Abstract
Natural products (NPs) are useful sources of bioactive compounds and play important roles in the development and discovery of new drugs for diverse human diseases. Most natural products originate from terrestrial species, but diverse marine organisms are another source of new agents for cancer therapy. Natural products derived from marine organisms show diverse pharmacological activities via bioactive secondary metabolites. They regulate biological activities, such as cell proliferation, cell viability, induction of ROS production, ER stress, and apoptosis via modulation of cellular mechanisms in many cancers. Many natural products isolated from marine species require further study to elucidate the efficacy of their biological activity and anticancer effects. In this review, we summarize the biological properties and anticancer effects of diverse natural products extracted from marine organisms and their roles in tumor therapy.
Cancer is one of the leading causes of death and an economic burden worldwide (1). Cancer involves an abnormal proliferation of cells and tissues, and is affected by various risk factors such as age, diet, genetics, and environmental factors (2, 3). It is also caused by the mutation of several cancer-related genes called tumor suppressors and oncogenes (4). Cancer also presents the ability of metastasis and recurrence, which are difficult to treat (5). Although conventional anticancer therapy includes both chemotherapy to induce apoptosis of target cancer cells and surgical therapy to remove tumors, these methods are limited by issues of therapeutic efficacy, safety, and side effects. Thus, it is necessary to develop novel strategies for cancer therapy, and natural products (NPs) are a promising source for novel drug development because they show diverse biological activities and anticancer effects via inhibition of tumor growth by interacting with several signaling pathways (6, 7).
NPs have been a useful source of bioactive compounds and play an important role in the discovery and development of drugs. Most NPs, originated from terrestrial microbes, fungi, and plants, have been discovered to possess many pharmacologically active factors and used to treat several human diseases. Some of these are utilized as clinically valuable drugs for anticancer therapy (8-10). However, marine organisms have recently attracted substantial attention because 70% of the earth is covered by water, representing 95% of biodiversity (11-13). NPs derived from marine organisms have been researched for novel bioactive secondary metabolites due to their diverse pharmacological activities. Marine environments are estimated to harbor more than one million species and one billion different types of marine microbes (14). Today, around 28,000 new compounds isolated from marine species, such as algae, seaweed, sponges, and starfish, have been reported, and this species diversity provides a diverse array of secondary metabolic products (15, 16).
In this review, we present NPs derived from marine environments, and summarize their anticancer activities, such as inhibition of tumor growth, cancer drug resistance, and metastasis. Finally, we discuss NPs as therapeutic agents for safe and efficient cancer treatment.
The Potential Therapeutic Effects of Marine Seaweed- and Algae-derived Natural Products for Cancer Therapy
Marine algae or seaweeds are plants living in marine or brackish water and are autotrophic organisms that contain chlorophyll for oxygenic photosynthesis (17, 18). These plants demonstrate metabolic plasticity and produce several compounds that can be used for drug development (19). Moreover, they can be easily cultivated in bioreactors to obtain high amounts of biomass and provide diverse marine compounds for drug discovery (20).
Inhibition of cancer cell proliferation and survival by Carotenoids derived from marine seaweed and algae. Chlorella species can be used to extract diverse carotenoids, such as lutein, β-carotene, zeaxanthin, and astaxanthin. One study showed that carotenoids extracted from the green algae Chlorella ellipsoidea and C. vulgaris inhibited the proliferation of human colon cancer cells (21). The carotenoid extract of C. ellipsoidea contains violaxanthin and two other xanthophylls, such as antheraxanthin and zeaxanthin, whereas the extract from C. vulgaris mainly contains lutein. The anti-cancer activity of carotenoid extracts was measured using the MTT assay after 24 h exposure to the two compounds. To confirm the apoptotic effects linked to the anti-proliferative effects, the authors also performed an annexin V-fluorescein assay and reported that the two extracts have an apoptotic effect (21). Fucoxanthin is a marine carotenoid that is mainly isolated from brown seaweeds and some microalgae (22, 23). Fucoxanthinol is the deacetylated derivative of fucoxanthin, and is an active form of fucoxanthin (24). One study has shown that fucoxanthin inhibits proliferation in colorectal cancer. The NMR analysis of fucoxanthin following degradation via ozonolysis showed that fucoxanthin divides into two types of cyclohexyl derivatives, and the treatment of degraded fucoxanthin induced antiproliferative effects in colon cancer (25). Another study has confirmed that fucoxanthin and fucoxanthinol have anticancer effects in colorectal cancer (26). The treatment with the two compounds induced an increase in dose dependent drug sensitivity, inhibited cancer cell growth, and induced apoptosis in colorectal cancer (26). Other study has indicated that fucoxanthinol reduaced cell viability of breast cancer cells via modulation of the NF-kappa B pathway. Fucoxanthin and fucoxanthinol decreased cell viability and induced apoptosis. Fucoxanthinol was more potent in inducing apoptosis compared to fucoxanthin (27). These results suggest that fucoxanthinol and fucoxanthin might be potential therapeutic reagents against different types of cancers, including colon and breast cancer.
