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Marine Drugs
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Marine Natural Products as Anticancer Agents 3.0
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Marine Natural Products as Anticancer Agents 3.0

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Pharmacology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 14401

Special Issue Editors

Dr. Celso Alves

E-Mail Website
Guest Editor
MARE—Marine and Environmental Sciences Centre, Polytechnic of Leiria, 2520-630 Peniche, Portugal
Interests: marine natural products; biotechnological applications; pharmaceutical applications; signal transduction; anticancer activities; compounds isolation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marc Diederich

E-Mail Website
Guest Editor
Department of Pharmacy, College of Pharmacy, Seoul National University, Building 29 Room 223, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
Interests: oncology; signal transduction; cell death; inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite advances in cancer biology and therapeutic strategies in recent decades, cancer remains a huge threat to human health and one of the deadliest diseases worldwide. Therapy failure and consequent cancer relapse are the main factors contributing to high cancer mortality. Accordingly, it is crucial to discover and develop new therapeutic options, including innovative and targeted drugs. Marine natural products reveal unique and rare chemical features not found in terrestrial environments. Such unique scaffolds can inspire the molecular modeling and chemical synthesis of novel anticancer drugs. As these compounds were produced in coevolution with biological systems, they present greater efficiency and specificity for interacting with biological target sites (e.g., receptors, DNA, proteins, etc.). These compounds also exhibit novel mechanisms of action, the ability to modulate distinct intracellular signaling pathways, and present fewer side effects. International regulatory authorities have already approved several marine molecules for treating distinct types of cancer.

Based on the success of the Special Issue “Marine Natural Products as Anticancer Agents 2.0” (https://www.mdpi.com/journal/marinedrugs/special_issues/AnticancerAgents2), as well as the critical relevance of this topic, we are pleased to announce the third edition of this Special Issue.

The focus of this Special Issue will be on highlighting the potential of marine natural products as anticancer agents, empathizing with the diversity of the molecular targets and the mechanistic effects. The application of innovative scientific approaches, including cocultures, 3D cultures, and organoid models, is encouraged in order to avoid the gap between in vitro and in vivo experiments. Approaches describing synergistic combination treatments of marine compounds with clinically used or experimental anticancer agents are welcome.

As compounds with anticancer immunomodulatory functions are well-known, publications describing the cancer activity of such marine compounds alone or in combination with checkpoint inhibitors or others are encouraged to be submitted.

For this Special Issue, we invite academic and industry scientists to submit reviews and original as well as conceptual research articles highlighting the biological activities of known, novel, or derived natural marine compounds with potential anticancer activity.

Dr. Celso Alves
Prof. Dr. Marc Diederich
Guest Editors

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
  • anti-tumor
  • immune
  • molecular targets
  • co-cultures
  • 3D culture models
  • marine natural products
  • receptors
  • proteins
  • molecular modeling
  • chemical synthesis
  • immune-modulatory

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Published Papers (9 papers)

