in the literature as a distinct and self-contained group. These plants have traditionally been treated either as the poor relations of marine animals in courses and texts on marine biology or as examples of particular groups of algae, where the essential 'marineness' of marine plants tends to disappear among the taxonomic and morphological parallels with freshwater algae. Over 90% of marine plant species are algae [67]. Because there is great chemical diversity in marine plants, including marine algae and mangroves, products isolated from these plants have been shown to possess antibacterial, antifungal, analgesic, anti-inflammatory, cytotoxic, hypotensive, and spasmogenic activities [68,69].

Macroalgae (Seaweed)
Macroalgae have long been recognized as food, functional food and potential drug sources [70]. Also known as seaweed, multicellular macroalgae contain numerous pharmacologically important bioactive elements to include carotenoids, dietary fiber, protein, essential fatty acids, vitamins (A, B, B12, C, D, E), and minerals such as Ca, P, Na, and K [70][71][72][73], in addition to polyphenols [74,75]. An alcoholic extract of the red alga Acanthophora spicifera was supplemented to mice treated with Ehrlich's ascites carcinoma cells, and to exhibit anti-tumor activity at an oral dose of 100 and 200 mg/kg [76]. Similarly, an extract of the brown seaweed Sargassum thunbergii displayed antitumor activity against transplanted tumor such as sarcoma 180 and Ehrlich solid carcinoma (in vivo) [77]. The anti-proliferative effect of fucoidan, isolated from Ascophyllum nodosum was demonstrated against sigmoid colon adenocarcinoma cells (COLO320 DM), in comparison to fibroblasts (hamster kidney fibroblast CCL39) [78]. Caulerpenyne from Caulerpa sp. algea attributed to anticancer and antiproliferative effects against neuroblastoma cell line through induction of cells inhibition proliferation with an IC50 of 10 µM [79]. Condriamide-A, isolated from Chondria sp., showed a

Macroalgae (Seaweed)
Macroalgae have long been recognized as food, functional food and potential drug sources [70]. Also known as seaweed, multicellular macroalgae contain numerous pharmacologically important bioactive elements to include carotenoids, dietary fiber, protein, essential fatty acids, vitamins (A, B, B 12 , C, D, E), and minerals such as Ca, P, Na, and K [70][71][72][73], in addition to polyphenols [74,75]. An alcoholic extract of the red alga Acanthophora spicifera was supplemented to mice treated with Ehrlich's ascites carcinoma cells, and to exhibit anti-tumor activity at an oral dose of 100 and 200 mg/kg [76]. Similarly, an extract of the brown seaweed Sargassum thunbergii displayed antitumor activity against transplanted tumor such as sarcoma 180 and Ehrlich solid carcinoma (in vivo) [77]. The anti-proliferative effect of fucoidan, isolated from Ascophyllum nodosum was demonstrated against sigmoid colon adenocarcinoma cells (COLO320 DM), in comparison to fibroblasts (hamster kidney fibroblast CCL39) [78]. Caulerpenyne from Caulerpa sp. algea attributed to anticancer and antiproliferative effects against neuroblastoma cell line through induction of cells inhibition proliferation with an IC 50 of 10 µM [79]. Condriamide-A, isolated from Chondria sp., showed a cytotoxic effect at a dose of 0.5 µg/mL against KB cells and 5 µg/mL against LOVO cells (colon cancer) [80]. Two compounds isolated from Cystophora sp., namely, meroterpene and usneoidone, have demonstrated antitumor properties [79,[81][82][83]. Sulfated polysaccharides purified from the brown alga Eclonia cava selectively and dose-dependently suppressed the proliferation of murine colon carcinoma (CT-26) and human leukemic monocyte lymphoma (U-937) cell lines [84]. Equally important, stylopoldione, a potent cytotoxic metabolite isolated from Stypodium sp., disrupted mitotic spindle formation functioning via inhibiting synchronous cell division using urchin egg assay (Strongylocentrotus purpuratus Stimpson) at ED 50 = 1.1 µg/mL, and to inhibit cells cleavage via inhibition of tubulin polymerization [85].