Therapeutic effects on cancer of Polysaccharides from marine seaweed and algae. Polysaccharides, polymers of monosaccharides, are natural products that are present in a large amount in marine algae and are found intracellularly and in the cell wall. Some of them exert diverse pharmacological and anticancer effects: alginic acid fucoidan from brown algae and carrageenans from red algae (28, 29).
Carrageenans isolated from Kappaphycus alvarezii have been evaluated for their anticancer effects in vitro. The carrageenans suppressed the growth of breast, colon, liver, and osteosarcoma cell lines (30). In addition, carrageenan extracted from red seaweed of the Rhodophyceae family and L. papillosa showed cytotoxicity via inhibition of cell proliferation and induction of apoptosis in human intestinal cancer, breast cancer, and liver cancer cells (31, 32). Consistent with the anticancer activity, the administration of λ-carrageenan stimulated the immune system via up-regulation of proinflammatory IL17A and TNF-α, thereby stimulating the activities of tumor infiltrating M1 macrophages, dendritic cells, and T lymphocytes (33). Furthermore, a recent study has confirmed that the extracted sulfated carrageenan (ESC) consists of ι-carrageenan, which infers a direct damage to DNA by modulating nuclear condensation and DNA fragmentation in breast cancer MDA-MB-231 cells. ESC induced cell death via the apoptotic caspase 8 pathway (34).
The fucoidan isolated from the brown seaweeds Cladosiphon okamuranus and Fucus evanescens consists of fucose and galactose, mannose, and xylose (35). Fucoidan treatment suppressed cell proliferation, apoptosis, and migration via down-regulation of prion in colon cancers (36) and modulation of PI3K-AKT-GSK3b axis in breast cancer (37). In addition, administration of fucoidan for 28 days inhibited tumor growth and angiogenesis via modulation of JAK and STAT3 phosphorylation in animal studies (38). Furthermore, the administration of fucoidan suppressed endothelial mesenchymal transition (EMT) and induced apoptosis in breast cancer cells. Fucoidan inhibited cell migration and invasion via up-regulation of E-cadherin and down-regulation of MMP-9, and promoted apoptosis in breast cancer cells (39). In addition, fucoidan inhibited tumorigenesis and tumor growth via induction of ER stress, which resulted in apoptosis in vitro and in a lung cancer animal model. Fucoidan treatment increased the levels of reactive oxygen species (ROS), and induced an increase in ATF4, CHOP, and ER stress via modulation of Toll-like receptor 4 in lung cancer cells, leading to apoptosis and inhibition of cell proliferation (40).
Some studies confirmed successful applications of the complex of fucoidan and multiple nanoparticles in cancer therapy. One study employed the complex of fucoidan (Fu) and synthetic rutin (Ru) in anticancer therapy. Treatment with the Ru-Fu complex, which has no adverse effects on normal cells, resulted in disruption of cell cycle regulation and apoptosis via nuclear fragmentation, production of ROS, and induction of mitochondrial damage (41). Another study synthesized fucoidan-coated copper sulfide nanoparticles (F-CuS) as a candidate in chemo-photothermal cancer therapy. F-CuS, which acts as a nanocarrier promoting intracellular delivery of fucoidan, was applied as a photothermal agent in cancer cells. The administration of F-CuS induced cellular apoptosis following 808 nm diode laser irradiation in diverse cancer cells in vitro and in vivo (42).
