Marine-derived Drugs Research Articles

PH-sensitive nanoliposomes for passive and CXCR-4-mediated marine yessotoxin delivery for cancer therapy.

Background: Yessotoxin (YTX), a marine-derived drug, was encapsulated in PEGylated pH-sensitive nanoliposomes, covalently functionalized (strategy I) with SDF-1αand by nonspecific adsorption (strategy II), to actively target chemokine receptor CXCR-4. Methods: Cytotoxicity to normal human epithelial cells (HK-2) andprostate (PC-3) and breast (MCF-7) adenocarcinoma models, with different expression levels of CXCR-4, weretested. Results: Strategy II exerted the highest cytotoxicity toward cancer cells while protecting normal epithelia. Acid pH-induced fusion of nanoliposomes seemed to serve as a primary route of entry into MCF-7 cells but PC-3 data support an endocytic pathway for their internalization. Conclusion: This work describes an innovative hallmark in the current marine drug clinical pipeline, as the developed nanoliposomes are promising candidates in the design of groundbreaking marine flora-derived anticancer nanoagents.

In vitro Anticancer and Antioxidant Activity of Partially Purified Poly-saccharides from Marine Bivalves Against Human Lung Cancer Cell Lines (A549 and NCI-H460)

Marine-derived bioactive polysaccharide have aroused extensive attention because of their potential nutritional and therapeutic benefits. Polysaccharides from marine molluscs have high potential as promising candidates for drug development. In this study, partially purified polysaccharide from various bivalve species were investigated for its bioactivity. Enzyme assisted extraction technique was applied for polysaccharide extraction from marine bivalves. Five papain released crude polysaccharide extracts were prepared from four clams (Donax variabilis, Donax incarnatus, Donax cuneatus, Sunetta scripta) and one mussel (Perna viridis). Initially, all five species were subjected to biochemical and proximate analyses. Five distinct partially purified polysaccharide extracts were tested in vitro for antioxidant and anticancer properties. The cytotoxicity and cell viability of five marine bivalve extracts was investigated in normal (Vero) and two lung cancer cell lines (lung adenocarcinoma (A549) and lung large cell carcinoma (NCI-H460)). In the performed antioxidant assays, almost all the polysaccharide extracts showed strong antioxidant activity in a dose dependent manner. Likewise, all the five polysaccharide extracts showed significant inhibitory effects on growth of human lung cancer cells. In particular, polysaccharide from clam Donax variabilis showed high activity in the growth inhibition of both non-small cell lung cancers. This research can be considered as the foundation for the development of a new marine-derived drug whose biological activity can be assessed by further purification and characterization of the active bio-compound.

Marine-Derived Compounds for the Potential Treatment of Glucocorticoid Resistance in Severe Asthma

One of the challenges to the management of severe asthma is the poor therapeutic response to treatment with glucocorticosteroids. Compounds derived from marine sources have received increasing interest in recent years due to their prominent biologically active properties for biomedical applications, as well as their sustainability and safety for drug development. Based on the pathobiological features associated with glucocorticoid resistance in severe asthma, many studies have already described many glucocorticoid resistance mechanisms as potential therapeutic targets. On the other hand, in the last decade, many studies described the potentially anti-inflammatory effects of marine-derived biologically active compounds. Analyzing the underlying anti-inflammatory mechanisms of action for these marine-derived biologically active compounds, we observed some of the targeted pathogenic molecular mechanisms similar to those described in glucocorticoid (GC) resistant asthma. This article gathers the marine-derived compounds targeting pathogenic molecular mechanism involved in GC resistant asthma and provides a basis for the development of effective marine-derived drugs.

1547P Trabectedin in soft-tissue sarcoma patients in Italy: Analysis of real-world data from a national registry

Trabectedin (Yondelis®) is a marine-derived drug with anticancer activity approved for the treatment of patients with advanced soft-tissue sarcomas (STS) previously treated with at least one line of therapy. In Italy, the use of trabectedin for STS patients has been monitored since 2013 through a registry run by the national drug regulator, i.e. the Italian Medicines Agency (AIFA).