Microalgae
Cyanobacteria, also known as blue-green algae, are prolific sources of more than 400 novel metabolites, particularly unique, biologically active peptide and polyketide metabolites [86], effective at either killing cancer cells by inducing apoptotic death or affecting cell signaling via activation of the protein kinase c family [31]. Approximately half of the 41 screened strains of cyanobacteria exhibited the ability to cause cancer cell death [87]. Two cyanobacteria-derived anti-microtubule agents, i.e., dolastatin 10 and curacin A, have been clinically evaluated for the treatment of cancer and to serve as lead structures for the synthesis of a number of synthetic analogs/derivatives [88]. Calothrixins A and B, are pentacyclic metabolites isolated from Calothrix cyanobacteria with anticancer potent activity against human HeLa cancer cells in a dose-dependent manner at an IC 50 of 40 and 350 nM, respectively (in vitro studies) [89]. Ulithiacyclamide and patellamide, produced by cyanobacteria Prochloron spp. and Lissoclinum patella [90][91][92], exhibited potent cytotoxic activity against a human nasopharyngeal carcinoma cell line at IC 50 value of 17 and 3000 ng/mL, respectively [93]. Borophycin, a boron-containing metabolite isolated from marine cyanobacterial strains of Nostoc linckia and Nostoc spongiaeforme var. tenue [94], attributed potent cytotoxicity against human epidermoid carcinoma (LOVO) and human colorectal adenocarcinoma (KB) cell lines [95]. Potent cytotoxicity was displayed by cryptophycin 1, isolated from Nostoc sp. GSV 224, against tumor cells in vitro (human tumor cell lines (KB and LOVO with IC 50 = 0.005; 0.003 ng/mL)) and in vivo (human solid tumors (colon adenocarcinomas, pancreatic ductal adenocarcinoma and mammary adenocarcinoma) [96,97]. Largazole represented a unique chemical scaffold derived from Symploca spp. with impressive anti-proliferative activity [98]. The parental compound, apratoxin A, isolated from a strain of Lyngbya boulloni, exhibited cytotoxicity against adenocarcinoma [99]. Coibamide A, a promising anti-cancer agent with a new potential mechanism of action, derived from a strain of Leptolyngbya, exhibited significant cytotoxicity against NCIH460 lung and mouse neuro-2a cells (LC 50 < 23 nM) [100]. Cyanobacteria produce a family of antitumor agents known as cryptophycins, which interfere with tubulin assembly [101]. Scytonemin, is a protein serine/threonine kinase inhibitor of the cell division cycle 25C (cdc25C) in a dose-dependent manner with an IC 50 of 2.3 µM where significant inhibition was observed at concentrations as low as 300 nM [102]. Scytonemin is present in the extracellular sheaths of different genera of aquatic and terrestrial blue-green algae. This compound regulates mitotic spindle formation as well as enzyme kinases involved in cell cycle control, and to also inhibit the proliferation of human fibroblasts and endothelial cells [103]. Curacin A, isolated from the organic extracts of Curacao collections of Lyngbya majuscule, is an exceptionally potent anti-proliferative agent that inhibited tubulin polymerization and also exhibited selective inhibitory activity against leukemia and Burkitt lymphoma cell lines (IC 50 = 9 nM and 200 nM) [104,105]. Apratoxins represent are another class of cyanobacterial compounds that inhibited a variety of cancer cell lines at nanomolar dose levels.
Various strains of cyanobacteria exhibited apoptotic activity against acute myeloid leukemia cells without affecting non-malignant cells, e.g., hepatocytes and cardiomyoblasts [106]. Based on modern research, cultured benthic cyanobacteria from temperate marine environments provide a promising, under-exploited source for novel drugs against leukemia [107]. Nevertheless, there are some compounds isolated from marine sources, not been yet applied in clinical trials like as calothrixins A, B, ulithiacyclamide, patellamide, borophycin, largazole, etc. This all compound shows anticancer activity against various types of cancer cells with different mechanisms hence we recommend further investigation of their potential biological activities and clinical uses.
Actinomycetes, Streptomyces and Micromonosporaceae are good candidates for the isolation of potent growth-inhibiting compounds and novel antitumor agents [31,106,[126][127][128]. In the exploration of marine-derived actinomycetes as sources of antitumor compounds, lucentamycins A-D, which are 3-methyl-4-ethylideneproline-containing peptides were isolated from Nocardiopsis lucentensis (strain CNR-712). Lucentamycins A and B exhibited significant in vitro cytotoxicity against HCT-116 human colon carcinoma using MTS assay with IC 50 = 0.20 and 11 µM, respectively [129]. Thicoraline, a depsipeptide isolated from Micromonospora marina, displayed cytotoxic activity against both LOVO and SW620 human colon cancer cell lines with IC 50 of 15 nM and 500 nM, respectively in vitro.