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Research

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15 pages, 1775 KiB  
Article
The Salmon Oil OmeGo Reduces Viability of Colorectal Cancer Cells and Potentiates the Anti-Cancer Effect of 5-FU
by Caroline H. H. Pettersen, Helle Samdal, Pål Sætrom, Arne Wibe, Erland Hermansen and Svanhild A. Schønberg
Mar. Drugs 2023, 21(12), 636; https://doi.org/10.3390/md21120636 - 12 Dec 2023
Viewed by 1450
Abstract
Colorectal cancer (CRC) is one of the most common cancer types worldwide. Chemotherapy is toxic to normal cells, and combinatory treatment with natural well-tolerated products is being explored. Some omega-3 polyunsaturated fatty acids (n-3 PUFAs) and marine fish oils have anti-cancer effects on [...] Read more.
Colorectal cancer (CRC) is one of the most common cancer types worldwide. Chemotherapy is toxic to normal cells, and combinatory treatment with natural well-tolerated products is being explored. Some omega-3 polyunsaturated fatty acids (n-3 PUFAs) and marine fish oils have anti-cancer effects on CRC cells. The salmon oil OmeGo (Hofseth BioCare) contains a spectrum of fatty acids, including the n-3 PUFAs docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA). We explored a potential anti-cancer effect of OmeGo on the four CRC cell lines DLD-1, HCT-8, LS411N, and LS513, alone and in combination with the chemotherapeutic agent 5-Fluorouracil (5-FU). Screening indicated a time- and dose-dependent effect of OmeGo on the viability of the DLD-1 and LS513 CRC cell lines. Treatment with 5-FU and OmeGo (IC20–IC30) alone indicated a significant reduction in viability. A combinatory treatment with OmeGo and 5-FU resulted in a further reduction in viability in DLD-1 and LS513 cells. Treatment of CRC cells with DHA + EPA in a concentration corresponding to the content in OmeGo alone or combined with 5-FU significantly reduced viability of all four CRC cell lines tested. The lowest concentration of OmeGo reduced viability to a higher degree both alone and in combination with 5-FU compared to the corresponding concentrations of DHA + EPA in three of the cell lines. Results suggest that a combination of OmeGo and 5-FU could have a potential as an alternative anti-cancer therapy for patients with CRC. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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13 pages, 875 KiB  
Article
Rifamycin-Related Polyketides from a Marine-Derived Bacterium Salinispora arenicola and Their Cytotoxic Activity
by Cao Van Anh, Jong Soon Kang, Jeong-Wook Yang, Joo-Hee Kwon, Chang-Su Heo, Hwa-Sun Lee and Hee Jae Shin
Mar. Drugs 2023, 21(9), 494; https://doi.org/10.3390/md21090494 - 15 Sep 2023
Viewed by 1218
Abstract
Eight rifamycin-related polyketides were isolated from the culture broth of a marine-derived bacterium Salinispora arenicola, including five known (2–5 and 8) and three new derivatives (1, 6, and 7). The structures of the new [...] Read more.
Eight rifamycin-related polyketides were isolated from the culture broth of a marine-derived bacterium Salinispora arenicola, including five known (2–5 and 8) and three new derivatives (1, 6, and 7). The structures of the new compounds were determined by means of spectroscopic methods (HRESIMS and 1D, 2D NMR) and a comparison of their experimental data with those previously reported in the literature. The isolated compounds were evaluated for their cytotoxicity against one normal, six solid, and seven blood cancer cell lines and 1 showed moderate activity against all the tested cell lines with GI50 values ranging from 2.36 to 9.96 µM. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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14 pages, 3256 KiB  
Article
Actinoquinazolinone, a New Quinazolinone Derivative from a Marine Bacterium Streptomyces sp. CNQ-617, Suppresses the Motility of Gastric Cancer Cells
by Sultan Pulat, Da-Ae Kim, Prima F. Hillman, Dong-Chan Oh, Hangun Kim, Sang-Jip Nam and William Fenical
Mar. Drugs 2023, 21(9), 489; https://doi.org/10.3390/md21090489 - 13 Sep 2023
Viewed by 1436
Abstract
A HPLC-UV guided fractionation of the culture broth of Streptomyces sp. CNQ-617 has led to the isolation of a new quinazolinone derivative, actinoquinazolinone (1), as well as two known compounds, 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (2) and 7-methoxy-8-hydroxy cycloanthranilylproline (3). The [...] Read more.
A HPLC-UV guided fractionation of the culture broth of Streptomyces sp. CNQ-617 has led to the isolation of a new quinazolinone derivative, actinoquinazolinone (1), as well as two known compounds, 7-hydroxy-6-methoxy-3,4-dihydroquinazolin-4-one (2) and 7-methoxy-8-hydroxy cycloanthranilylproline (3). The interpretation of 1D, 2D NMR, and MS spectroscopic data revealed the planar structure of 1. Furthermore, compound 1 suppressed invasion ability by inhibiting epithelial–mesenchymal transition markers (EMT) in AGS cells at a concentration of 5 µM. In addition, compound 1 decreased the expression of seventeen genes related to human cell motility and slightly suppressed the signal transducer and activator of the transcription 3 (STAT3) signal pathway in AGS cells. Together, these results demonstrate that 1 is a potent inhibitor of gastric cancer cells. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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20 pages, 2442 KiB  
