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Antitumor Compounds from Marine Invertebrates

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A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (23 December 2019) | Viewed by 48363

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Special Issue Editor

Dr. Cécile Debitus

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IRD, Univ Brest, CNRS, Ifremer, LEMAR, F-29280 Plouzane, France
Interests: marine invertebrates; natural products extraction; natural product isolation; bioactive compounds; chemotaxonomy; quorum sensing; anticancer drugs
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Special Issue Information

Dear Colleagues,

Since the discovery of the cytarabine derived from the spongothymidine isolated from the sponge Cryptotethya crypta in the 1950s, marine invertebrates have been an amazing source of innovative molecules, particularly in the field of anti-cancer drugs. Developed in the very first place to act for the survival of organisms in their environment, and refined by the evolution and adaptation needs of these often sessile and soft animals, these compounds are of unequalled originality. These molecules have most often been detected by screening on cellular targets, but the fine analysis of complex extracts leads to the isolation and identification of active principles, but also often to the isolation of analogues allowing better understanding of the mode of action of molecules and of the structural patterns essential to their activity.

We invite you to submit manuscripts for this Special Issue for reviews and original research articles describing novel naturally-occurring molecules and their close derivatives of anticancer interest, their cellular target, mode of action and structure-activity relationships, and their in vivo activities where appropriate.

Dr. Cécile Debitus
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Anticancer
Cancer cell lines
Chemotherapeutics
Extraction and analysis
Marine invertebrate
Marine natural products
Mechanism of action
Molecular target
Target based screening

Published Papers (11 papers)

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Research

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11 pages, 8979 KiB

Open AccessArticle

Small-Scale Preparation of Fluorescently Labeled Chemical Probes from Marine Cyclic Peptides, Kapakahines A and F

by Rie Kamihira and Yoichi Nakao

Mar. Drugs 2021, 19(2), 76; https://doi.org/10.3390/md19020076 - 31 Jan 2021

Cited by 3 | Viewed by 2049

Abstract

A number of bioactive marine natural products have been isolated so far, but it is still difficult to disclose their modes of action. In this study, we prepared fluorescently labeled chemical probes from the cytotoxic marine cyclic peptides kapakahines A (1) and F (2) to visualize their localization as the first step of the study of their modes of action. We used fluorescent dyes 3a or 3a/b (a 1:1 mixture of 3a and 3b) whose terminal N-hydroxysuccinimide (NHS) group can react with the free amino groups of kapakahines. The fluorescently labeled kapakahine A (Kap A-5-FL, 5a) stained P388 murine leukemia cells and HeLa human cervical cancer cells, while cells treated with fluorescently labeled kapakahine F (Kap F-5-FL, 6a) only weakly stained them. Further analysis of the confocal images of the stained cells with higher magnification (×100) indicated the localization of Kap A-5-FL (5a) in the cells. In this paper, we report the small-scale preparation and a new delivery method of fluorescent probes, as well as the application of these procedures to cell staining. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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13 pages, 2175 KiB

Open AccessArticle

Proapoptotic Index Evaluation of Two Synthetic Peptides Derived from the Coneshell Californiconus californicus in Lung Cancer Cell Line H1299

by Irasema Oroz-Parra, Carolina Álvarez-Delgado, Karla Cervantes-Luevano, Salvador Dueñas-Espinoza and Alexei F. Licea-Navarro

Mar. Drugs 2020, 18(1), 10; https://doi.org/10.3390/md18010010 - 20 Dec 2019

Cited by 6 | Viewed by 2363

Abstract

Lung cancer is one of the most common types of cancer, accounting for approximately 15% of all cancer cases worldwide. Apoptosis is the dominant defense mechanism against tumor development. The balance between pro- and antiapoptotic members of the Bcl-2 protein family can determine cellular fate. The venom of predatory marine snails Conus is estimated to have 100–400 toxins called conotoxins. The family of α-conotoxins is known to consist of selective antagonists of nicotinic acetylcholine receptors (nAChRs). Lung cancer cells overexpress several subunits of nAChRs and are considered as an excellent target for new anticancer drugs. We compared the cytotoxic effect of two synthetic peptides derived from Californiconus californicus, Cal14.1a, and Cal14.1b, which only differ by one amino acid in their sequence, and compared their proapoptotic balance by Bax and Bcl-2 mRNA expression. We determined the caspase-3 and -7 activation to demonstrate apoptosis induction. Results showed that Cal14.1a induces a high Bax/Bcl-2 ratio in H1299 (lung cancer cells). Although Cal14.1b has a cytotoxic effect on H1299 cells, reducing cell viability by 30%, it does not increase the Bax/Bcl-2 ratio, which could be explained by the Glu in the 15th residue, which is crucial for the ability of Cal14.1a to induce apoptosis. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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12 pages, 3352 KiB