Marine Sponges
These organisms contributed to nearly 30% of all-natural products discovered to date [147]. The initial discoveries from marine sponges led to the belief that it would not be long before true marine-derived drugs would reach the market. One successful example is the discovery and identification of spongothymidine and spongouridine from the Caribbean sponge Tethya crypta. These compounds were found to possess antiviral activity and synthetic analogs studies eventually led to the development of cytosine arabinoside (AraC) as a clinically anticancer agent [148]. Eribulin, a truncated synthetic version of halichondrin B, derived from the sponge Halichondria okadai [149], has clinically potential activity against pretreated metastatic breast cancer cells [150,151].

Soft Corals
Sarcophyton is one of the most widely distributed soft coral genera in the tropical and sub-tropical oceans, and approximately 30 species from this genus have been collected and tested for the presence of bioactive secondary metabolites, i.e., fatty acids (arachidonic, eicosapentaenoic, docosahexaenoic acids) that showed cytotoxic activity against brine shrimp in dose-dependent manner (LC 50 of 96.7 ppm) [152,153]. Among the most important components of soft coral are cembranoids, which are present at high concentrations (up to 5% dry weight). Cembranoids have an impact on biological activities, i.e., ichthyotoxic, cytotoxic, anti-inflammatory, and antagonistic activity. In vitro cytotoxicity testing showed that furano-cembranoids and decaryiol isolated from Nephthea spp. and Sarcophyton cherbonnieri are effective against several tumor cell lines (gastric epithelial, breast and liver) (with GI 50 values ranging from 0.15 to 8.6 µg mL −1 ) via arrests the cell cycle in the G2/M phase [154]. In addition, crassumolide C isolated for the first time from (the soft coral Lobophytum crissum) was found to inhibit the accumulation of the pro-inflammatory proteins iNOS and COX-2 at 10 µM, as well has a cytotoxic effect toward Ca9-22 cancer cells with IC 50 of 1.7 µg mL −1 compared to doxorubicin; appositive control [155].

Bioactive Constituents of Marine Organisms
Polyphenols, polysaccharides, and alkaloids are among the highly active, biologically potent and predominant anticancer compounds isolated from marine organisms.

Polyphenols
Polyphenols (Figure 4; Table 1), are categorized into phenolic acids, flavonoids, tannins, catechin, anthocyanidins, epigallocatechin, lignin, epicatechin, epigallate, and gallic acid [74,75]. Polyphenolic compounds are known for their potential to reduce the mitotic index and decrease the levels of cellular proteins needed for cancer cell proliferation and colony formation. For example, scutellarein 4'-methyl ether exhibited anticancer effects in vitro and in vivo due to its cytotoxic activities. In addition to anticancer effects, the phenols exhibited anti-inflammatory activity, antiviral effects, and inhibited the human platelet aggregation [156][157][158][159][160]. Palmaria palmata, an edible seaweed, is rich in polyphenols with potential antioxidant and anticancer properties [161][162][163]. These polyphenols showed metabolic inhibition of xenobiotic-metabolizing enzymes [164], leading to alteration of the mitotic process in the telophase and thus disruption of cell division [159].

