What is Squalamine? Benefits and Uses in Health

Sharks have roamed the oceans for over 400 million years, and their remarkably robust immune systems have long intrigued scientists. One of the most fascinating discoveries to emerge from studying these ancient predators is squalamine – a natural compound first isolated from the liver of the dogfish shark (Squalus acanthias) in 1993. Squalamine belongs to a class of molecules called aminosterols, which combine features of steroids and polyamines. What started as a search for new antimicrobial agents has since revealed a compound with a surprisingly wide range of health benefits – from fighting infections and cancer to addressing Parkinson’s disease symptoms.

What exactly is squalamine? 🔗

Squalamine is a water-soluble cationic steroid that consists of a cholesterol-like core linked to a polyamine called spermidine. It is found naturally in several tissues of the dogfish shark, including the liver, gallbladder, intestines, stomach, and testes. However, the concentrations are extremely low – shark liver tissue contains only about 10-20 micrograms per gram, which makes harvesting it from wild sharks impractical.

Because of this scarcity, researchers have developed methods to synthesize squalamine in laboratories. Today, the compound used in research and clinical trials is entirely lab-produced, which eliminates the need to source it from sharks. This synthetic version is chemically identical to the natural molecule and retains all its biological properties.

Antibacterial and antifungal properties 🔗

One of the first things scientists noticed about squalamine was its powerful antimicrobial activity. It is effective against a wide range of pathogens, including both gram-negative and gram-positive bacteria, fungi, and even protozoa.

How does squalamine kill microbes? 🔗

Squalamine works by disrupting the cell membranes of bacteria and fungi. As a positively charged (cationic) molecule, it is attracted to the negatively charged components of microbial membranes, particularly the lipopolysaccharides (LPS) found on gram-negative bacteria. Once squalamine binds to these membranes, it creates structural damage that leads to cell death.

Research published in Microorganisms has shown that squalamine and its synthetic derivatives demonstrate bactericidal activity comparable to established antibiotics like colistin and polymyxins. Importantly, squalamine has also shown effectiveness against multidrug-resistant (MDR) bacteria, which is significant given the growing global crisis of antibiotic resistance.

In laboratory tests, squalamine achieved minimum inhibitory concentrations (MICs) as low as 2 mg/L against common pathogens like E. coli and S. aureus. It has also demonstrated antifungal activity and can cause osmotic lysis (bursting) of protozoan organisms.

Antiviral potential 🔗

Beyond bacteria and fungi, evidence suggests squalamine may also have antiviral activity against both RNA- and DNA-enveloped viruses. While this area is still being explored, it adds another dimension to squalamine’s potential as a broad-spectrum antimicrobial agent.

Anti-tumor and anti-cancer activity 🔗

Perhaps the most exciting area of squalamine research involves its anti-cancer properties. Squalamine does not directly kill cancer cells in the way conventional chemotherapy drugs do. Instead, it targets a process that tumors depend on for survival – the formation of new blood vessels, known as angiogenesis.

How squalamine blocks tumor blood supply 🔗

Tumors need a constant supply of oxygen and nutrients to grow beyond a few millimetres in size. They achieve this by releasing signalling molecules, especially vascular endothelial growth factor (VEGF), which stimulate nearby blood vessels to sprout new branches toward the tumor.

Squalamine interferes with this process at multiple levels. It blocks VEGF-induced activation of signalling pathways in endothelial cells (the cells lining blood vessels), inhibits endothelial cell proliferation and migration, disrupts the organisation of structural proteins within these cells, and reduces the expression of molecules that help cells adhere together. The net result is that new blood vessels cannot form properly, effectively starving the tumor of its supply lines.

Results in cancer models 🔗

Preclinical studies have been encouraging. In animal models, squalamine has shown anti-tumor activity against several types of cancer, including lung, breast, brain, ovarian, and prostate cancers. The compound appears to be most effective when combined with standard chemotherapy drugs like cisplatin, carboplatin, and paclitaxel.

For example, research using human non-small cell lung cancer xenografts found that squalamine combined with cisplatin produced significantly better tumor growth inhibition than cisplatin alone. Similar enhancement was seen when squalamine was added to platinum-based regimens for ovarian cancer and neuroblastoma models. In Lewis lung carcinoma models, squalamine treatment cut the number of metastases roughly in half.

Clinical trials in humans 🔗

Based on the strong preclinical data, squalamine moved into human clinical trials. A Phase I study involving 19 patients with advanced cancers established that squalamine can be safely administered intravenously. The main side effect at higher doses was reversible liver enzyme elevation. Following this, combination trials were initiated for patients with late-stage non-small cell lung cancer and ovarian cancer.

A subsequent Phase I study confirmed that at the recommended dose, squalamine plasma concentrations were well above the levels needed for anti-angiogenic effects in preclinical models. The U.S. FDA designated squalamine as an “orphan drug” for the development of ovarian cancer treatment, highlighting its therapeutic promise.

Eye disease treatment 🔗

Squalamine’s ability to inhibit abnormal blood vessel growth is not only relevant to cancer. It has also been investigated for age-related macular degeneration (AMD), particularly the “wet” form, where abnormal blood vessels grow beneath the retina and leak fluid, causing vision loss.

In early clinical studies, squalamine eye drops and intravenous squalamine showed encouraging results. The compound received FDA fast-track status for the treatment of wet AMD, and at concentrations as low as 1 part per million, intravenous squalamine promoted shrinkage of the abnormal blood vessels and improved vision in some patients.