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone Vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone Vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma

Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

Simple SummaryThe marine drug lurbinectedin revealed an unprecedented efficacy against patient-derived malignant pleural mesothelioma cells, regardless of the histological type and the BAP1 mutation status. By inducing strong DNA damages, it dramatically arrested cell cycle progression and induced apoptosis. These results may be translated into the use of lurbinectedin as an effective agent for malignant pleural mesothelioma patients.Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.

Lurbinectedin in the treatment of relapsed small cell lung cancer.

Lurbinectedin is a marine-derived drug that inhibits transcription, a process that is frequently dysregulated in small cell lung cancer. The activity of lurbinectedin has been studied in many solid tumors, showing not only promising results but also a favorable safety profile. In relapsed small cell lung cancer, the drug has shown encouraging activity both as a single agent and in combination with doxorubicin, paclitaxel or irinotecan. The USA FDA has recently granted accelerated approval to lurbinectedin monotherapy in this setting. This article provides an update on available data and ongoing studies of lurbinectedin in small cell lung cancer, including Phase I combination trials, the basket Phase II trial and the ATLANTIS Phase III trial.

Exploring the Diversity of the Marine Environment for New Anti-cancer Compounds

Marine ecosystems contain over 80% of the world’s biodiversity, and many of these organisms have evolved unique adaptations enabling survival in diverse and challenging environments. The biodiversity within the world’s oceans is a virtually untapped resource for the isolation and development of novel compounds, treatments, and solutions to combat human disease. In particular, while over half of our anti-cancer drugs are derived from natural sources, almost all of these are from terrestrial ecosystems. Yet, even from the limited analyses to date, a number of marine-derived anti-cancer compounds have been approved for clinical use, and several others are currently in clinical trials. Here, we review the current suite of marine-derived anti-cancer drugs, with a focus on how these compounds act upon the hallmarks of cancer. We highlight potential marine environments and species that could yield compounds with unique mechanisms. Continued exploration of marine environments, along with the characterization and screening of their inhabitants for unique bioactive chemicals, could prove fruitful in the hunt for novel anti-cancer therapies.

Pharmacokinetics of Marine-Derived Drugs.

Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has attracted increasing interest in recent decades due to its effective and potential contribution to the selection of rational dosage recommendations and the optimal use of the therapeutic arsenal. In general, pharmacokinetics studies how drugs change after administration via the processes of absorption, distribution, metabolism, and excretion (ADME). This review provides a summary of the pharmacokinetics studies of marine-derived active compounds, with a particular focus on their ADME. The pharmacokinetics of compounds derived from algae, crustaceans, sea cucumber, fungus, sea urchins, sponges, mollusks, tunicate, and bryozoan is discussed, and the pharmacokinetics data in human experiments are analyzed. In-depth characterization using pharmacokinetics is useful for obtaining information for understanding the molecular basis of pharmacological activity, for correct doses and treatment schemes selection, and for more effective drug application. Thus, an increase in pharmacokinetic research on marine-derived compounds is expected in the near future.

Current Research Landscape of Marine-Derived Anti-Atherosclerotic Substances.

Atherosclerosis is a chronic disease characterized by lipid accumulation and chronic inflammation of the arterial wall, which is the pathological basis for coronary heart disease, cerebrovascular disease and thromboembolic disease. Currently, there is a lack of low-cost therapeutic agents that effectively slow the progression of atherosclerosis. Therefore, the development of new drugs is urgently needed. The research and development of marine-derived drugs have gained increasing interest from researchers across the world. Many marine organisms provide a rich material basis for the development of atherosclerotic drugs. This review focuses on the latest technological advances in the structures and mechanisms of action of marine-derived anti-atherosclerotic substances and the challenges of the application of these substances including marine polysaccharides, proteins and peptides, polyunsaturated fatty acids and small molecule compounds. Here, we describe the theoretical basis of marine biological resources in the treatment of atherosclerosis.

Synthesis, pharmacological evaluation and molecular docking of novel R-/S-2-(2-hydroxypropanamido)-5-trifluoromethyl benzoic acid as dual anti-inflammatory anti-platelet aggregation agents.

