Marine Ethnopharmacology: Medicines from the Sea

1. Introduction/Overview

The exploration of marine organisms as sources of novel therapeutic agents constitutes a significant frontier in pharmacology. Marine ethnopharmacology, a discipline intersecting marine biology, ethnobotany, and pharmacognosy, systematically investigates the medicinal properties of compounds derived from marine flora and fauna. The marine environment, representing over 70% of the Earth’s surface and hosting immense biodiversity, presents a unique chemical landscape shaped by extreme pressures, salinity, and competition for space. These conditions have driven the evolution of sophisticated secondary metabolites with potent biological activities, many of which have no terrestrial equivalents. The clinical translation of these compounds addresses critical unmet needs in oncology, analgesia, and infectious diseases, offering structurally unique scaffolds that often act via novel mechanisms of action.

The clinical relevance of marine-derived pharmaceuticals is substantial. Several agents are now integral to standard treatment regimens, particularly in hematological and solid tumor oncology. Their importance is underscored by their origin from diverse marine sources—including sponges, tunicates, mollusks, and cyanobacteria—and their subsequent development through sophisticated synthetic or semi-synthetic processes to ensure sustainability and supply. The continued investigation of marine natural products is considered a promising strategy for overcoming drug resistance and discovering new therapeutic pathways.

Learning Objectives

• Identify the primary marine-derived drugs currently used in clinical practice, including their source organisms and chemical classes.
• Explain the unique molecular mechanisms of action for key marine-derived agents, such as microtubule inhibition, DNA alkylation, and ion channel blockade.
• Analyze the pharmacokinetic profiles, therapeutic applications, and major adverse effect spectra of approved marine pharmaceuticals.
• Evaluate the special considerations for dosing, including adjustments for organ impairment and potential for drug-drug interactions.
• Appreciate the historical and ongoing role of marine ethnopharmacology in drug discovery and the challenges associated with the development of natural products from the sea.

2. Classification

Marine-derived drugs can be classified according to their chemical structure, biological source, and primary pharmacological activity. The following classification emphasizes clinically approved agents and their prototypical compounds.

Chemical and Pharmacological Classification

It is noteworthy that many marine-derived clinical agents are not administered as the naturally occurring compound but as synthetic or semi-synthetic analogs. This approach is often necessary to optimize pharmacokinetic properties, reduce toxicity, and enable large-scale production without depleting marine ecosystems. For instance, eribulin is a simplified, fully synthetic macrocyclic ketone analog of the complex natural product halichondrin B.

3. Mechanism of Action

The mechanisms of action of marine-derived drugs are diverse and frequently involve targeting fundamental cellular processes with high specificity. Their unique structures often confer novel binding interactions not seen with terrestrial compounds.

Cytarabine

Cytarabine (ara-C) is a pyrimidine nucleoside analog wherein the sugar arabinose replaces the natural deoxyribose. Following intracellular phosphorylation to its active triphosphate form (ara-CTP), it exerts multiple cytotoxic effects. The primary mechanism is inhibition of DNA polymerase, thereby halting DNA synthesis. Furthermore, ara-CTP is incorporated into elongating DNA strands, leading to premature chain termination. A secondary mechanism involves inhibition of ribonucleotide reductase, which depletes cellular pools of deoxycytidine triphosphate (dCTP), enhancing the incorporation of ara-CTP into DNA. This dual action makes it particularly effective against rapidly dividing cells.

Eribulin Mesylate

Eribulin is a synthetic analog of halichondrin B that inhibits microtubule dynamics through a mechanism distinct from other classes of tubulin-targeting agents like taxanes or vinca alkaloids. Eribulin binds with high affinity to specific sites on β-tubulin, predominantly at the plus (+) ends of microtubules. This binding suppresses microtubule growth phase dynamics without affecting shortening phases, leading to the formation of nonfunctional tubulin aggregates. The net result is a sustained mitotic blockade at the G2/M phase, ultimately triggering apoptotic cell death. This mechanism may also affect tumor vasculature and reverse epithelial-to-mesenchymal transition.

