Nudibranchs (sea Slugs) Emerge As A Promising Source Of Cancer Drugs

Brightly colored oversea slugs could clasp nan cardinal to tomorrow’s crab treatments, pinch their diet-derived and self-made chemicals showing potent tumor-killing abilities.

​​​​​​​Review: Nudibranchs arsenic Sources of Marine Natural Products pinch Antitumor Activity: A Comprehensive Review. ​​​​​​​Image Credit: Sakis Lazarides / Shutterstock

In a caller study published successful nan diary Marine Drugs, researchers successful Spain reviewed nan bioactive imaginable of nudibranch-derived compounds, pinch accent connected their antitumor properties.

Background

Cancer is among nan starring causes of mortality and morbidity. In 2022, 20 cardinal crab diagnoses and 9.7 cardinal cancer-related deaths were recorded. Moreover, 30% of premature deaths successful group aged 30–69 were owed to cancer. Thus, it is paramount to augment existing treatments aliases create caller therapies. The hunt for caller narcotics has focused connected earthy resources, extending to oceans.

Marine organisms person adapted to utmost conditions, resulting successful nan accumulation of secondary metabolites pinch precocious bioactivity. Besides, marine metabolites person much halogen atoms, longer c chains, and larger ringing systems pinch less oxygen and much nitrogen atoms than terrestrial metabolites.

To date, much than 20 marine-derived narcotics person been approved by nan U.S. Food and Drug Administration, galore for crab treatment. However, these often look limitations specified arsenic supplier guidance and a deficiency of selectivity, underscoring nan request for continued bioprospecting. Nudibranchs are a group of marine gastropod mollusks pinch astir 4,700 species.

Due to nan deficiency of an outer ammunition and different beingness defenses, nudibranchs person unsocial chemic defense strategies, involving de novo synthesis of bioactive metabolites aliases accumulation and modification of toxins and secondary dietary compounds, which are often concentrated successful accessible tissues for illustration nan mantle aliases dorsal extensions called cerata.

In nan coming study, researchers reviewed nan imaginable of nudibranchs arsenic a root of marine earthy products pinch antitumor properties.

Nudibranchs and Their Antitumor Potential

Nudibranchs person emerged arsenic promising candidates for caller pharmacological agents for crab therapy. Studies person identified galore secondary metabolites successful nudibranchs that grounds cytotoxic properties, pinch galore showing antitumor potential. Alkaloids and terpenes, chiefly diterpenoids and sesquiterpenes, are nan awesome types of bioactive molecules successful nudibranchs.

The reappraisal notes that galore of these compounds are not made by nan nudibranchs themselves but are sequestered from their diet, specified arsenic sponges, and sometimes chemically modified for their ain defense.

A study demonstrated potent cytotoxic effects of methanol-dichloromethane extracts derived from Dolabella auricularia and Phyllidia varicosa against colorectal crab (CRC) compartment lines. Another study reported little cytotoxic effect of acetone extracts derived from Armina maculata, Armina tricolorata, and Armina tigrina against lung and tummy crab compartment lines.

Acetone extracts from Phyllidia coelestis person been purified to get bisabolane-type sesquiterpenoids specified arsenic 7-isocyano-7,8-dihydro-α-bisabolene, theonellin isothiocyanate, and 3-isocyanotheonellin. Notably, nan insubstantial highlights that structural analogs of these compounds were besides recovered successful nan nudibranch's sponge prey, Axinissa variabilis, powerfully suggesting a dietary root for these metabolites.

Studies person reported cytotoxicity of 3-isocyanotheonellin against lung, liver, CRC, and pancreatic crab compartment lines, and 7-isocyano-7,8-dihydro-α-bisabolene and theonellin isothiocyanate against 1 liver crab compartment statement only.

Potent isoquinolinequinone alkaloids derived from Jorunna funebris person shown antitumor activity against various crab compartment lines. Examples see fennebricin A against leukemia and lung crab compartment lines, renieramycin M against CRC and lung crab compartment lines, and jorumycin against melanoma, lymphocytic leukemia, and lung crab compartment lines. These compounds beryllium to a people of aromatic alkaloids characterized by fused quinone and isoquinoline ringing systems, often associated pinch DNA-interactive and pro-apoptotic activity.

In different illustration of compounds showing activity against hard-to-treat cancers, nan insubstantial mentions phorbazole alkaloids from Aldisa andersoni, which demonstrated cytotoxicity against respective compartment lines known to beryllium resistant to pro-apoptotic stimuli.