Polysaccharides
The other potent group of compounds that is abundantly present in several marine organisms is polysaccharides ( Figure 5; Table 1), primarily alginates, agar, and carrageenans [31]. The main mechanism of action of polysaccharides cytotoxic effect is the activation of the innate immune system [165][166][167][168], leading to attraction of macrophages and natural killer cells to the target site and production of tumoricidal cytokines [166,[169][170][171]. A sulfated polysaccharide isolated from a marine Pseudomonas spp. (B-1) filtrate induced apoptosis of human leukaemic cells (U937) [172], whereas pancreatic islet carcinoma apoptosis was observed with PI-88, a sulfated oligosaccharide [173]. Glycosaminoglycans are sulfated internally and thus induced murine melanoma cell apoptosis by altering transcription [174]. Fucoidan, a sulfated polysaccharide (sulfated L-fucose) from the brown algal cell wall [175][176][177], was able to modulate atherosclerosis, angiogenesis, and metastasis [178], when tested against human lymphoma HS-Sultan cell line. This effect was explained by the consequent activation of caspase-3 and down regulation of the kinase pathway [179]. Fucoidan can disrupt heparansulfate-growth factor/cytokine complexes and act as a substitute for cell surface heparansulfates by stabilizing the interaction between growth factors and their receptors [31].

Alkaloids
Alkaloids derived of marine origin are divided into four groups, namely, indoles, halogenated indoles phenylethylamines, and other alkaloids ( Figure 6; Table 1), most of which belong to phenylethylamines and indoles [31]. Two derivatives, namely, lophocladine A and lophocladine B, have been isolated from the red alga Lophocladia spp. [180]. Similarly, the presence of alkaloids, e.g., acanthicifolin, brugine and benzoquinones, in Acanthus illicifolius, Bruguiera sexangula, and Kandelia candel has been reported [31]. "Rhizophrine" is a major alkaloid constituent of the leaves of Rhizophora mucronata and R. stylosa, species of mangrove found on coasts and river banks in East Africa and the Indo-Pacific region. The growth inhibitory activity of these compounds has been successfully demonstrated using various cancer cell lines. compound exhibited cytotoxic activities against different carcinomas, i.e., pancreatic, colon, breast and prostate sarcomas, as well as melanoma, representing a promising anticancer therapeutic lead. The exact mechanism of this depsipeptide is unknown, but a recent study showed an interaction between a heat shock protein (HSP90) and client cancer protein in a mammalian cell line. Sansalvamide A binds to the N-middle domain of HSP90 and allosterically inhibits protein complex formation, which is necessary for promotion of tumor growth [187].       . Alkaloids from marine organisms for anticancer. Figure 6. Alkaloids from marine organisms for anticancer.

