Invest New Drugs.
2017 ; 35 ( 6 ) : 820–826 . department of the interior :10.1007/s10637-017-0505-5
PMCID:
PMC5694523
PMID : 28920157
Mechanisms of cancer cell killing by sea cucumber-derived compounds
1 and 2 and
Teresa Liliana Wargasetia
1Faculty of Medicine, Universitas Kristen Maranatha ( Maranatha Christian University ), Jl. Prof. Drg. Suria Sumantri MPH No. 65, Bandung, 40164 indonesia Find articles by Teresa Liliana Wargasetia
Widodo
2Biology Department, Faculty of Mathematics and Natural Sciences, The University of Brawijaya, Jl. Veteran, Malang, 65145 indonesia Find articles by Widodo Author information Article notes Copyright and License information Disclaimer 1Faculty of Medicine, Universitas Kristen Maranatha ( Maranatha Christian University ), Jl. Prof. Drg. Suria Sumantri MPH No. 65, Bandung, 40164 indonesia 2Biology Department, Faculty of Mathematics and Natural Sciences, The University of Brawijaya, Jl. Veteran, Malang, 65145 indonesia Teresa Liliana Wargasetia , electronic mail :[email protected] phone : +62 22 2012186 ,Corresponding author. Corresponding author .Copyright © The Author(s) 2017 Open Access This article is distributed under the terms of the creative Commons Attribution 4.0 International License ( hypertext transfer protocol : //creativecommons.org/licenses/by/4.0/ ), which permits unrestricted manipulation, distribution, and reproduction in any medium, provided you give appropriate credit rating to the original author ( second ) and the reservoir, provide a link to the creative Commons license, and indicate if changes were made .
Summary
The aim of cancer therapy is to specifically eradicate tumor cells while causing minimal wrong to normal tissues and minimal side-effects. Because of this, the manipulation of natural substances with low toxicity is a good option. Sea cucumbers are one of many potential nautical animals that contain valuable nutrients and medicative properties. The medicative value of ocean cucumbers is attributed to the presence of bioactive agents with promising biological and pharmacological properties that include cytotoxic activity, induction of apoptosis, cell hertz collar, prohibition of tumor emergence, anti-metastatic and anti-angiogenic properties, and prohibition of drug resistance. This review discusses the mechanism of cancer cell end induced by sea cucumber-derived compounds with esteem to exploring the electric potential use of these nautical natural products for cancer therapy. Keywords:
Sea cucumbers, Triterpene glycosides, Anti-cancer, apoptosis, metastasis
Introduction
cancer is the moment lead campaign of death cosmopolitan, and the incidence is on the rise in both grow and develop countries [ 1 ]. The rapid exploitation of underground to cancer drugs, and the gamey toxicity and side-effects of some cancer chemotherapy drugs have caused an increase in the demand for new anti-cancer drugs, peculiarly from natural products [ 2 ]. For more than 40 years, natural products have played a outstanding function in cancer treatment, either in their native or modified forms [ 3 ]. A 15-year survey conducted by the National Cancer Institute of the United States discovered that 4 % of marine species tested ( largely animals ) contained anti-tumour properties [ 4 ]. recently, the search for anticancer agents derived from marine natural products has increased [ 5 ].
historically, the marine environment has proven a rich source of potent natural anti-cancer metabolites. Spongothymidine was the first marine-derived substance, found in 1945, to be developed for the treatment of acute accent myeloid leukemia and lymphoma. Currently, four other marine cytotoxic compounds, including eribulin, trabectedin, cytarabine, and vedotin, have been established as conventional clinical medicines [ 6 ]. Sea cucumbers ( or holothurians ), belonging to the class Holothuroidea, phylum Echinodermata, are marine invertebrates that are found in benthic areas and deep seas. They have a coriaceous skin and gelatinous soundbox, shaped like soft-bodied cucumbers. Sea cucumbers, besides called trepang, bêche-de-mer, gamat, balate, or haishen ( marine ginseng ), have long been utilized in food and Asiatic folk music [ 7, 8 ]. They contain valuable nutrients such as vitamin A, B1, B2, B3, magnesium, calcium, zinc, cast-iron [ 8 ], triterpene glycosides ( saponins, sti-choposides, frondoside A, cucumariosides, Ds-echinoside A ) [ 8 – 14 ], fucoidan [ 15, 16 ], triterpenoid aglycones ( philinopgenin ) [ 17 ], non-glycosaminoglycan sulfated glycans [ 18 ], sulfated polysaccharides [ 19 ], non-sulphated triterpene glycosides ( variegatusides ) [ 20 ], sphingoid bases [ 21 ], and chondroitin sulfates [ 22 ]. many researchers have reported anti-cancer activity of substances derived from sea cucumbers and have published the molecular mechanism of these agents in cancer cells. In this review, we will discuss the anti-cancer activities and molecular mechanisms of bioactive metabolites derived from ocean cucumbers. This revue is expected to provide modern insight into the possible therapeutic natural process of bioactive compounds derived from ocean cucumbers for the treatment of many different types of cancers .