Furthermore, tambjamines are nan superior metabolites from Tambja brasiliensis and Tambja stegosauriformis. Tambjamine K has demonstrated antitumor activity successful glioma and cervical crab compartment lines, though nan reappraisal notes that immoderate tambjamines besides grounds toxicity against non-tumor cells, highlighting nan captious situation of achieving selectivity.

Nudibranch morphological groups: cladobranch nudibranchs, including Nemesignis banyulensis (a) and Facelina vicina (b), and dorid nudibranchs, including Felimare picta (c,d).

A Reservoir of Defense: The Role of Egg Masses

The reappraisal besides highlights that nan brightly colored and exposed ovum masses of immoderate nudibranchs, specified arsenic Hexabranchus sanguineus, service arsenic concentrated reservoirs for protect compounds. Molecules for illustration ulapualides, isolated from these ovum masses, person shown potent antitumor activity and whitethorn beryllium easier to isolate successful larger quantities compared to extracting them from nan big animals, offering different strategical avenue for supplier discovery.

Mechanisms of Action of Nudibranch Derivatives

Research has unveiled respective mechanisms of action contributing to nan antitumor activity of nudibranch compounds. These see DNA harm induction, oxidative and endoplasmic reticulum (ER) stress, reactive oxygen type (ROS) generation, compartment rhythm arrest, and apoptosis. A study reported that dendrodoristerol isolated from Dendrodoris fumata exhibits antitumor activity by inducing apoptosis successful leukemia cells.

Further, different study showed that palmadorin M isolated from Austrodoris kerguelenensis inhibits nan activation of extracellular signal-regulated kinase 1 and 2 (Erk1/2), Janus kinase 2 (Jak2), and awesome transducer and activator of transcription 5 (STAT5), inducing apoptosis successful leukemia cells. The methanol-dichloromethane extracts from P. varicosa and D. auricularia grounds antitumor and anti-proliferative effects by inducing DNA damage, oxidative stress, and apoptosis successful CRC compartment lines.

A consequent study reported that nan D. auricularia extract had selective cytotoxicity against CRC cells and minimal effect connected normal colon fibroblasts; nan antitumor activity was mediated done nan procreation of ROS, inducing ER accent and activating unfolded macromolecule response. The ROS-mediated ER accent resulted successful G2/M shape compartment rhythm arrest, DNA damage, and apoptosis.

​​​​​​​Main mechanisms of action of nudibranch-derived molecules and extracts.

In addition, akin mechanisms of action were reported for KLM155, a toluhydroquinone (a hydroquinone derivative) derived from Leminda millecra, successful an esophageal crab compartment line. Its antitumor activity was associated pinch compartment rhythm apprehension successful nan G2 phase, ROS production, and apoptosis induction. In summation to antitumor activity, various nudibranch derivatives grounds different biologic activities. For instance, A. tigrina, A. tricolorata, and A. maculata extracts grounds anti-inflammatory activity.

Echinoclerodane A, a diterpenoid from Hexabranchus sanguineus, has potent inhibitory effects connected inflammatory responses successful RAW264.7 macrophages. Besides, fennebricin A acts arsenic an inhibitor of atomic facet kappa B (NF-κB) signaling. Nudibranchs person besides been recognized for antiparasitic and antimicrobial potential. For example, compounds pinch leishmanicidal and antibacterial activity person been isolated from Chromodoris willani and Doriprismatica stellata, respectively.

Concluding Remarks

Together, nudibranchs are a group of marine invertebrates pinch mostly underexplored pharmacological and biologic potential. The study has highlighted nan singular antitumor activity of extracts and compounds derived from nan constricted number of nudibranchs studied to date.

Despite nan promising findings, nan reappraisal emphasizes that further investigation is needed to corroborate nan objective imaginable of nudibranch derivatives. More specifically, nan insubstantial suggests that early studies should attraction not only connected standardization of extraction methodologies and optimization of isolation and purification protocols, but besides connected respective cardinal areas. These see exploring nan comparatively unstudied cladobranch group of nudibranchs, which person different diets and whitethorn output caller compounds; analyzing different anatomical parts of nan organisms, specified arsenic nan mantle versus nan viscera; and investigating nan microbiome associated pinch nudibranchs, arsenic their symbiotic germs correspond different important root of bioactive molecules.