Article
An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells
by Maria Orfanoudaki, Emily A. Smith, Natasha T. Hill, Khalid A. Garman, Isaac Brownell, Brent R. Copp, Tanja Grkovic and Curtis J. Henrich
Mar. Drugs 2023, 21(9), 474; https://doi.org/10.3390/md21090474 - 29 Aug 2023
Cited by 1 | Viewed by 2787
Abstract
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged [...] Read more.
A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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18 pages, 4663 KiB  
Article
Marine Polyether Phycotoxin Palytoxin Induces Apoptotic Cell Death via Mcl-1 and Bcl-2 Downregulation
by Jaemyun Kim, Seungwon Ji, Jin-Young Lee, Jean Lorquin, Barbora Orlikova-Boyer, Claudia Cerella, Aloran Mazumder, Florian Muller, Mario Dicato, Olivier Detournay and Marc Diederich
Mar. Drugs 2023, 21(4), 233; https://doi.org/10.3390/md21040233 - 06 Apr 2023
Cited by 1 | Viewed by 1769
Abstract
Palytoxin is considered one of the most potent biotoxins. As palytoxin-induced cancer cell death mechanisms remain to be elucidated, we investigated this effect on various leukemia and solid tumor cell lines at low picomolar concentrations. As palytoxin did not affect the viability of [...] Read more.
Palytoxin is considered one of the most potent biotoxins. As palytoxin-induced cancer cell death mechanisms remain to be elucidated, we investigated this effect on various leukemia and solid tumor cell lines at low picomolar concentrations. As palytoxin did not affect the viability of peripheral blood mononuclear cells (PBMC) from healthy donors and did not create systemic toxicity in zebrafish, we confirmed excellent differential toxicity. Cell death was characterized by a multi-parametric approach involving the detection of nuclear condensation and caspase activation assays. zVAD-sensitive apoptotic cell death was concomitant with a dose-dependent downregulation of antiapoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL. Proteasome inhibitor MG-132 prevented the proteolysis of Mcl-1, whereas the three major proteasomal enzymatic activities were upregulated by palytoxin. Palytoxin-induced dephosphorylation of Bcl-2 further exacerbated the proapoptotic effect of Mcl-1 and Bcl-xL degradation in a range of leukemia cell lines. As okadaic acid rescued cell death triggered by palytoxin, protein phosphatase (PP)2A was involved in Bcl-2 dephosphorylation and induction of apoptosis by palytoxin. At a translational level, palytoxin abrogated the colony formation capacity of leukemia cell types. Moreover, palytoxin abrogated tumor formation in a zebrafish xenograft assay at concentrations between 10 and 30 pM. Altogether, we provide evidence of the role of palytoxin as a very potent and promising anti-leukemic agent, acting at low picomolar concentrations in cellulo and in vivo. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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14 pages, 4504 KiB  
Article
The Blockade of Mitogen-Activated Protein Kinase 14 Activation by Marine Natural Product Crassolide Triggers ICD in Tumor Cells and Stimulates Anti-Tumor Immunity
by Keng-Chang Tsai, Chia-Sheng Chen, Jui-Hsin Su, Yu-Ching Lee, Yu-Hwei Tseng and Wen-Chi Wei
Mar. Drugs 2023, 21(4), 225; https://doi.org/10.3390/md21040225 - 31 Mar 2023
Viewed by 1591
Abstract
Immunogenic cell death (ICD) refers to a type of cell death that stimulates immune responses. It is characterized by the surface exposure of damage-associated molecular patterns (DAMPs), which can facilitate the uptake of antigens by dendritic cells (DCs) and stimulate DC activation, resulting [...] Read more.
Immunogenic cell death (ICD) refers to a type of cell death that stimulates immune responses. It is characterized by the surface exposure of damage-associated molecular patterns (DAMPs), which can facilitate the uptake of antigens by dendritic cells (DCs) and stimulate DC activation, resulting in T cell immunity. The activation of immune responses through ICD has been proposed as a promising approach for cancer immunotherapy. The marine natural product crassolide, a cembranolide isolated from the Formosan soft coral Lobophytum michaelae, has been shown to have cytotoxic effects on cancer cells. In this study, we investigated the effects of crassolide on the induction of ICD, the expression of immune checkpoint molecules and cell adhesion molecules, as well as tumor growth in a murine 4T1 mammary carcinoma model. Immunofluorescence staining for DAMP ectolocalization, Western blotting for protein expression and Z′-LYTE kinase assay for kinase activity were performed. The results showed that crassolide significantly increased ICD and slightly decreased the expression level of CD24 on the surface of murine mammary carcinoma cells. An orthotopic tumor engraftment of 4T1 carcinoma cells indicated that crassolide-treated tumor cell lysates stimulate anti-tumor immunity against tumor growth. Crassolide was also found to be a blocker of mitogen-activated protein kinase 14 activation. This study highlights the immunotherapeutic effects of crassolide on the activation of anticancer immune responses and suggests the potential clinical use of crassolide as a novel treatment for breast cancer. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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12 pages, 1167 KiB  