Cytotoxicity activity
Anti-cancer agents parade cytotoxic activity through blocking or preventing growth or mitosis of cancer cells [ 5 ]. The cytotoxic activeness of sea cucumber compounds in human tumor cell lines are well established. For exemplar, holothurin A3 and A4, produced by the Holothuria scabra species, were discovered to be highly cytotoxic in human epidermoid carcinoma ( KB ) and homo hepatocellular carcinoma ( Hep-G2 ) cell lines [ 23 ]. similarly, philinopside E, a newly discovered sulfated triterpene glycoside derived from Pentacta quadrangularis, showed potent cytotoxicity ( IC50 = 0.75–3.50 μg/mL ) in respective tumor cell lines ( human leukemia cells-HL60, mouse lymphocytic leukemia cells-P388, human non-small lung carcinoma cells-A549, gastric carcinoma cells-MKN28, lung adenocarcinoma cells-SPC-A4, gastric carcinoma cells-SGC7901, human epithelial carcinoma cells-A431, human hepatoma cells-BEL7402, homo ovarian carcinoma-HO8901, and human fetal lung fibroblasts-W138 ) [ 24 ]. Sea cucumber compounds that induce cytotoxic effects in a across-the-board compass of cancer cell lines are presented in Table. table shows that triterpenoid glycosides ( saponins ) are the most abundant type of metabolites derived from ocean cucumbers .
Table 1
| Compound | Species | Human cell line tested | Ref. |
|---|---|---|---|
| Aqueous extract | Holothuria arenicola | CT26 | [25] |
| Arguside A | Bohadschia argus | HCT-116 | [26] |
| Arguside B, C, D, E | A549, HCT-116, HepG2, MCF-7 | [27] [28] | |
| Bivittoside | Holothuria polii | HCT116, MCF7 | [29] |
| Colochiroside A | Colochirus anceps | p388, HL60, A-549, SpC-A4, MKN28 | [30] |
| Crude saponin | Holothuria leucospilota | B16F10 | [31] |
| Cucumarioside A2–2 | Cucumaria japonica | Ehrlich ascite carcinoma, HL-60 | [32] [33] |
| Ds-echinoside A | Peasonothuria graeffei | Hep G2 | [14] [34] |
| Echinoside A | Holothuria nobilis | 26 human cell line | [35] |
| Echinoside A | Peasonothuria graeffei | Hep G2 | [34] |
| Frondanol A5 | Cucumaria frondosa | HCT116, AsPC-1, S2013 | [36] [37] |
| Frondoside A and B | MDA-MB-23, A549,MDA-MB-435, MCF-7, HepG2, HL-60, AsPC-1, AsPC-1, S2013, AsPC-1 | [38] [13] [39] [33] [40] [41] | |
| Frondoside A | Cucumaria okhotensis | THP-1, HeLa, RT112, RT4, HT-1197 | [42] [43] |
| Griseaside A | Holothuria grisea | HL-60, BEL-7402, Molt-4, A549 | [44] |
| Hillasides A and B | Holothuria hilla Lesson | A549, MCF7, IA9, CAKI-1, PC-3, KB | [45] |
| Holothurin A3 and A4 | Holothuria scabra | KB, Hep-G2 | [23] |
| Okhotoside B1,B2,B3 | Cucumaria okhotensis | HeLa cervical cancer | [42] |
| Organic/water extract | Stichopus chloronotus | C33A, A549 | [46] |
| Pentactasides I,II, III, Philinopsides A and B | Pentacta quadrangularis | P-388, A-549, MCF-7, MKN-28, HCT-116, U87MG | [47] |
| Philinopsides E | P388, HL60, A549, SPC-A4, MKN28 | [24] | |
| Sphingoid bases | Stichopus variegates | Caco-2, DLD-1, WiDr | [21] |
| Sphingoid bases | Sea cucumber | HepG2 | [48] |
| Stichoposide D | Thelenota anax | HL-60, K562 | [49] |
| Violaceusides A and B | Pseudocolochirus violaceus | HL-60, BEL-7402 | [50] |
| Stichorrenoside C and B | Stichopus horrens | Hep-G2, KB, LNCaP, MCF7, SK-Mel2 | [51] |
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Induction of apoptosis