Trabectedin

Trabectedin is a complex alkaloid that binds to the minor groove of DNA, forming covalent adducts primarily at guanine residues. This binding bends the DNA helix toward the major groove. The trabectedin-DNA adduct is then recognized by transcription-coupled nucleotide excision repair (TC-NER) proteins. However, instead of facilitating repair, the formation of these protein-DNA complexes generates lethal double-strand DNA breaks when collision occurs with advancing replication forks. Trabectedin also exhibits modulatory effects on the tumor microenvironment by targeting transcription factors and reducing the production of pro-inflammatory cytokines by tumor-associated macrophages.

Ziconotide

Ziconotide is a synthetic analog of ω-conotoxin MVIIA, a peptide from cone snail venom. It is a selective and potent blocker of N-type voltage-gated calcium channels (Cav2.2). These channels are predominantly located in the dorsal horn neurons of the spinal cord and are crucial for the presynaptic release of neurotransmitters involved in nociceptive signaling, such as substance P and glutamate. By blocking calcium influx through these channels, ziconotide inhibits neurotransmitter release, thereby interrupting pain signal transmission in the spinal cord. It does not act on opioid receptors, and thus its analgesic effect is not associated with tolerance or respiratory depression.

4. Pharmacokinetics

The pharmacokinetic profiles of marine-derived drugs vary widely due to their diverse chemical structures, necessitating specific administration routes and dosing schedules.

Absorption and Administration

Most marine-derived antineoplastics exhibit poor oral bioavailability due to extensive first-pass metabolism, susceptibility to gastric acid degradation, or poor intestinal permeability. Consequently, cytarabine, eribulin, and trabectedin are administered parenterally—intravenously or, in the case of cytarabine, sometimes intrathecally. Ziconotide is administered exclusively via continuous intrathecal infusion due to its peptide nature and inability to cross the blood-brain barrier when given systemically.

Distribution

Distribution volumes are generally moderate to high. Cytarabine distributes widely throughout total body water and crosses the blood-brain barrier, achieving cerebrospinal fluid concentrations approximately 40-50% of plasma levels, which underpins its utility in treating meningeal leukemia. Eribulin has a large volume of distribution, suggesting extensive tissue binding. Trabectedin is highly bound to plasma proteins (>95%), primarily albumin, which influences its distribution and potential for displacement interactions. Ziconotide, when administered intrathecally, is confined to the cerebrospinal fluid and spinal cord tissue, with minimal systemic distribution.

Metabolism and Elimination

The extended half-life of trabectedin is a notable feature, allowing for dosing schedules every three weeks. Eribulin’s prolonged half-life supports its administration on days 1 and 8 of a 21-day cycle. The rapid deamination of cytarabine necessitates continuous intravenous infusion or frequent dosing to maintain effective plasma concentrations for antileukemic activity.

5. Therapeutic Uses/Clinical Applications

Marine-derived drugs have secured established roles in specific therapeutic niches, particularly where conventional agents have limited efficacy.

Approved Indications

• Cytarabine: A cornerstone in the treatment of acute myeloid leukemia (AML) and other acute leukemias. It is used in induction, consolidation, and maintenance therapy. High-dose cytarabine regimens are employed for consolidation in AML. It is also a key component in the prophylaxis and treatment of lymphomatous or leukemic meningitis via intrathecal administration.
• Eribulin Mesylate: Approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. It is also indicated for the treatment of unresectable or metastatic liposarcoma in patients who have received prior anthracycline-containing therapy.
• Trabectedin: Approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received prior anthracycline-containing chemotherapy. It is also indicated in Europe and other regions for the treatment of patients with advanced soft tissue sarcoma and for relapsed platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.
• Ziconotide: Approved for the management of severe chronic pain in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatments, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. It is specifically used for neuropathic and nociceptive pain of malignant or non-malignant origin.