Open AccessArticle

Sinulariolide Inhibits Gastric Cancer Cell Migration and Invasion through Downregulation of the EMT Process and Suppression of FAK/PI3K/AKT/mTOR and MAPKs Signaling Pathways

by Yu-Jen Wu, Shih-Hsiung Lin, Zhong-Hao Din, Jui-Hsin Su and Chih-I Liu

Mar. Drugs 2019, 17(12), 668; https://doi.org/10.3390/md17120668 - 27 Nov 2019

Cited by 39 | Viewed by 4084

Abstract

Cancer metastasis is the main cause of death in cancer patients; however, there is currently no effective method to predict and prevent metastasis of gastric cancer. Therefore, gaining an understanding of the molecular mechanism of tumor metastasis is important for the development of new drugs and improving the survival rate of patients who suffer from gastric cancer. Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. We employed sinulariolide and gastric cancer cells in experiments such as MTT, cell migration assays, cell invasion assays, and Western blotting analysis. Analysis of cell migration and invasion capabilities showed that the inhibition effects on cell metastasis and invasion increased with sinulariolide concentration in AGS and NCI-N87 cells. Immunostaining analysis showed that sinulariolide significantly reduced the protein expressions of MMP-2, MMP-9, and uPA, but the expressions of TIMP-1 and TIMP-2 were increased, while FAK, phosphorylated PI3K, phosphorylated AKT, phosphorylated mTOR, phosphorylated JNK, phosphorylated p38MAPK, and phosphorylated ERK decreased in expression with increasing sinulariolide concentration. From the results, we inferred that sinulariolide treatment in AGS and NCI-N87 cells reduced the activities of MMP-2 and MMP-9 via the FAK/PI3K/AKT/mTOR and MAPKs signaling pathways, further inhibiting the invasion and migration of these cells. Moreover, sinulariolide altered the protein expressions of E-cadherin and N-cadherin in the cytosol and Snail in the nuclei of AGS and NCI-N87 cells, which indicated that sinulariolide can avert the EMT process. These findings suggested that sinulariolide is a potential chemotherapeutic agent for development as a new drug for the treatment of gastric cancer. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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21 pages, 4180 KiB

Open AccessArticle

Selective Inhibition of Liver Cancer Cells Using Venom Peptide

by Prachi Anand, Petr Filipenko, Jeannette Huaman, Michael Lyudmer, Marouf Hossain, Carolina Santamaria, Kelly Huang, Olorunseun O. Ogunwobi and Mandë Holford

Mar. Drugs 2019, 17(10), 587; https://doi.org/10.3390/md17100587 - 17 Oct 2019

Cited by 13 | Viewed by 5770

Abstract

Increasingly cancer is being viewed as a channelopathy because the passage of ions via ion channels and transporters mediate the regulation of tumor cell survival, death, and motility. As a result, a potential targeted therapy for cancer is to use venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here we describe the selectivity and mechanism of action of terebrid snail venom peptide, Tv1, for treating the most common type of liver cancer, hepatocellular carcinoma (HCC). Tv1 inhibited the proliferation of murine HCC cells and significantly reduced tumor size in Tv1-treated syngeneic tumor-bearing mice. Tv1’s mechanism of action involves binding to overexpressed transient receptor potential (TRP) channels leading to calcium dependent apoptosis resulting from down-regulation of cyclooxygenase-2 (COX-2). Our findings demonstrate the importance of modulating ion channels and the unique potential of venom peptides as tumor specific ligands in the quest for targeted cancer therapies. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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13 pages, 2992 KiB

Open AccessArticle

Inhibition of Liver Tumor Cell Metastasis by Partially Acetylated Chitosan Oligosaccharide on A Tumor-Vessel Microsystem