Squalamine and Parkinson’s disease 🔗

One of the more recent and perhaps surprising applications of squalamine research involves Parkinson’s disease (PD). This connection emerged from the discovery that squalamine can displace proteins that are stuck to the inner surfaces of cell membranes.

The alpha-synuclein connection 🔗

Parkinson’s disease is characterised by the abnormal accumulation of a protein called alpha-synuclein within neurons. These protein clumps, known as Lewy bodies, damage nerve cells and lead to the movement problems and other symptoms associated with the disease. Critically, alpha-synuclein aggregation often begins in the enteric nervous system (the network of nerves in the gut) years before the classic motor symptoms appear, causing severe constipation in many patients.

Research has shown that squalamine can prevent alpha-synuclein from clustering on neuronal membranes and can reduce the toxicity of existing aggregates. In laboratory worm models engineered to overproduce human alpha-synuclein, squalamine treatment prevented the paralysis that normally results from protein aggregation.

Clinical progress 🔗

A biotech company called Enterin developed a synthetic squalamine salt called ENT-01 specifically for oral administration to treat gut-related symptoms in Parkinson’s patients. The Phase 2b KARMET study involving 150 participants showed that ENT-01 significantly improved bowel function compared to placebo. Patients experienced better stool consistency, easier passage, and reduced need for laxatives. Remarkably, the benefits persisted for weeks after the treatment period ended.

Even more intriguing, participants with psychotic symptoms at baseline who received the squalamine derivative showed substantial improvement in those symptoms as well, along with gains in cognitive function. These observations have led researchers to suggest a possible disease-modifying effect, and Phase 3 trials have been planned.

Appetite suppression and metabolic health 🔗

Squalamine and its related aminosterol MSI-1436 (trodusquemine) have demonstrated appetite-suppressing properties in animal studies. MSI-1436 has been shown to decrease body fat content by reducing the levels of appetite-stimulating molecules – specifically agouti-related peptide and neuropeptide Y – in the hypothalamus of mice.

While squalamine itself has shown appetite-suppressing effects, much of the obesity-related research has focused on trodusquemine, which differs from squalamine by having a spermine (rather than spermidine) side chain. Both compounds belong to the same aminosterol family and share the ability to interact with metabolic pathways that regulate hunger and fat storage. Given the global rise in obesity and its connection to type 2 diabetes, these properties represent an important area for future investigation.

From shark liver to fish by-product utilisation 🔗

The story of squalamine also highlights an important aspect of fish by-product utilisation. Shark liver and other tissues that might otherwise be discarded during fish processing contain bioactive compounds with significant pharmaceutical potential. While modern squalamine is synthesised in laboratories, the initial discovery came from studying these by-products.

Marine organisms, having evolved over millions of years in challenging environments, produce bioactive compounds that often have stronger biological activities than their land-based counterparts. This makes fish processing by-products – livers, gallbladders, intestines, and other organs – a valuable resource for discovering new nutraceuticals and pharmaceutical leads.

Challenges and limitations 🔗

Despite its promise, squalamine research faces several important challenges. The natural concentration in shark tissues is extremely low, making extraction impractical at scale. Chemical synthesis is complex and expensive, though companies like Pfizer CentreOne have taken on large-scale manufacturing.

From a clinical perspective, there is still insufficient evidence to confirm squalamine’s safety and efficacy for many of the conditions it is being explored for. Most of the cancer-related benefits have been observed in preclinical models, and while early-phase clinical trials are encouraging, larger randomised controlled trials are needed before squalamine can become a standard treatment option.

It is also worth noting that squalamine is distinct from shark cartilage or shark liver oil, which are sometimes marketed as health supplements. These products may contain trace amounts of squalamine, but they are not equivalent to the purified compound used in research.

The future of squalamine research 🔗

Squalamine sits at the intersection of marine biotechnology, antimicrobial research, oncology, and neuroscience. Its ability to fight infections, starve tumors, protect neurons, and influence metabolism makes it one of the most versatile natural compounds currently under investigation.

Ongoing and planned clinical trials – particularly for Parkinson’s disease and various cancers – will determine whether squalamine or its derivatives can translate their impressive laboratory results into real-world treatments. The development of synthetic analogues with improved potency and fewer side effects is also an active area of research, with several promising derivatives already showing strong results in preclinical studies.

What do you think? Could compounds derived from marine organisms like shark liver hold the key to addressing some of the most stubborn diseases we face today? And as we advance in synthesising these molecules in laboratories, how might the field of fish by-product utilisation evolve to contribute more meaningfully to pharmaceutical research?

References

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC45871/
2. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/squalamine
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC9229800/
4. https://www.mdpi.com/2076-2607/10/6/1205
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC1062159/
6. https://pubmed.ncbi.nlm.nih.gov/11297269/
7. https://aacrjournals.org/clincancerres/article/7/12/3912/203115/A-Phase-I-and-Pharmacokinetic-Study-of-Squalamine
8. https://parkinsonsnewstoday.com/news/natural-compound-squalamine-shows-promise-as-parkinsons-treatment/
9. https://practicalneurology.com/news/a-synthetic-derivative-of-squalamine-restored-the-function-of-enteric-nerve-cells-in-parkinson-disease/2469810/
10. https://pubs.acs.org/doi/10.1021/cen-10024-cover2
11. https://www.webmd.com/vitamins/ai/ingredientmono-751/squalamine