Peptides
Different types of peptides ( Figure 7; Table 1), have been isolated from a wide variety of marine flora. In the last decade, ca. 2500 new peptides with anti-proliferative activity have been identified [110]. Purified peptides have exhibited cytotoxic effects against various human cell lines, including pancreatic, breast, bladder and lung cell lines [110]. Apratoxin A, a cyclic depsipeptide, exerted cytotoxic effects against human HeLa cervical carcinoma cells via cell cycle inhibition [181]. A similar mechanistic effect was reported for the cyclic depsipeptide coibamide A, isolated from Leptolyngbya sp. [100], and lyngbyabellin B, isolated from Lyngbya majuscule [182]. The linear pentapeptides dolastatin 10 and symplostatin 1 were isolated from Symploca spp. and exhibited cytotoxic effects against human lung and breast cancer cell lines, via both Bcl-2 phosphorylation and caspase-3 protein activation [183,184]. In addition, several different types of active peptides have been isolated from Lyngbya spp. and Nostoc spp., exhibiting anti-proliferative effects via microfilament disruption, secretory pathway inhibition and other intracellular mechanisms [185]. Two novel cyclodepsipeptides, namely, scopularide A and B, isolated from the marine fungus Scopulariopsis brevicaulis [186], significantly inhibited the growth of pancreatic and colon cancer cell lines. Sansalvamide A is a structurally unique cyclic depsipeptide isolated from various marine fungi. This compound exhibited cytotoxic activities against different carcinomas, i.e., pancreatic, colon, breast and prostate sarcomas, as well as melanoma, representing a promising anticancer therapeutic lead. The exact mechanism of this depsipeptide is unknown, but a recent study showed an interaction between a heat shock protein (HSP90) and client cancer protein in a mammalian cell line. Sansalvamide A binds to the N-middle domain of HSP90 and allosterically inhibits protein complex formation, which is necessary for promotion of tumor growth [187].     Phloroglucinol/polyphenol Brown seaweed Colon cancer Induce DNA damage, and cell death at 300 µM [190] Heparin/Heparan/Ppolysaccharides Dictyopteris delicatula, Seaweed Colon cancer Inhibit the proliferation of arterial smooth muscle cells at 80 to 100 µg/mL [78,191] Chondroitin-4-sulphate/Polysaccharides Cucumaria frondosa, sea cucumber Not reported [31,192] Chondroitin-6-sulphate/Polysaccharides Cucumaria frondosa, sea cucumber Not reported [31,192]  Inhibition of gelatinolytic and elastinolytic activities of MMP-2, MMP-9, and MMP-12. The MMP's are often over expressed in tumors and play an important role in the degradation of the (extracellular matrix allowing tumor growth and invasion (metastasis) Drug, phase 3, Investigationa, Interventional [44,193,194] Actinomycin/Peptide Streptomyces parvullus, Streptomyces sp. ZZ338 Actinomyces Childhood cancer, Wilms tumor Inhibition of RNA polymerase Drug, phase 4, Interventional [195][196][197] Aplidine (Plitidepsin, Dehydrodide-mnin B)/Peptide Aplidium albicans, Tunicate, Ascidiacea Pancreatic, stomach, bladder, and prostate cancers Activation of protein kinase C Drug Investigational [198,199] Leukemia Non Hodgkin Lymphoma Induce the apoptotic cascade Drug phase 2, Interventional [44,198,200] Bryostatin-1/Polyketide Bugula neritina, Bryozoa Metastatic solid tumors Inhibition of growth and alteration of differentiation Drug phase 1, 2 Interventional [44,198,201] Citarabine/Alkaloid Sponge Leukemia (acute non-lymphoblastic) Inhibition of DNA synthesis Drug Approved, Investigational [198,202] Cryptophycins/Peptide Nostoc sp., Macroalgae & Dysidea arenaria, Sponge Not reported Tubulin (inhibition of polymerization of microtuble) Phase 1 [44] Dolastatin 10/Peptide Dolabella auricularia, Mollusc Pancreatic cancer Inhibition of microtubules and pro-apoptotic effects Drug phase 2, Interventional [44,198,203] ET-743 (Trabectedin, Ecteinascidin)/Alkaloid

Sarcomas and ovarian cancer
Binding to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery Drug Approved, Investigational [44,198,204] Breast cancer Alkylation ofguanine residues in the DNA minor groove Drug phase 2, Interventional [198,205]