apoptosis is the march of program cell death that is characterized by cell shrinkage and morphologic changes including membrane blebbing, chromosomal DNA fragmentation, nuclear annihilation, loss of organelle position in the cytoplasm, and translocation of phosphatidylserine to the out membrane booklet [ 52, 53 ]. Apoptosis results in the removal of unwanted, old, or injured cells including cancer cells and is, consequently, an important mechanism for tumor suppression [ 53, 54 ]. For this rationality, reductions in apoptosis or apoptotic resistor shimmer important roles in carcinogenesis. In general, the mechanisms by which reductions in apoptosis or resistor to apoptosis occurs are due to 1 ) disruptions in the balance between pro-apoptotic and anti-apoptotic proteins, 2 ) deactivation or loss of caspase bodily process, or 3 ) impaired death sense organ signaling [ 55 ]. initiation of apoptosis is one the most outstanding markers of cytotoxic anticancer agents. It has been shown that some natural compounds isolated from sea cucumbers induce apoptotic pathways through several different mechanisms to inhibit cancer progress. Marzouqi et aluminum. ( 2011 ) found that frondoside A, a saponin isolated from Cucumaria frondosa, increased the sub-G1 ( apoptotic ) cell fraction through increases in p53, and subsequent initiation of the caspase 9 and 3/7 cell death pathways in breast cancer cells [ 38 ]. Frondoside A besides demonstrated potent anti-tumor activeness through evocation of apoptosis, increase formula of p21, and through increased natural process of caspase 3, 7, and 9 in AsPC-1 and S2013 human pancreatic cancer cell lines [ 39 ]. discussion with Frondanol A5, an isopropyl alcohol/water extract of Cucumaria frondosa, induce apoptosis that was associated with H2AX phosphorylation and led to cleavage of caspase-2 in HCT116 colon cancer cell lines. This study demonstrated the chemopreventive effects of Frondanol A5 against the development of colon cancer [ 36 ]. Another study found that a polar fraction of Frondanol A5 potently induced apoptosis in pancreatic cancer cells, AsPC and S2013 [ 37 ]. Philinopside A and E, glycosides isolated from Pentacta quadrangularis , reportedly induced apoptosis in sneak Sarcoma-180 tumors and tumor-associated endothelial cells [ 56, 57 ]. Stichoposide C, isolated from Thelenota anax, was found to induce apoptosis as demonstrated by mitochondrial injury and induction of signaling nerve pathway break of cancer cells in human leukemia and mouse colorectal cancer cells. In this study, Stichoposide C induced apoptosis in a dose-dependent manner through energizing of Fas, caspase-3 and caspase-8, cleavage of Bid, and mitochondrial damage in cancer cells [ 58 ]. Increased levels of reactive oxygen species ( ROS ) induce cells to undergo apoptosis. Administration of methanolic extracts of Holothuria parva led to increased ROS production, mitochondrial swelling, mitochondrial membrane electric potential ( MMP ), and cytochrome C spill in the mitochondrion in an animal mannequin of hepatocellular carcinoma [ 59 ]. initiation of apoptosis and other mechanisms related to anticancer activity induced by metabolites isolated from ocean cucumbers are summarized in Table .