Off-Label and Investigational Uses

Investigational applications are an active area of research. Cytarabine is sometimes used in high-dose regimens for certain lymphomas. Eribulin is being studied in other solid tumors, including prostate and non-small cell lung cancer. Trabectedin’s unique effect on the tumor microenvironment prompts investigation in other inflammation-associated cancers. Several other marine-derived compounds, such as the antibody-drug conjugate belantamab mafodotin (which uses a toxin derived from a marine bacterium) and the CDK inhibitor seliciclib (originally from a marine sponge), highlight the expanding pipeline.

6. Adverse Effects

The adverse effect profiles of these agents are often class-specific but can also include unique toxicities related to their distinct mechanisms.

Common Side Effects

• Cytarabine: Myelosuppression (neutropenia, thrombocytopenia, anemia) is dose-limiting and universal. Nausea, vomiting, diarrhea, and mucositis are frequent. A characteristic “cytarabine syndrome” featuring fever, myalgia, bone pain, maculopapular rash, and conjunctivitis may occur 6-12 hours after administration.
• Eribulin: The most common adverse reactions are neutropenia, anemia, alopecia, peripheral neuropathy (sensory), fatigue, nausea, and constipation. Peripheral neuropathy is typically cumulative.
• Trabectedin: Predominant toxicities include myelosuppression (neutropenia, thrombocytopenia), transient increases in liver transaminases and creatine phosphokinase (CPK), nausea, vomiting, fatigue, and anorexia.
• Ziconotide: Adverse effects are primarily central nervous system-related and often dose-dependent. They include dizziness, nystagmus, confusion, headache, somnolence, nausea, and abnormal gait. Psychiatric effects such as hallucinations and depression may occur.

Serious/Rare Adverse Reactions

• Cytarabine: High-dose regimens can cause severe cerebellar neurotoxicity (ataxia, dysarthria), which may be irreversible, and pulmonary edema (cytarabine lung). Chemical conjunctivitis requires prophylactic steroid eye drops.
• Eribulin: Severe neutropenia may occur, necessitating monitoring. QT interval prolongation has been reported, though it is less common.
• Trabectedin: Rhabdomyolysis and severe hepatotoxicity are potential serious risks. Capillary leak syndrome and extravasation injury leading to tissue necrosis have been reported.
• Ziconotide: Severe psychiatric symptoms and neurological impairment can occur. Meningitis is a risk associated with the intrathecal delivery system. Suicidal ideation has been reported, warranting careful patient screening and monitoring.

Black Box Warnings

Trabectedin carries a black box warning for the risks of myelosuppression, rhabdomyolysis, and hepatotoxicity. Hepatotoxicity can be fatal, and liver function tests must be monitored closely. Ziconotide has a black box warning regarding severe psychiatric symptoms and neurological impairment, emphasizing that it should be administered only by clinicians experienced in intrathecal therapy.

7. Drug Interactions

Significant drug interactions are primarily pharmacokinetic, stemming from effects on metabolic enzymes.

Major Drug-Drug Interactions

Contraindications

Absolute contraindications are specific to each agent. Trabectedin is contraindicated in patients with known hypersensitivity to the drug and in those with severe hepatic impairment (Child-Pugh Class C). Ziconotide is contraindicated in patients with a history of psychosis and for use in the intravenous or epidural routes. Cytarabine is contraindicated in patients with known hypersensitivity. Eribulin is contraindicated in patients with congenital long QT syndrome.

8. Special Considerations

Dosing and administration of marine-derived drugs require careful adjustment in specific patient populations due to altered pharmacokinetics and increased susceptibility to toxicity.