Anticancer activity of extracts of Ulva lactuca. Many studies indicated that a variety of Ulva lactuca extracts possess biological and pharmacological properties, including anticoagulant, antiviral, antioxidant, and anti-inflammatory properties (43-46). Extracts from the sea lettuce U. lactuca may have chemopreventive properties. Treatment of an DMBA-induced breast cancer rat model with ulvan polysaccharides for 10 weeks showed chemopreventive effects via prevention of histological alterations and carcinogenic lesions (47). Furthermore, ulvan polysaccharides have demonstrated cytotoxic effects against hepatocellular carcinoma (HCC), human breast cancer, and HeLa cells (48). In addition, administration of sulfated polysaccharides extracted from U. lactuca showed chemopreventive effects of DENA-induced hepatocarcinogenesis via suppression of cell proliferation and apoptosis induction. Treatment with these products improved hepatic damage and regulated antioxidant mechanisms, indicating their potential as novel chemopreventive and therapeutic agents for HCC (49).
These results indicate that diverse natural products derived from marine algae and seaweed show cytotoxic effects and could be novel agents for cancer therapy (Table I).
The Anticancer Activity of Natural Products Isolated from Sea Cucumber
Sea cucumbers belong to the class Holothuroidea, phylum Echinodermata, and are marine invertebrates that are phylogenetically associated with starfish, sea urchins, and sea lilies (50, 51). Sea cucumbers contain many nutrients and natural products, such as vitamins, calcium, triterpene glycosides, fucoidan, and sphingoid bases (51-55). Natural compounds extracted from sea cucumber have been reported to exhibit strong cytotoxic activity in human cancer cell lines (Table II).
The anticancer activity of Frondoside A and Cucumarioside A2–2. Frondoside A, isolated from Cucumaria frondosa exhibited enhanced apoptosis through increased expression of p53, p21 and caspase 3/7, 9 genes when used in the treatment of human breast and pancreatic cancer (56, 57). Frondoside A has been shown to enhance the therapeutic effects of the anti-cancer drugs oxaliplatin and 5-fluorouracil in colon cancer cells. Use of frondoside A enabled reduction in dosage of oxaliplatin or 5-fluorouracil. The combination treatment inhibited cell colony growth via inactivation of ERK 1/2 phosphorylation and induction of apoptosis (58). Another study has found that frondoside A extracted from sea cucumber Cucumaria okhotensis shows high anticancer activity in human prostate cancer, while normal cells were less affected. The mode of action included inhibition of cell proliferation and colony formation via induction of cell-cycle arrest and apoptosis and reduction of pro-survival autophagy in drug-resistant prostate cancer cells. Frondoside A has been shown to inhibit metastasis and bring about immunomodulatory effects by increasing in lymphocyte concentration (59). It also exhibited high cytotoxicity in urothelial carcinoma cells through induction of apoptosis by modulation of diverse apoptosis-related proteins, such as caspase 3, 8, and 9, PARP, and through DNA fragmentation. It inhibited pro-survival autophagy and exhibited synergistic effects with cisplatin and gemcitabine (60). In addition, cucumarioside A2–2, isolated from the sea cucumber, Cucumaria japonica has been shown to exhibit cytotoxic effects in ehrlich carcinoma cells and to inhibit cell viability, cell proliferation, and DNA biosynthesis and to induce apoptosis via the caspase dependent pathway (61, 62).