R-/S-2-(2-hydroxypropanamido) benzoic acid (R-/S-HPABA), marine-derived anti-inflammatory antiplatelet drugs, were initially synthesised in our group. However, preliminary research showed that R-/S-HPABA were eliminated rapidly because of extensive hydroxylation metabolism of phenyl ring in vivo. In order to reduce significant hydroxylation metabolism to improve pharmacological activity and bioavailability, trifluoromethyl group was incorporated into R-/S-HPABA to synthesise R-/S-2-(2-hydroxypropanamido)-5-trifluoromethyl benzoic acid (R-/S-HFBA), respectively. The purposes of this study were to report the synthesis of R-/S-HFBA and compare the anti-inflammatory antiplatelet effect and pharmacokinetic properties of R-/S-HFBA with those of R-/S-HPABA. Carrageenan-induced rat paw edema assay was used for the evaluation of the anti-inflammatory activity. R-/S-HFBA showed better results in inhibiting edema and were able to prolong the anti-inflammatory effect after carrageenan injection. The antiplatelet aggregation activity of R-/S-HFBA and R-/S-HPABA was studied on arachidonic acid-induced platelet aggregation of rabbit platelet-rich plasma. The aggregation inhibition rate of R-/S-HFBA was significantly (p < 0.05) higher than that of R-/S-HPABA, respectively. Molecular docking study revealed that R-/S-HFBA possess more potent binding affinity with COX-1/COX-2 than R-/S-HPABA, respectively, and that the presence of trifluoromethyl group leads to increase in activity of R-/S-HFBA. R-/S-HFBA also afford more favorable pharmacokinetic properties than R-/S-HPABA, respectively, such as higher Cmax, larger AUC0-∞, and longer t1/2, which, as expected, are more metabolically stable.

Antimetastatic and antiangiogenic activity of trabectedin in cutaneous melanoma.

Trabectedin is a marine-derived antineoplastic drug. Besides targeting the cancer cells, trabectedin has a peculiar activity on the tumor microenvironment with marked effects on the vasculature and the immune response. Because a favorable microenvironment is a key factor in the progression of cutaneous melanoma, we hypothesized that trabectedin might affect the growth and metastasis of this highly aggressive cancer. This study shows that trabectedin inhibited the subcutaneous growth of the murine melanoma B16-BL6 and K1735-M2. In line with its known activities on the environment of other tumor types, it caused a significant reduction of tumor blood vessel density and tumor-associated macrophages. Trabectedin had a significant antimetastatic activity, inhibiting the formation of lung colonies following intravenous injection of B16-BL6 or K1735-M2 cells. The drug was also active in a clinically relevant spontaneous metastasis assay, where it inhibited lung metastasis when administered before (neoadjuvant) or after (adjuvant) surgical removal of the primary tumor. Relevant to its antimetastatic activity, trabectedin inhibited melanoma cell invasiveness in vitro, associated with increased tissue inhibitor of metalloproteinase-1 production and alteration in cell shape and cytoskeleton organization. This study shows that trabectedin affects melanoma growth and metastasis, acting with tumor-dependent mechanisms on both the tumor cells and the vascular and the inflammatory tumor microenvironment.

Fatty Acids Pattern from the French Polynesian Monanchora n. sp. Marine Sponge

Marine sponges are prolific producers of physiologically active secondary metabolites [1, 2]. The chemical exploration of fatty acids derived from of marine organisms is a vital research area [3,4,5]. Fatty acids and lipids obtained from marine sources display unique molecular diversity, including saturated, mono-, di-, and polyunsaturated, branched, halogenated, hydroxylated, methoxylated, epoxide, and non-methylene-interrupted structure [6]. Marine fatty acids exhibit a variety of bioactivities, including antifungal, antibacterial, antimalarial [7], and anticancer [8]. Among the marketed eight marine-derived drugs, the ethyl esters of several omega-3 fatty acids from fish oils, in particular, ethyl esters of the major constituents eicosapentaenoic acid and docosahexaenoic acid, are approved as anti-hypertriglyceridemia and antibacterial drugs [9,10,11].