Use in Pregnancy and Lactation

All marine-derived antineoplastics are classified as Pregnancy Category D (positive evidence of human fetal risk). They can cause fetal harm and should be avoided during pregnancy unless the potential benefit justifies the risk to the fetus. Women of childbearing potential should use effective contraception during and for several months after therapy. It is not known if these drugs are excreted in human milk, but due to the potential for serious adverse reactions in nursing infants, breastfeeding is generally discontinued during treatment. Ziconotide is classified as Pregnancy Category C; animal studies have shown adverse effects, but human data are lacking.

Pediatric and Geriatric Considerations

Pediatric: Cytarabine is extensively used in pediatric leukemia protocols, with dosing often based on body surface area. Neurotoxicity from high-dose cytarabine may be more frequent in older children and adults than in young children. Data on eribulin and trabectedin in children are limited. Ziconotide use in patients under 18 years is not well-established.

Geriatric: Older patients may have diminished renal or hepatic function and increased susceptibility to myelosuppression and neuropathy. Dose reductions for eribulin and trabectedin are often recommended for patients with mild hepatic impairment and are required for moderate impairment. Careful monitoring of blood counts and organ function is essential.

Renal and Hepatic Impairment

9. Summary/Key Points

• Marine ethnopharmacology provides access to structurally unique compounds with novel mechanisms of action, addressing significant unmet clinical needs, particularly in oncology and pain management.
• Key approved agents include the antimetabolite cytarabine (from a sponge), the microtubule inhibitor eribulin (from a sponge), the DNA-binding agent trabectedin (from a tunicate), and the N-type calcium channel blocker ziconotide (from a cone snail).
• Mechanisms are diverse and specific: cytarabine inhibits DNA synthesis; eribulin disrupts microtubule dynamics; trabectedin causes DNA damage via transcription-coupled repair interference; ziconotide blocks pain neurotransmitter release in the spinal cord.
• Pharmacokinetics generally necessitate parenteral administration. Trabectedin is metabolized by CYP3A4, leading to significant drug interactions. Eribulin and cytarabine have major routes of elimination via feces and urine, respectively.
• Therapeutic applications are niche but critical: cytarabine for acute leukemias; eribulin for late-line metastatic breast cancer and liposarcoma; trabectedin for advanced soft tissue sarcomas; ziconotide for severe chronic intractable pain.
• Adverse effects are often serious and require vigilant monitoring. These include myelosuppression (cytarabine, eribulin, trabectedin), neurotoxicity (cytarabine, eribulin, ziconotide), hepatotoxicity (trabectedin), and severe psychiatric effects (ziconotide).
• Dose adjustments are frequently required for hepatic impairment (eribulin, trabectedin) and must be considered in renal impairment (cytarabine). These agents are generally contraindicated in pregnancy.

Clinical Pearls

• Prophylactic corticosteroid eye drops are mandatory during high-dose cytarabine administration to prevent chemical conjunctivitis.
• Patients receiving trabectedin require pre- and post-treatment monitoring of liver function tests (ALT, AST, bilirubin) and creatine phosphokinase (CPK) due to risks of hepatotoxicity and rhabdomyolysis.
• Ziconotide must be initiated at a very low dose and titrated slowly to minimize CNS adverse effects; rapid titration is a common cause of intolerance.
• The development of marine-derived drugs often relies on synthetic or semi-synthetic production to ensure supply and reduce ecological impact, moving beyond direct extraction from the source organism.
• The future pipeline of marine ethnopharmacology remains robust, with ongoing research focused on anticancer, antimicrobial, anti-inflammatory, and neuroprotective compounds from diverse marine sources.

References

1. Quattrocchi U. CRC World Dictionary of Medicinal and Poisonous Plants. Boca Raton, FL: CRC Press; 2012.
2. Evans WC. Trease and Evans' Pharmacognosy. 16th ed. Edinburgh: Elsevier; 2009.
3. Heinrich M, Barnes J, Gibbons S, Williamson EM. Fundamentals of Pharmacognosy and Phytotherapy. 3rd ed. Edinburgh: Elsevier; 2017.
4. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
5. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
8. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.