The inhibitory effects of Echinoside A, Ds-echinoside A, Frondanol A5 on cancer cell proliferation. Echinoside A and Ds-echinoside A are triterpenoid glycosides, isolated from Pearsonothuria graeffei, and cause cell cycle arrest in hepatocellular carcinoma cells (63). Ds-echinoside A has been shown to inhibit the mouse double minute 2 homolog (MDM2) and C-X-C chemokine receptor type 4 (CXCR4), thereby enhancing apoptosis via modulation of p53, and to reduce cell proliferation and growth via protein tyrosine kinase 2 regulation (64). In addition, Ds-echinoside A has also been shown to inhibit proliferation of human hepatocellular carcinoma cells, and to suppress cell adhesion, migration, invasion, and angiogenesis via regulation of MMP9, TIMP-1, and VEGF expression (65). Frondanol A5 is an isopropyl alcohol/water extract derived from Cucumaria frondosa and its application has been shown to inhibit cell growth via modulation of p21WAF1/CIP and Cdc25c, thus inducing apoptosis of human colon cancer cells (66), as well as innate immune responses and inhibiting the growth of intestinal tumors in mice model (67). Frondanol A5P, a polar extract isolated from Cucumaria frondosa. has been shown to suppress cell proliferation and to induce cell cycle arrest via decrease in cell cycle-related proteins, such as cyclin A and cyclin B. It up-regulated stress-activated protein kinase, janus kinase, and p38 mitogen-activated protein kinase, resulting in enhanced apoptosis in pancreatic cancer cells (68).
The inhibitory effects of Philinopsides on cancer cell proliferation, migration, and angiogenesis. Philinopside A is isolated from the sea cucumber Pentacta quadrangularis and has been shown to inhibit cell proliferation, migration, and tube formation in human microvascular endothelial cells and animal models. Philinopside A also reduced tumor volume via induction of apoptosis and inhibited angiogenesis-related receptor tyrosine kinases, such as vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor (FGF) receptor-1, platelet-derived growth factor (PDGF) receptor-beta and epithelial growth factor (EGF) receptor (69). Philinopside E has been shown to interact with the extracellular domain of kinase domain containing receptor KDR and block the interaction between KDR and VEGF, thus inhibiting further downstream signalling pathway. These results indicated that philinopside E could inhibit cancer angiogenesis (70).
The anticancer effects of marine seaweed- and algae-derived compounds.
The Potential Anticancer Activity of Starfish and Sea Urchin Extracted NPs
The potential usage of NPs isolated from Starfish as anticancer reagent. Starfish contain diverse polar steroid, mono- and biglycosides of olyhydroxysteroids, as well as oligoglycosides. Starfish-derived steroid glycosides exert cytotoxic, neuritogenic, hemolytic, antiviral, antibacterial, antitumor, and cancer-preventive effects (71-73). One study has reported that two asterosaponins and six glycosylated polyhydroxylsteroids were isolated from the starfish Culcita novaeguineae. Among extracted products, four glycosylated polyhydroxylsteroids has shown slight cytotoxic effects against human hepatoma, epidermoid carcinoma, prostate cancer, breast cancer, and melanoma (74). Another study has confirmed the cytotoxic activity of six new polyhydroxylsteroidal glycosides and two previously known glycosides, which were isolated from starfish Anthenea sibogae. The mixture of two known glycosides has been shown to exert slightly inhibitory effects on cell proliferation in human breast cancer and to decrease colony size in vitro (75). Plancitoxin I derived from the venom of the crown-of-thorns starfish Acanthaster planci, has been reported to exert strong cytotoxic effects in human malignant melanoma cells (76, 77). Plancitoxin I decreased cell viability via induction of ROS, nitric oxide production, and reduction of mitochondrial membrane potential, inducing apoptosis (77). Another study has confirmed that pancitoxin I reduced antioxidant enzymes such as SOD and catalase, and induced mitochondrial dysfunction. Moreover, pancitoxin I increased Ca(2+) concentrations and induced ER stress, subsequently elevating apoptosis via an increase in apoptosis related proteins such as caspase 3, 8, and 9 (76). In addition, cyclic steroid glycosides isolated from starfish Echinaster luzonicus, such as luzonicoside A and D, have been shown to have anticancer activity in human melanoma. Luzonicoside A and D inhibited cell proliferation, colony formation, and migration via regulation of cell cycle and apoptosis induction (78).
Mode of action of anticancer activity of compounds extracted from marine sea cucumber.