Table 2
| Compound | Cell effect | Source | Ref. |
|---|---|---|---|
| 24-dehydroechino-side A (DHEA) | Inhibit HepG2 cell migration and invasion, decrease MMP-9, increase TIMP-1, VEGF, & NF-κB (by HA1) | Pearsonothuria graeffei | [60] |
| Aqueous extract | Attenuate tumor size, induce intrinsic apoptosis | Holothuria arenicola | [25] |
| Colochiroside A | Exhibit antitumor activity | Colochirus anceps | [30] |
| Crude saponin | Induce apoptosis: upregulation of caspase-3 & 9 | Holothuria leucospilota | [31] |
| Cucumarioside A2–2 | Inhibit growth of tumor cells multidrug resistance, induce apoptosis in a caspase-dependent way | Cucumaria japonica | [32] [33] [61] |
| Ds-echinoside A | Suppress migration, MMP-9, and VEGF; cell cycle arrest (increase p16, p21, and c-myc; decreased cyclin D1), induce apoptosis by decreased Bcl-2, NF-κB, and increase TIMP-1 & caspase-3 | Peasonothuria graeffei | [14] [34] |
| Echinoside A | Induce apoptosis (decrease Bcl-2, and enhance caspase-3), cell cycle arrest (increase p16, p21, and c-myc, decrease cyclin D1) | Holothuria nobilis Peasonothuria graeffei | [34] [35] |
| Frondanol A5 | Increase p21, GiLT expression, macrophage phagocytosis & apoptosis | Cucumaria frondosa | [36] [62] |
| Polar extract of frondanol A5 | Decrease expression of cyclin A, cyclin B, and cdc25c, and increased expression of p21 | Cucumaria frondosa | [36] |
| Frondoside A | Anti-metastatic (by antagonize EP4, TPA-induced MMP-9 activation via NF-κB and AP-1 signaling), inhibit tumor cells multidrug resistance, induce apoptosis (via caspase-3, −8, and −9, PARP, Bax, p21, p53), inhibit pro-survival autophagy | Cucumaria frondosa | [13] [38] [39] [43] [40] [41] [61] [63] [64] |
| Glycosides 1 & 2 | Activate NF-kappaB and degrade Ikappa B alpha in A549 tumor cell line (cytotoxic activity) | Psolus patagonicus | [65] |
| Intercedensides A, B, and C | Exhibit anti-neoplastic activity | Mensamaria intercedens | [66] |
| Methanolic extracts | Increase ROS formation, and cytochrome c release | Holothuria parva | [59] |
| Philinopside A | Inhibit proliferation, migration, angiogenesis, RTKs in several cell lines | Pentacta quadrangularius | [56] |
| Philinopside E | Induce cell apoptosis, inhibit tumor growth, anti-angiogenic via inhibition of KDR-αvβ3 integrin | Pentacta quadrangularius | [57] [67] |
| Sea cucumber fraction | Exhibit radical scavenging property, inhibit angiogenesis, and vascularization | Sea cucumber | [68] [69] |
| Sphingoid bases | Induce apoptosis through caspase-3 activity, upregulation of DR5, Bax, GADD45, and PPARγ, and downregulation of p-AKT | Stichopus variegates | [21] [48] |
| Stichoposide C | Induce apoptosis of leukemia and colorectal cancer cells | Thelenota anax | [58] |
| Stichoposide D | Induce cell apoptosis | Thelenota anax | [49] |
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Cell cycle arrest
mammal cells progress through respective cellular telephone motorbike phases ( G1, S, G2, and metaphase ) during cellular division. Cell bicycle checkpoints, luminary features of cell cycle progress, provide all-important surveillance to prevent cells from entering the adjacent phase before the previous phase has been completed [ 70 ]. thus, halting the cell bicycle can lead to prevention of cancer cell growth and division and is one of the major strategies for cancer therapy [ 71 ]. Cucumarioside A2–2 demonstrated anticancer effects through its ability to cause the halt of the cell cycle during the DNA deduction ( S ) phase and was shown to induce program death in Ehrlich carcinoma mouse tumor cells [ 32 ]. In another study, Echinoside A and Ds-echinoside A, triterpenoid glycosides isolated from Peasonothuria graeffei, caused the apprehension of the cellular telephone cycle during the G0/G1 phases in hepatocellular liver carcinoma cells ( HepG2 ). A reverse transcriptase-polymerase chain reaction assay showed that both triterpenoid glycosides increased expression of cell-cycle-related genes, including p16, p21, and c-myc, and decrease expression of cyclin D1 [ 34 ]. Frondanol A5, an isopropyl alcohol/water extract of Cucumaria frondosa, inhibit increase during the S and G2/M phases and led to increased levels of p21WAF1/CIP and decrease levels of Cdc25c [ 36 ]. A polar fraction of Frondanol A5 was effective at inducing G2/M cell cycle apprehension, and besides potently decreased construction of cyclin A, cyclin B, and Cdc25c in S2013 and AsPC-1 cells [ 37 ] .