by Bolin Jing, Gong Cheng, Jianjun Li, Zhuo A. Wang and Yuguang Du

Mar. Drugs 2019, 17(7), 415; https://doi.org/10.3390/md17070415 - 13 Jul 2019

Cited by 21 | Viewed by 3332

Abstract

Chitooligosaccharides (COS), the only cationic oligosaccharide in nature, have been demonstrated to have anti-tumor activity. However, the inhibitory effects of COS on different stages of tumor metastasis are still unknown, and it is not clear what stage(s) of tumor metastasis COS targeted. To study the inhibitory effects of a new partially acetylated chitooligosaccharide (paCOS) with fraction of acetylation (F_A) 0.46 on each phase of liver cancer cell metastasis, a dynamic tumor-vessel microsystem undergoing physiological flow was leveraged. paCOS (F_A = 0.46) significantly inhibited proliferation of HepG2 cells through vascular absorption on the chip, and inhibited migration of HepG2 cells by inhibiting the formation of pseudopod in liver tumor cells. It was also found that paCOS at 10 μg/mL had a stronger inhibitory effect on liver tumor cells invading blood vessels than that of paCOS at 100 μg/mL, and paCOS at 100 μg/mL, which had a significant destructive effect on tumor vascular growth and barrier function. Moreover, paCOS reduced the number of liver tumor cells adhering onto the surface of HUVECs layer after 3 h of treatment. Therefore, the results revealed that paCOS had considerable potential as drugs for anti-tumor metastasis. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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14 pages, 4349 KiB

Open AccessArticle

Flaccidoxide-13-Acetate-Induced Apoptosis in Human Bladder Cancer Cells is through Activation of p38/JNK, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress Regulated Pathway

by Yu-Jen Wu, Tzu-Rong Su, Guo-Fong Dai, Jui-Hsin Su and Chih-I Liu

Mar. Drugs 2019, 17(5), 287; https://doi.org/10.3390/md17050287 - 13 May 2019

Cited by 23 | Viewed by 3991

Abstract

Flaccidoxide-13-acetate, an active compound isolated from cultured-type soft coral Sinularia gibberosa, has been shown to have inhibitory effects against invasion and cell migration of RT4 and T24 human bladder cancer cells. In our study, we used an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation assay, and flow cytometry to determine the mechanisms of the anti-tumor effect of flaccidoxide-13-acetate. The MTT and colony formation assays showed that the cytotoxic effect of flaccidoxide-13-acetate on T24 and RT4 cells was dose-dependent, and the number of colonies formed in the culture was reduced with increasing flaccidoxide-13-acetate concentration. Flow cytometry analysis revealed that flaccidoxide-13-acetate induced late apoptotic events in both cell lines. Additionally, we found that flaccidoxide-13-acetate treatment upregulated the expressions of cleaved caspase 3, cleaved caspase 9, Bax, and Bad, and down-regulated the expressions of Bcl-2, p-Bad, Bcl-x1, and Mcl-1. The results indicated that apoptotic events were mediated by mitochondrial dysfunction via the caspase-dependent pathway. Flaccidoxide-13-acetate also provoked endoplasmic reticulum (ER) stress and led to activation of the PERK-eIF2α-ATF6-CHOP pathway. Moreover, we examined the PI3K/AKT signal pathway, and found that the expressions of phosphorylated PI3K (p-PI3K) and AKT (p-AKT) were decreased with flaccidoxide-13-acetate concentrations. On the other hand, our results showed that the phosphorylated JNK and p38 were obviously activated. The results support the idea that flaccidoxide-13-acetate-induced apoptosis is mediated by mitochondrial dysfunction, ER stress, and activation of both the p38 and JNK pathways, and also relies on inhibition of PI3K/AKT signaling. These findings imply that flaccidoxide-13-acetate has potential in the development of chemotherapeutic agents for human bladder cancer. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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15 pages, 5918 KiB

Open AccessArticle

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model

by Chung-I Yu, Chung-Yi Chen, Wangta Liu, Po-Chih Chang, Chiung-Wei Huang, Kuang-Fen Han, In-Pin Lin, Mei-Ying Lin and Chien-Hsing Lee

Mar. Drugs 2018, 16(10), 387; https://doi.org/10.3390/md16100387 - 16 Oct 2018

Cited by 27 | Viewed by 3801

Abstract

Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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Review

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30 pages, 8512 KiB

Open AccessReview

Bright Spots in the Darkness of Cancer: A Review of Starfishes-Derived Compounds and Their Anti-Tumor Action

by Valentina Lazzara, Vincenzo Arizza, Claudio Luparello, Manuela Mauro and Mirella Vazzana