The potential anticancer activity of NPs extracted from sea urchin. Sea urchins belong to echinoderms and are part of the same group of invertebrates, such as starfish, brittle stars, and sponges (79). Extracts derived from sea urchins have been shown to exhibit diverse biological properties such as anti-tumor activity and immunomodulation. The steroidal components from sea urchin Diadema savignyi Michelin were isolated and their cytotoxic activity was confirmed in human cancer cell lines, including human promyelocytic leukemia, prostate cancer, and embryonic lung cells. The steroidal components inhibited cell proliferation and viability and induced apoptosis via modulation of apoptosis-related protein expression, inactivation of MAPK pathway, and decrease in c-Myc expression (80). Ovothiols, extracted from eggs of the sea urchin Paracentrotus lividus, have been shown to play an important role in the protection of cells via modulation of the cellular redox balance and recycling of oxidized glutathione. In addition, one study has suggested that ovothiols may decrease cell proliferation via activation of autophagy in human liver carcinoma cells, without affecting normal lung cells (81). In another study, treatment with strongylocentrotus nudus egg polysaccharide (SEP), isolated from the eggs of sea urchins, was found to exhibit immunomodulatory activity via enhancement of splenocyte proliferation and stimulation of B and T cell proliferation. However, SEP treatment did not directly affect cancer cells, and the anticancer effects of SEP were associated with modulation of immune system functions (82). During investigation of the anti-cancer activity of four glycolipids extracted from the intestine of the sea urchin Strongylocentrotus intermedius, only one glycolipid (sulphonoquinovosyl-lysoglyceride) was found to exhibit significant cytotoxic effect in human lung adenocarcinoma. The application of the extract inhibited tumor growth and induced necrosis in mouse model (83). These results indicate that starfish and sea urchin derived extracts need to be further studied to establish their anticancer activity against different types of cancer (Table III).
The Therapeutic Effects of NPs Derived from Marine Sponges and Tunicate and Clinical Trials of Cancer Therapy
Marine sponges belong to the phylum Porifera and are the richest source of natural marine compounds (84). Diverse molecules derived from marine sponges, such as nucleosides, sterols, alkaloids, and amino acid derivatives have been discovered and at least 60 of them have be shown to have potential chemopreventive and anticancer activities (85, 86). These properties of marine sponge-derived natural products are affected by multiple cellular and molecular processes, such as cell cycle, apoptosis, and inflammation (Table IV).
Mode of action of anticancer activity of marine starfish and sea urchin derived compounds.
The preclinical and clinical trials of cancer therapy using Renieramycin M and its derivatives. Renieramycin M (RM) isolated from the blue sponge Xestospongia sp. is a tetrahydroisoquinoline, and is the first marine anticancer drug approved by the European Union and the Food and Drug Administration (FDA) for the treatment of advanced soft tissue sarcomas (87). These products have shown cytotoxic activity in human colon, lung, prostate, brain, and breast cancer cells (88-90). Treatment with RM isolated from the sponge Xestospongia species showed cytotoxic effects against lung cancer stem cells (CSC), reduced colony and spheroid formation, as well as CSC markers, such as CD133, CD44, and ALDH1A (90). Moreover, RM treatment has shown a therapeutic effect by resensitizing anoikis in anoikis-resistant lung cancer cells. Anoikis resistance is induced by modulating the up-regulation of survival and anti-apoptotic proteins, such as phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated ATP-dependent tyrosine kinase (p-AKT), and B-cell lymphoma-2 (BCL2). RM significantly suppressed cell viability and the expression of p-ERK, p-AKT, and BCL2 (91). Further, hydroquinone 5-O-cinnamoyl ester (CIN-RM), a newly-synthesized derivative of RM, has been shown to be more cytotoxic against non-small cell lung cancer cells compared to RM. CIN-RM treatment induced apoptosis by increasing apoptosis inducing factor and by activating of caspase 3 and 9 through a p53-dependent mechanism (92). Another study has reported the formation of bishydroquinone renieramycin M (HQ-RM) by modifying the quinone ring of RM. HQ-RM treatment has been shown to have stronger cytotoxic effects compared to RM. HQ-RM reduced the viability of lung cancer cells and induced apoptosis by increasing pro-apoptotic proteins, such as BAX, and decreasing the anti-apoptotic proteins BCL2 and MCL via mitochondrial apoptosis (93).