Anticancer Bioactive Antibiotics Derived from Marine Sources
Toxins that originally evolved to kill competing microorganisms can have a variety of physiological effects and could function as novel targets for anticancer drug discovery. In many cases, the targets of these compounds are components of signal transduction cascades that are conserved in many species [213]. Antitumor antibiotics are among the most important cancer chemotherapeutic agents and include members of the anthracycline, actinomycin, and aureolic acid families [19,34,214]. Clinically useful agents from these families (Figure 3, Figure 8; Table 2) include peptolides, dactinomycin, was found to downregulate several glioma metabolic enzymes of glycolysis, glutaminolysis, and lipogenesis, suggesting that targeting multiple tumor metabolic regulators might be a new anti-glioma mechanism of actinomycin D [195]. Anthracyclines are among the most widely used antitumor antibiotics in the clinic and exert antitumor activity mainly by inhibiting topoisomerase II [215][216][217][218][219].
Geldanamycin is a natural fermentation product of the benzoquinone ansamycin and inhibits the heat shock protein HSP90 [220], as well show cytotoxic effect against HeLa cells [221]. Trabectedin and pegylated liposomal doxorubicin have been combined in a randomized phase III study to combat ovarian cancer in vivo and compared to pegylated liposomal doxorubicin alone [222]. The three fused tetrahydroisoquinoline rings contributed to the trabectedin complex mechanism of action. It was claimed to block the substantial DNA and transcription interacting effect as the chemical structure binds to the minor groove of DNA covalently and interact with transcription factors (e.g., SP-1) directly [223]. Another chemotherapeutic agent is bryostatin that modulates the paclitaxel inhibitor of protein kinase C (PKC) [224].
Bryostatin 1, best known anticancer agent isolated from a species of bryozoan Bugula neritina, is able to induce ubiquitination and proteasome degradation of Bcl-2 in lymphoblastic leukemia and permits the growth of progenitor cells from bone marrow [225]. Bryostatins are potent activators of protein kinase C (PKC) and regulate the activation, growth, and differentiation of cells [226]. Some of the other suggested mechanism of actions were illustrated and included cell cycle arrest, inhibition of protein synthesis and antiangiogenic activity corresponding to didemnin B and aplidine. Several pathways are proposed for kahalalide F with specific interactions with cell membrane proteins [16]. Aplidine displays promising anti-proliferative activity (currently in phase I-II trials) via characterized delay of neuromuscular toxicity and promising anti-proliferative activity (Figure 8) [227]. Squalamine, neovastat, and LAF389 were investigated for their antiangiogenic activity where squalamine and neovastat are currently tested in phase II and III studies, respectively [16]. Squalamine and LAF389 inhibited sodium hydrogen antiporter sodium-proton exchangers thus targeting the phospholipid bilayer, and with LAF389 entered phase I trial [228]. On the other hand, neovastat stops the binding of VEGF to its receptor [227,229]. Plinabulin (NPI-2358), a potent and selective vascular disrupting agent (VDA) isolated from a marine fungal extract, is presently undergoing phase II clinical trials because of its activity against multi-drug resistant human tumor cell lines [25,101]. Tasidotin, Synthadotin (ILX-651), derived from a marine bacterium in phase II clinical trials, and Soblidotin (TZT 1027), the bacterial peptide of marine origin in phase III clinical trials, are promising anticancer agents [101].
Salinosporamide A, a novel long-lasting proteasome inhibitor isolated from a marine bacterium Salinispora tropica [230] in phase I clinical trials, has more efficacy against a wider range of hematologic malignancies and many solid tumor models, and less cytotoxicity to normal cells (Figure 8) [101]. Sorbicillactone-A, is an alkaloid produced by Penicillium chrysogenum and associated with marine sponge Ircinia fasciculate, showed antileukemic properties [231]. Depsipeptide (NSC 630176), a bicyclic peptide isolated from Chromobacterium violaceum, decreased the mRNA expression of the c-MYC oncogene, causing cell-cycle arrest at G0-G1 and acting as an inhibitor of a histone deacetylase [232].

Chemical Property Space
The chemical global positioning system of natural products shortly called ChemGPS-NP [233] was used to investigate the chemical property space produced by the marine compounds in this review. The chemical structures were converted to SMILES (simplified molecular-input line-entry system), formats using Chemsketsh [234], and submitted to ChemGPS-NPweb. Eight principle component (PC) values were obtained based on 35 molecular descriptors for each compound. The three major values were plotted on three dimensions graphs as PC1, PC2, and PC3 in order to indicate among others; the size, weight, aromaticity, rigidity, and lipophilicity. Principle component analysis represents the most group of variant properties where every position indicates a compound-specific value in a virtual chemical property space. Figure 9 showed the diversities of studied marine compounds within their respective chemical class as their specific positions did not form a tight cluster in chemical property space. The unique diversity within a single chemical class was noted to be in agreement with Muigg et al 2013 who reported a unique distinction between marine and terrestrial compounds by using chemical property space [235]. For example, marine peptides did spread over and did not form a close cluster forms indicating an interesting diversity within a similar chemical class. The demonstration of marine anticancer compounds as a set of compounds in term of chemical property space can be used to compare different activities using other specific set or databases. Natural marine compounds are no exception from the natural compounds that continue to be a source of unique diversity even by their chemical-property. be in agreement with Muigg et al 2013 who reported a unique distinction between marine and terrestrial compounds by using chemical property space [235]. For example, marine peptides did spread over and did not form a close cluster forms indicating an interesting diversity within a similar chemical class. The demonstration of marine anticancer compounds as a set of compounds in term of chemical property space can be used to compare different activities using other specific set or databases. Natural marine compounds are no exception from the natural compounds that continue to be a source of unique diversity even by their chemical-property.