Mar. Drugs 2019, 17(11), 617; https://doi.org/10.3390/md17110617 - 29 Oct 2019

Cited by 27 | Viewed by 4460

Abstract

The fight against cancer represents a great challenge for researchers and, for this reason, the search for new promising drugs to improve cancer treatments has become inevitable. Oceans, due to their wide diversity of marine species and environmental conditions have proven to be precious sources of potential natural drugs with active properties. As an example, in this context several studies performed on sponges, tunicates, mollusks, and soft corals have brought evidence of the interesting biological activities of the molecules derived from these species. Also, echinoderms constitute an important phylum, whose members produce a huge number of compounds with diverse biological activities. In particular, this review is the first attempt to summarize the knowledge about starfishes and their secondary metabolites that exhibited a significant anticancer effect against different human tumor cell lines. For each species of starfish, the extracted molecules, their effects, and mechanisms of action are described. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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23 pages, 835 KiB

Open AccessReview

The Phylum Bryozoa as a Promising Source of Anticancer Drugs

by Blanca Figuerola and Conxita Avila

Mar. Drugs 2019, 17(8), 477; https://doi.org/10.3390/md17080477 - 17 Aug 2019

Cited by 34 | Viewed by 6981

Abstract

Recent advances in sampling and novel techniques in drug synthesis and isolation have promoted the discovery of anticancer agents from marine organisms to combat this major threat to public health worldwide. Bryozoans, which are filter-feeding, aquatic invertebrates often characterized by a calcified skeleton, are an excellent source of pharmacologically interesting compounds including well-known chemical classes such as alkaloids and polyketides. This review covers the literature for secondary metabolites isolated from marine cheilostome and ctenostome bryozoans that have shown potential as cancer drugs. Moreover, we highlight examples such as bryostatins, the most known class of marine-derived compounds from this animal phylum, which are advancing through anticancer clinical trials due to their low toxicity and antineoplastic activity. The bryozoan antitumor compounds discovered until now show a wide range of chemical diversity and biological activities. Therefore, more research focusing on the isolation of secondary metabolites with potential anticancer properties from bryozoans and other overlooked taxa covering wider geographic areas is needed for an efficient bioprospecting of natural products. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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26 pages, 4957 KiB

Open AccessReview

The Anticancer Drug Discovery Potential of Marine Invertebrates from Russian Pacific

by Vladimir L. Katanaev, Salvatore Di Falco and Yuri Khotimchenko

Mar. Drugs 2019, 17(8), 474; https://doi.org/10.3390/md17080474 - 16 Aug 2019

Cited by 15 | Viewed by 5125

Abstract

Despite huge efforts by academia and pharmaceutical industry, cancer remains the second cause of disease-related death in developed countries. Novel sources and principles of anticancer drug discovery are in urgent demand. Marine-derived natural products represent a largely untapped source of future drug candidates. This review focuses on the anticancer drug discovery potential of marine invertebrates from the North-West Pacific. The issues of biodiversity, chemodiversity, and the anticancer pharmacophore diversity this region hides are consecutively discussed. These three levels of diversity are analyzed from the point of view of the already discovered compounds, as well as from the assessment of the overall, still undiscovered and enormous potential. We further go into the predictions of the economic and societal benefits the full-scale exploration of this potential offers, and suggest strategic measures to be taken on the national level in order to unleash such full-scale exploration. The transversal and multi-discipline approach we attempt to build for the case of marine invertebrate-based anticancer drug discovery from a given region can be applied to other regions and disease conditions, as well as up-scaled to global dimensions. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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18 pages, 1166 KiB

Open AccessFeature PaperReview

The “Utility” of Highly Toxic Marine-Sourced Compounds

by David J. Newman

Mar. Drugs 2019, 17(6), 324; https://doi.org/10.3390/md17060324 - 31 May 2019

Cited by 35 | Viewed by 5738

Abstract

Currently a few compounds isolated from marine sources have become drugs, mainly directed towards cancer and pain. Compounds from marine sources have exquisite potencies against eukaryotic cells, as they act as protective agents against attack by predators in the marine environment. Their toxicities act as a “double-edged sword” as they are often too toxic for direct use in humans and thus have to be chemically modified. By linking suitably modified compounds to monoclonal antibodies directed against specific epitopes in mammalian cancer cells, they can be delivered to a specific cell type in humans. This review updates and extends an article published in early 2017, demonstrating how by careful chemical modifications, highly toxic compounds, frequently peptidic in nature, can be utilized as antitumor drug candidates. The antibody-drug- conjugates (ADCs) discussed are those that are currently in clinical trials listed in the NIH Clinical Trials Registry as, “currently active, recruiting or in some cases, recently completed”. There are also some ADCs discussed that are at the advanced preclinical stage, that in some cases, are repurposing current drug entities, and the review finishes with a short discussion of the aplyronines as potential candidate warheads as a result of scalable synthetic processes. Full article

(This article belongs to the Special Issue Antitumor Compounds from Marine Invertebrates)

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