Review of Chromatographic Bioanalytical Assays for the Quantitative Determination of Marine-Derived Drugs for Cancer Treatment.

The discovery of marine-derived compounds for the treatment of cancer has seen a vast increase over the last few decades. Bioanalytical assays are pivotal for the quantification of drug levels in various matrices to construct pharmacokinetic profiles and to link drug concentrations to clinical outcomes. This review outlines the different analytical methods that have been described for marine-derived drugs in cancer treatment hitherto. It focuses on the major parts of the bioanalytical technology, including sample type, sample pre-treatment, separation, detection, and quantification.

The Marine Pharmacology and Pharmaceuticals Pipeline in 2017

The ocean's organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2017, the clinical marine pharmaceutical pipeline consisted of six marine‐derived drugs approved by the United States Food and Drug Administration (FDA): for cancer, cytarabine (Cytosar‐U®, Depocyt®, FDA‐approved 1969); for pain, ziconotide (Prialt®, FDA‐approved 2004); for hypertriglyceridemia, omega‐3‐acid ethyl esters (Lovaza®, FDA‐approved 2004); for cancer, eribulin mesylate (Halaven®, FDA‐approved 2010), brentuximab vedotin (Adcetris®, FDA‐approved 2011), and trabectedin (Yondelis®, FDA‐approved 2015). Furthermore, there were 23 marine‐derived compounds in clinical trials: 6 marine‐derived compounds in Phase III, 8 compounds in Phase II, and at least 9 compounds in Phase I, many of them auristatin‐containing antibody drug conjugates. Regular updates on the clinical marine pharmaceutical pipeline are posted at http://marinepharmacology.midwestern.edu/clinPipeline.htm. Furthermore, the global preclinical marine pharmacology pipeline continues to generate considerable data on multiple pharmacological classes, as highlighted in a recent review: A. M. S. Mayer, A. D. Rodríguez, O. Taglialatela‐Scafati and N. Fusetani. Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti‐Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action. Marine Drugs 15 (9): 273, 2017. We thus conclude that in November 2017, both the marine pharmacology preclinical and clinical pharmaceutical pipelines continued to remain very active.Support or Funding InformationSupported by Midwestern University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

SULFATION PATHWAYS: Sources and biological activities of marine sulfated steroids.

Marine environment is rich in structurally unique molecules and can be an inspiring source of novel drugs. Currently, six marine-derived drugs are in the market with FDA approval and several more are in the clinical pipeline. Structurally diverse and complex secondary metabolites have been isolated from the marine world and these include sulfated steroids. Biological activities of nearly 150 marine sulfated steroids reported from 1978 to 2017 are compiled and described, namely antimicrobial, antitumor, cardiovascular and antifouling activities. Structure-activity relationship for each activity is discussed.

Drugs from the Oceans: Marine Natural Products as Leads for Drug Discovery.

The marine environment harbors a vast number of species that are the source of a wide array of structurally diverse bioactive secondary metabolites. At this point in time, roughly 27'000 marine natural products are known, of which eight are (were) at the origin of seven marketed drugs, mostly for the treatment of cancer. The majority of these drugs and also of drug candidates currently undergoing clinical evaluation (excluding antibody-drug conjugates) are unmodified natural products, but synthetic chemistry has played a central role in the discovery and/or development of all but one of the approved marine-derived drugs. More than 1000 new marine natural products have been isolated per year over the last decade, but the pool of new and unique structures is far from exhausted. To fully leverage the potential offered by the structural diversity of marine-produced secondary metabolites for drug discovery will require their broad assessment for different bioactivities and the productive interplay between new fermentation technologies, synthetic organic chemistry, and medicinal chemistry, in order to secure compound supply and enable lead optimization.