Reduction of tumor growth
Tumour growth inhibition by Frondoside A was initially demonstrated in a heterograft model using AsPC-1 pancreatic cancer cells [ 38 ]. Frondoside A was besides shown to inhibit tumor growth and reduce tumor volume by 87 % in an athymic mouse exemplar using MDA-MB-231 summit cancer cells [ 63 ]. Philinopsides A and E, novel sulfated triterpenoid glycosides derived from Pentacta quadrangulari, were besides shown to reduced tumor growth. Philinopside A reduce tumor growth in the sarcoma 180 sneak model, whereas philinopside E inhibited tumor growth in both sarcoma 180 and hepatoma 22 mouse models [ 56, 57 ]. other glycosides that demonstrate the ability to reduce tumor growth are summarized in Table .
Anti-metastatic and anti-angiogenic effects
metastasis and angiogenesis are the most dangerous processes acquired by cancer cells. metastasis is the development of secondary malignant growths at a distance from the basal site of the tumor and one of the principal causes of mortality in cancer patients [ 14 ]. angiogenesis is the constitution of new blood vessels from preexistent vessels that involves the emergence, migration, and differentiation of endothelial cells, which line the inside walls of blood vessels. Angiogenesis occurs in tumors to help them to survive and proliferate. Anti-angiogenic agents inhibit this work, thereby preventing the supply of oxygen and nutrients from reaching cancer cell such that tumor cells starve and finally die [ 72 ]. The ability of the cancer drugs to inhibit metastasis and angiogenesis is essential for effective cancer treatment strategies. Ds-echinoside A, a intensify isolated from Pearsonothuria graeffei, caused reductions in cell attachment, migration, and invasion in HepG2 cells. Immunocytochemical studies revealed that treatment with Ds-echinoside A led to decreased expression of matrix metalloproteinase-9 ( MMP-9 ) and resulted in increases in both angiogenesis and metastasis through abasement of the extracellular matrix. Ds-echinoside A besides enhanced expression of tissue inhibitors of metalloproteinase-1 ( TIMP-1 ), a crucial governor of MMP-9 activation. The anti-angiogenic effect of Ds-echinoside A was besides studied in a series of in vitro and in vivo tumor models. These studies showed that Ds-echinoside A decrease tube formation of human endothelial cells ECV-304 mature in Matrigel and attenuated neovascularization in a dame embryo chorioallantoic membrane ( CAM ) model [ 14 ]. similar results were obtained by Zhao et alabama. ( 2010 ), in which two sulfated triterpene glycosides, Holothurin A ( HA ) and 24-dehydroechinoside A ( DHEA ), from Pearsonothuria graeffei were identified. Both of these glycosides showed anti-metastatic effects both in vitro and in vivo. The cogitation revealed that HA and DHEA administration reduced adhesiveness of HepG2 cells and human endothelial cells ( ECV-304 ) adult in Matrigel and inhibited HepG2 cell migration and invasion in a dose-dependent manner. Both compounds suppressed pipe constitution of ECV-304 cells in Matrigel and attenuated neovascularization using the CAM assay. Immunocytochemical analysis showed that both HA and DHEA importantly reduced expression of MMP-9 and increased expression of TIMP-1. westerly blot analysis revealed that both compounds markedly suppressed the expression of vascular endothelial growth divisor ( VEGF ). inhibition of VEGF is a key indicator of anti-angiogenic demeanor, displayed by HA and DHEA compounds. furthermore, only HA downregulated expression of nuclear factor-kappa B ( NF-κB ). NF-κB regulates expression of MMP-9 such that inhibition of NF-κB energizing suppresses MMP-9 and tumor invasion [ 73 ]. This find suggests that the anti-metastatic activity of saponins derived from P. graeffei could be mediated through NF-κB-dependent or -independent pathways, depending on their chemical structures [ 60 ]. A report by Ma et alabama. found that Frondoside