Conclusions
Several marine natural products have been found to exhibit anticancer activity in vitro on a wide range of tumor cell lines, including renal, lung, prostate, bladder, melanoma, osteosarcoma, mammary, and lymphoid cancer-derived cell lines. In addition, most of the reports on the mechanism of action of marine products in inhibiting tumor growth both in vitro and in vivo suggest it is mediated via apoptosis, necrosis, and lysis of the tumor cells. Marine flora, including microalgae, fungi, seaweeds, mangroves, bacteria, cyanobacteria, actinobacteria, and halophytes were found to have anticancer activity in in vitro and in vivo models are extremely important oceanic resources. In this context, reports on the bioactive molecules combating a wide range of tumor cells such as prostate, bladder, renal, lung, mammary, melanoma, bone, and blood cancers, together with the known knowledge of the mechanism of action mediated via necrosis, apoptosis, and tumor cells lysis were discussed herein to illustrate the medicinally potent chemicals associated with the discovery of new anti-cancer drugs. Polyphenols, polysaccharides, alkaloids, peptides, and terpenoids (cembranoids) are some of the potential marine organism metabolites (Table 2), that exhibited an array of antioxidant, antitumor activities, in addition to immunostimulation. The technological innovation and scientific advances provided a baseline for exploring a great scope of the chemically unique, biologically active, and taxonomically diverse marine floras. Eribulin, trabectedin, cytarabine, and brentuximab vedotin, derived from marine resources, are some of the successful examples that predominantly have proven effective in preventing oxidative damage of DNA, induce apoptosis, control carcinogenesis and activate macrophages in pre-clinical and clinical trials. In this review, we summarized the contributions of marine natural products to treat cancer via modulation of cancer-related factors involving oxidative stress, inflammation, and cell survival. We discussed the pharmaceutical prospects and the chemical space properties that provided crucial insights and valuable knowledge on the largely unexplored marine flora-based anticancer leads. Although more detailed investigations are essential to meet the most common challenges of the clinical utility, it is clear that marine products are promising in providing a platform for improving the anti-cancer therapeutic strategies.

Conclusions
Several marine natural products have been found to exhibit anticancer activity in vitro on a wide range of tumor cell lines, including renal, lung, prostate, bladder, melanoma, osteosarcoma, mammary, and lymphoid cancer-derived cell lines. In addition, most of the reports on the mechanism of action of marine products in inhibiting tumor growth both in vitro and in vivo suggest it is mediated via apoptosis, necrosis, and lysis of the tumor cells. Marine flora, including microalgae, fungi, seaweeds, mangroves, bacteria, cyanobacteria, actinobacteria, and halophytes were found to have anticancer activity in in vitro and in vivo models are extremely important oceanic resources. In this context, reports on the bioactive molecules combating a wide range of tumor cells such as prostate, bladder, renal, lung, mammary, melanoma, bone, and blood cancers, together with the known knowledge of the mechanism of action mediated via necrosis, apoptosis, and tumor cells lysis were discussed herein to illustrate the medicinally potent chemicals associated with the discovery of new anti-cancer drugs. Polyphenols, polysaccharides, alkaloids, peptides, and terpenoids (cembranoids) are some of the potential marine organism metabolites (Table 2), that exhibited an array of antioxidant, antitumor activities, in addition to immunostimulation. The technological innovation and scientific advances provided a baseline for exploring a great scope of the chemically unique, biologically active, and taxonomically diverse marine floras. Eribulin, trabectedin, cytarabine, and brentuximab vedotin, derived from marine resources, are some of the successful examples that predominantly have proven effective in preventing oxidative damage of DNA, induce apoptosis, control carcinogenesis and activate macrophages in pre-clinical and clinical trials. In this review, we summarized the contributions of marine natural products to treat cancer via modulation of cancer-related factors involving oxidative stress, inflammation, and cell survival. We discussed the pharmaceutical prospects and the chemical space properties that provided crucial insights and valuable knowledge on the largely unexplored marine flora-based anticancer leads. Although more detailed investigations are essential to meet the most common challenges of the clinical utility, it is clear that marine products are promising in providing a platform for improving the anti-cancer therapeutic strategies.