The clinical trials and therapeutic effects of Cytarabine and Zalypsis. Werner Bergmann's group isolated arabino nucleoside spongothymidine and spongouridine from the Caribbean sponge Cryptotethya crypta (94). Cytarabine (Ara-C) is the synthetic analog of natural arabino nucleosides and cytosine arabinose and has been used as an anti-metabolite drug in cancer therapy. An anti-metabolite drug is similar to the structure of a natural metabolite and blocks normal cell metabolism (95). Cytarabine has been shown to interrupt DNA synthesis (96, 97) and approved for clinical use in 1969 and is still widely used in the treatment of various types of leukemia. Cytarabine is commonly used for the treatment of acute leukemia therapy. Treatment with cytarabine has been shown to induce apoptosis via phosphatidylserine exposure, caspase activation, and inhibition of RNA synthesis in B-chronic lymphocytic leukemia (98). In acute myeloid leukemia therapy, cytarabine is also used as one of the important drugs. Treatment with cytarabine has been shown to inhibit cell growth and to induce apoptosis via regulation of autophagy pathway in human leukemia cell lines (99).
Zalypsis® is a newly synthetic dimeric isoquinoline alkaloid structurally related to renieramycin J isolated from the species of marine sponge, Netropsia. The molecular pharmacology of this compoud has been reported to be similar to that of ET743, but it does not activate the DNA damage checkpoint response (100). Treatment of Zalypsis® has been shown to increase double strand breaks (DSBs), inhibit transcription and cell cycle, and then increase apoptosis in human cancer cells (100). In addition, Zalypsis® has shown potent anti-leukemic activity and synergetic effect with conventional antileukemic drugs, including cytarabine, fludarabine and daunorubicin. Treatment of Zalypsis® has been shown to induce apoptosis via modulation of DSBs related pathway in leukemia cells and patients samples (101). Zalypsis® has been tested three Phase I/II clinical trials. One clinical trial, aimed at developing novel treatments for advanced malignant solid tumors or lymphoma, was terminated (NCT00359294). This Phase I study investigated the safety, tolerability, dose limiting toxicity and recommended dose of Zalypsis®. Another clinical trial, aimed at developing novel treatments for advanced and/or metastatic endometrial or cervical cancer, was also terminated (NCT00900562). This Phase II study evaluated the antitumor activity, safety profile, pharmacokinetic profile and pharmacogenomic profile of Zalypsis®. The third clinical trial, aimed at developing novel treatments for unresectable locally advanced and/or metastatic Ewing family of tumors, has been completed (NCT01222767). This Phase II study evaluated the antitumor activity of Zalypsis®.
The anticancer effects of compounds extracted from marine sponges.
The clinical trials and therpeutic effects Eribulin mesylate and E7974 on cancer. Eribulin mesylate is a synthetic product of halichondrin B isolated from the Poriferan Halichondria okadai, and it is the only commercial anticancer drug derived from marine sponges available for the treatment of breast cancer (102). Eribulin mesylate has been shown to induce microtubule destabilization, which leads to irreversible mitotic arrest via the formation of abnormal mitotic spindles (103). In addition, eribulin mesylate has been shown to reverse the epithelial-to-mesenchymal transition in cancer (104). Eribulin mesylate has shown anticancer activity against diverse cancers, including breast, ovarian, colon, and pancreatic cancer (105-107). In a clinical study, administration of eribulin mesylate has shown anticancer effects with manageable side effects including neutropenia and fatigue (108). E7974 is a synthetic product of hemiasterlin, which is extracted from the marine sponge Hemiasterella minor (109, 110). E7974 has been found to suppress microtubule polymerization and to alter the mitotic spindle, thus inducing cell cycle arrest and apoptosis. E7974 has shown an inhibitory effect on cell proliferation in several cancer cell lines (111). Three Phase I clinical trials with E7974 have been completed (NCT00165802, NCT00130169, NCT00121732). These clinical trials have been performed in patients with refractory solid tumors and therapeutic effects of E7974 were observed. Administration of E7974 has shown reversible and manageable side-effects.