Highlights of This Issue

Treatment options for osteosarcoma remain anchored to surgery and conventional chemotherapy, and are in need of additional and less toxic approaches. Ratti and colleagues developed osteosarcoma models in immunocompetent mice and showed the therapeutic efficacy of trabectedin, a clinically approved marine-derived drug, in halting osteosarcoma growth and metastases. The action of trabectedin was dual: direct on neoplastic cells, inducing their differentiation, and indirect on the immune microenvironment, increasing the infiltration of T cells. However, the latter highly expressed the inhibitory immune checkpoint PD-1. Consistently, combination of trabectedin and anti PD-1 antibody resulted in the best therapeutic effect.The authors investigate whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment of epidermal growth factor receptor (EGFR) mutated lung cancer. To investigate methylation changes at the whole-genome level, Niu and colleagues applied methyl-sensitive cut counting sequencing (MSCC) in EGFR 19 deletion lung adenocarcinoma tissues before and after erlotinib treatment. A differential methylated region (DMR) of the GABBR2 gene was identified and validated based on the results of whole methylome profiling, and upregulation of GABBR2 rescued erlotinib-induced apoptosis in vitro. This research shows promise in the epigenetic study of EGFR-mutated lung adenocarcinoma treated with TKI.Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, Jaworski and colleagues adopted a strategy to remodel the stroma using hemin, a well-known inducer of the enzyme Heme Oxygenase-1, to counteract tumor development. Their results showcase a novel function of an already human-used drug as a means of boosting the endogenous response against prostate cancer, a major health care problem worldwide. In particular, hemin conditioning limits tumor development by simultaneously targeting both tumor vascularization and the cytotoxic T-cell responses.Hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) patients have limited treatment options. Targeting cyclin-dependent kinases (CDK), key components in the cell cycle that are dysregulated in many cancers, has emerged as a viable therapy strategy. In a phase II study of heavily pretreated refractory HR+/HER2− mBC patients, abemaciclib, a selective oral inhibitor of CDK4 and CDK6, exhibited promising single-agent activity and a safety profile that allowed for dosing on a continuous schedule. Abemaciclib may represent a possible therapy advancement for HR+/HER2− mBC patients.

Chemistry of Renieramycins. 17. A New Generation of Renieramycins: Hydroquinone 5-O-Monoester Analogues of Renieramycin M as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells

A series of hydroquinone 5-O-monoester analogues of renieramycin M were semisynthesized via bishydroquinonerenieramycin M (5) prepared from renieramycin M (1), a major cytotoxic bistetrahydroisoquinolinequinone alkaloid isolated from the Thai blue sponge Xestospongia sp. All 20 hydroquinone 5-O-monoester analogues possessed cytotoxicity with IC50 values in nanomolar concentrations against the H292 and H460 human non-small-cell lung cancer (NSCLC) cell lines. The improved cytotoxicity toward the NSCLC cell lines was observed from the 5-O-monoester analogues such as 5-O-acetyl ester 6a and 5-O-propanoyl ester 7e, which exhibited 8- and 10-fold increased cytotoxicity toward the H292 NSCLC cell line (IC50 3.0 and 2.3 nM, respectively), relative to 1 (IC50 24 nM). Thus, the hydroquinone 5-O-monoester analogues are a new generation of the renieramycins to be further developed as potential marine-derived drug candidates for lung cancer treatment.

Marine actinomycete crude extracts with potent TRAIL-resistance overcoming activity against breast cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, as it can kill tumor cells selectively. In our search of bioactive natural products to overcome TRAIL-resistance, we isolated 47 actinomycete strains from different sediments and seawater samples collected from the Red Sea coast in Egypt and found four crude extracts (EGY1, EGY3, EGY24 and EGY34) displaying TRAIL sensitizing activity in the resistant breast cancer cell line MDA-MB-231. None of these crude extracts exhibited cytotoxic effect on normal mouse embryonic fibroblasts (MEF), with the exception of EGY34. Analysis of the signaling pathways underlying the sensitization of MDA-MB-231 cells to TRAIL-induced apoptosis, by western blotting, revealed that all crude extracts facilitated initiator caspase‑8/-10 activation upon TRAIL stimulation, but that in addition, EGY3 and EGY34, alone, induced strong ER-stress activation, with the appearance of BiP in the cytosolic extracts. Our results pave the way to the discovery and the development of marine-derived drugs for cancer therapy.