Review
Bacterioruberin: Biosynthesis, Antioxidant Activity, and Therapeutic Applications in Cancer and Immune Pathologies
by Micaela Giani, Carmen Pire and Rosa María Martínez-Espinosa
Mar. Drugs 2024, 22(4), 167; https://doi.org/10.3390/md22040167 - 09 Apr 2024
Viewed by 534
Abstract
Halophilic archaea, also termed haloarchaea, are a group of moderate and extreme halophilic microorganisms that constitute the major microbial populations in hypersaline environments. In these ecosystems, mainly aquatic, haloarchaea are constantly exposed to ionic and oxidative stress due to saturated salt concentrations and [...] Read more.
Halophilic archaea, also termed haloarchaea, are a group of moderate and extreme halophilic microorganisms that constitute the major microbial populations in hypersaline environments. In these ecosystems, mainly aquatic, haloarchaea are constantly exposed to ionic and oxidative stress due to saturated salt concentrations and high incidences of UV radiation (mainly in summer). To survive under these harsh conditions, haloarchaea have developed molecular adaptations including hyperpigmentation. Regarding pigmentation, haloarchaeal species mainly synthesise the rare C50 carotenoid called bacterioruberin (BR) and its derivatives, monoanhydrobacterioruberin and bisanhydrobacterioruberin. Due to their colours and extraordinary antioxidant properties, BR and its derivatives have been the aim of research in several research groups all over the world during the last decade. This review aims to summarise the most relevant characteristics of BR and its derivatives as well as describe their reported antitumoral, immunomodulatory, and antioxidant biological activities. Based on their biological activities, these carotenoids can be considered promising natural biomolecules that could be used as tools to design new strategies and/or pharmaceutical formulas to fight against cancer, promote immunomodulation, or preserve skin health, among other potential uses. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
33 pages, 2168 KiB  
Review
Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition
by Maria Rita Garcia, Paula B. Andrade, Florence Lefranc and Nelson G. M. Gomes
Mar. Drugs 2024, 22(4), 143; https://doi.org/10.3390/md22040143 - 23 Mar 2024
Viewed by 780
Abstract
The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as [...] Read more.
The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as ‘anticancer leads,’ most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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19 pages, 2005 KiB  
Review
Shark IgNAR: The Next Broad Application Antibody in Clinical Diagnoses and Tumor Therapies?
by Xiaofeng Jiang, Ling Sun, Chengwu Hu, Feijian Zheng, Zhengbing Lyu and Jianzhong Shao
Mar. Drugs 2023, 21(9), 496; https://doi.org/10.3390/md21090496 - 16 Sep 2023
Cited by 1 | Viewed by 1921
Abstract
Antibodies represent a relatively mature detection means and serve as therapeutic drug carriers in the clinical diagnosis and treatment of cancer—among which monoclonal antibodies (mAbs) currently occupy a dominant position. However, the emergence and development of small-molecule monodomain antibodies are inevitable due to [...] Read more.
Antibodies represent a relatively mature detection means and serve as therapeutic drug carriers in the clinical diagnosis and treatment of cancer—among which monoclonal antibodies (mAbs) currently occupy a dominant position. However, the emergence and development of small-molecule monodomain antibodies are inevitable due to the many limitations of mAbs, such as their large size, complex structure, and sensitivity to extreme temperature, and tumor microenvironments. Thus, since first discovered in Chondroid fish in 1995, IgNAR has become an alternative therapeutic strategy through which to replace monoclonal antibodies, thus entailing that this novel type of immunoglobulin has received wide attention with respect to clinical diagnoses and tumor therapies. The variable new antigen receptor (VNAR) of IgNAR provides an advantage for the development of new antitumor drugs due to its small size, high stability, high affinity, as well as other structural and functional characteristics. In that respect, a better understanding of the unique characteristics and therapeutic potential of IgNAR/VNAR in clinical and anti-tumor treatment is needed. This article reviews the advantages of its unique biochemical conditions and molecular structure for clinical diagnoses and novel anti-tumor drugs. At the same time, the main advantages of the existing conjugated drugs, which are based on single-domain antibodies, are introduced here, thereby providing new ideas and methods for the development of clinical diagnoses and anti-tumor therapies in the future. Full article
(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)
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