The clinical trials and therapeutic effects of NPs isolated from Tunicate as anticancer agents. Trabectedin is a synthetic marine-derived alkylating agent extracted from the Caribbean tunicate, Ecteinascidia turbinata (112). Trabectedin has succeeded in the treatment of soft tissue sarcomas in preliminary clinical trials and approved in the EU for treatment of advanced soft tissue sarcoma and recurrent platinum-sensitive ovarian cancer. Currently, large, randomized phase III clinical trials proceed in many countries. One clinical trial, aimed at developing combination therapy of gemcitabine and trabectedin for L-sarcomas, has been completed (NCT01426633) (113). This Phase I study evaluated the antitumor activity of combination therapy and provided negative results for the treatment of advanced and/or metastatic leiomyosarcoma or liposarcoma. Another clinical trial, aimed at developing combination therapy with doxorubicin and trabectedin for soft tissue sarcoma, has also been completed (NCT00102609) (114). This Phase I study evaluated the safety and toleration, and antitumor activity of the combination therapy, and the results showed that the combination therapy is safe and well tolerated, and exerts anticancer activity. A phase II clinical trial, aimed at confirming the therapeutic effect of trabectedin for retroperitoneal leiomyosarcoma and well differentiated/dedifferentiated liposarcoma, has also been completed (NCT02247544). This Phase II study assessed the activity of trabectedin as a secondary treatment. This clinical study is completed, but the results are not yet published. A phase III trial clinical, aimed at confirming the therapeutic efficacy and safety of trabectedin for advanced relapsed ovarian cancer, has also been completed (NCT00113607) (115). This Phase III study assessed the effect of conbination of trabectedin and pegylated liposomal doxorubicin. The results showed that the combination treatment has little or no decrement in patient-reported functional status and symptoms, and led to manageable and non-cumulative toxicity with fewer adverse events and a significant improvement in progression-free survival and overall response rate.
A schema illustrating the overview of anticancer activity of marine-derived compounds in diverse cancers.
Conclusion
Marine organisms have provided a promising source of useful natural products, molecules, and drugs for therapeutic use. The results of numerous studies, summarized in this review, suggest that natural products derived from marine organisms are novel candidate therapeutic agents for the prevention and treatment of cancer. Marine extracts possess cytotoxic activity against many cancers, including breast and colon cancer, via inhibition of cell proliferation and cell viability, induction of ROS production, mitochondrial dysfunction, ER stress, and apoptosis. In addition, many marine organisms are promising sources of anticancer compounds and have shown beneficial effects upon combination with traditional anticancer drugs (Figure 1). However, it is still necessary to further study the natural products isolated from a large number of marine species.
The therapeutic and commercial usage of promising marine natural product is dependent on the results of preclinical and clinical studies. Many studies have reported that marine isolated natural products and its derivatives show potential therapeutic efficacy for cancer therapy. Cytarabine and Zalypsis have been studied in many preclinical and clinical trials and are used to treat various leukemias and cancer. Also, eribulin mesylate and E7974 have proceeded to clinical trials to investigate their therapeutic effects on several cancers. Currently, many marine derived compounds have been reported to be in the process of development into drugs. Therefore, it is necessary to study the anticancer activities of marine extracted natural products in order to develop novel anticancer drugs for diverse cancers.
Acknowledgements
This work was supported by a National Research Foundation grant funded by the Korean government (Grant number: NRF-2016R1D1A3B01007727 and NRF-2017M3A9B4032528).
Footnotes
Authors' Contributions
Chul Won Yun: Data collection and drafting of manuscript; Hyung Joo Kim: drafting of manuscript; Sang Hun Lee: organizing the structure of the manuscript, drafting and editing of the manuscript, procurement of funding.
This article is freely accessible online.
Conflicts of Interest
The Authors have no conflicts of interest to declare with regards to this study.
- Received August 1, 2019.
- Revision received August 20, 2019.
- Accepted August 21, 2019.
- Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
References
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- Abstract
- The Potential Therapeutic Effects of Marine Seaweed- and Algae-derived Natural Products for Cancer Therapy
- The Anticancer Activity of Natural Products Isolated from Sea Cucumber
- The Potential Anticancer Activity of Starfish and Sea Urchin Extracted NPs
- The Therapeutic Effects of NPs Derived from Marine Sponges and Tunicate and Clinical Trials of Cancer Therapy
- Conclusion
- Acknowledgements
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