A had potent anti-metastatic bodily process in a syngeneic murine exemplar of metastatic breast cancer. Intraperitoneal government of Frondoside A in mouse implanted with mammary tumors in mammary glands, inhibit tumor metastasis to the lungs. Along with the anti-metastatic bodily process described in vivo, Frondoside A besides inhibited migration of tumor cells in vitro through prohibition of prostaglandin E receptors, EP2, and EP4 [ 63 ]. other studies have besides reported that Frondoside A has the promise anti-metastatic electric potential for breast cancer therapy. Park et aluminum. investigated the anti-metastatic effects of Frondoside A in MBA-MB-231 human front cancer cells, and found that Frondoside A suppress TPA-induced activation of AP-1 and NF-κB and decreased TPA-induced activation of ERK1/2, PI3K/Akt, and p38 MAPK signals caused a decrease in construction of MMP-9 [ 64 ]. In accession, Frondoside A decrease invasion of MDA-MB-231 tumor cells in a Matrigel invasion assay [ 38 ]. Frondoside A was shown to inhibit angiogenesis as indicated by reduce CD31 stain, used to measure microvessel concentration, in LNM35 lung cancer xenografts and was shown to block basal and bFGF-induced angiogenesis using the CAM try. Frondoside A treatment demonstrated significant prohibition of metastasis in a lung cancer heterograft model and an in vitro Matrigel invasion assay, without toxic side effects [ 13 ] .
Inhibition of drug resistance
resistance to chemotherapy is a major problem for cancer therapeutics. One of the major factors that contribute to chemotherapy electric resistance is a process called autophagy. pharmacological inhibitors of autophagy are important to prevent the development of resistance to anti-cancer drugs. Frondoside A, a triterpenoid glycoside from Cucumaria okhotensis, inhibited pro-survival autophagy in human urothelial carcinoma cell lines resistant to standard therapies [ 43 ]. Another sketch showed that Frondoside A isolated from the Cucumaria okhotensis and cucumarioside А2–2 isolated from Cucumaria japonica decreased multidrug resistor in the Ehrlich ascites carcinoma shiner tumor model. Frondoside A or cucumarioside А2–2 both demonstrated the ability to form a building complex with cholesterol to block membrane transportation P-glycoprotein activity in tumor ascites derived from the sneak Ehrlich carcinoma tumor model, resulting in decrease multidrug resistance [ 61 ] .
Conclusion
Bioactive compounds isolated from the ocean cucumber for use as anti-cancer agents has attracted the attention of cancer researchers because of their natural origin and farseeing history as a alimentary food. Sea cucumbers contain many marine-derived agents that have the electric potential to inhibit the growth of respective different types of human tumor cells as demonstrated in in vitro studies, in vivo murine models, and homo studies. several secondary coil metabolites derived from ocean cucumbers demonstrate anti-cancer properties through multiple mechanisms including cytotoxic activity, evocation of apoptosis, cell cycle collar, reduction of tumor growth, inhibition of invasion and metastasis of tumor cells, inhibition of angiogenesis, and decreased drug electric resistance. Nevertheless, detail mechanism of the anti-cancer activities of sea cucumber derived-compounds remain ill-defined and comprehensive studies that identify these mechanisms are needed. Above all, the electric potential anti-cancer activeness of bioactive compounds isolated from sea cucumbers gives promising hope for the treatment and prevention of homo cancers.
Funding
The work was supported by the Ministry of Research, Technology, and Higher department of education of Republic of Indonesia under Postdoctoral Research Scheme in 2017 .
Compliance with ethical standards
Conflict of interest
All authors declare to have no battle of interest regarding the article .
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors .
