Squalamine; natural anti cancer drug

What is Squalamine?

Squalamine is an essential ingredient which may be derived from various sources in nature. One known source of squalamine is predominantly found in the liver tissue (not the "liver oil") of the deep water shark. The "liver oil" of the shark contains only trace amounts of the compound squalamine, however, it also contains many other exotic compounds. Squalamine is not a protein. Instead, it is the first known example of a class of compounds called aminosterols, each being a steroid chemically linked to an amino acid. Proteins are easily destroyed by digestive enzymes in the stomach, however, squalamine remains unscathed through the digestive tract.

Benefits of Squalamine

Angiogenesis is a function in the body where unhealthy cells develop their own blood vessel structure in order to nourish and support themselves. The immune system, in response, uses certain compounds in the body to naturally counter angiogenesis. This normal body function is called anti-angiogenesis.

If the immune system is successful in carrying out this designed natural function, unhealthy cells can not survive. However, if the body is deficient in these vital compounds, anti-angiogenesis can not occur. Therefore, it is important to supplement the body with natural anti-angiogenesis factors. Squalamine is an aminosterol compound which the body readily uses to carry out its normal anti-angiogenesis function.

Squalamine: an appropriate strategy against the emergence of multidrug resistant gram-negative bacteria?

Salmi C, Loncle C, Vidal N, Letourneux Y, Fantini J, Maresca M, Taïeb N, Pagès JM, Brunel JM. UMR-MD1, Facultés de Médecine et de Pharmacie, Marseille, France.

We reported that squalamine is a membrane-active molecule that targets the membrane integrity as demonstrated by the ATP release and dye entry. In this context, its activity may depend on the membrane lipid composition. This molecule shows a preserved activity against bacterial pathogens presenting a noticeable multi-resistance phenotype against antibiotics such as polymyxin B. In this context and because of its structure, action and its relative insensitivity to efflux resistance mechanisms, we have demonstrated that squalamine appears as an alternate way to combat MDR pathogens and by pass the gap regarding the failure of new active antibacterial molecules.

Identification of squalamine in the plasma membrane of white blood cells in the sea lamprey, Petromyzon marinus.


Department of Fisheries and Wildlife, Michigan State University, East Lansing, MI 48824, USA. Yun SS, Li W.

It is well established that innate mechanisms play an important role in the immunity of fish. Antimicrobial peptides have been isolated and characterized from several species of teleosts. Here, we report the isolation of an antimicrobial compound from the blood of bacterially challenged sea lamprey, Petromyzon marinus. An acetic acid extract from the blood cells of challenged fish was subjected to solid-phase extraction, cation-exchange chromatography, gel-filtration chromatography, and reverse-phase high-performance liquid chromatography, with the purified fractions assayed for antimicrobial activity. Surprisingly, antimicrobial activity in these fractions originated from squalamine, an aminosterol previously identified in the dogfish shark, Squalus acanthias. Further chromatographic and mass spectrometric analyses confirmed the identity of squalamine, an antimicrobial and antiangiogenic agent, in the active fraction from the sea lamprey blood cells. Immunocytochemical analysis localized squalamine to the plasma membrane of white blood cells. Therefore, we postulate that squalamine has an important role in the innate immunity that defends the lamprey against microbial invasion. The full biochemical and immunological roles of squalamine in the white blood cell membrane remain to be investigated.

Squalamine: an aminosterol antibiotic from the shark.

Moore KS, Wehrli S, Roder H, Rogers M, Forrest JN Jr, McCrimmon D, Zasloff M.
Division of Human Genetics and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia 19104.

In recent years, a variety of low molecular weight antibiotics have been isolated from diverse animal species. These agents, which include peptides, lipids, and alkaloids, exhibit antibiotic activity against environmental microbes and are thought to play a role in innate immunity. We report here the discovery of a broad-spectrum steroidal antibiotic isolated from tissues of the dogfish shark Squalus acanthias. This water-soluble antibiotic, which we have named squalamine, exhibits potent bactericidal activity against both Gram-negative and Gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. The chemical structure of the antibiotic 3 beta-N-1-(N-[3-(4-aminobutyl)]- 1,3-diaminopropane)-7 alpha,24 zeta-dihydroxy-5 alpha-cholestane 24-sulfate has been determined by fast atom bombardment mass spectroscopy and NMR. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. The discovery of squalamine in the shark implicates a steroid as a potential host-defense agent in vertebrates and provides insights into the chemical design of a family of broad-spectrum antibiotics.

Aminosterols from the dogfish shark Squalus Acanthias.

Rao MN, Shinnar AE, Noecker LA, Chao TL, Feibush B, Snyder B, Sharkansky I, Sarkahian A, Zhang X, Jones SR, Kinney WA, Zasloff M. Magainin Pharmaceuticals, Inc., 5110 Campus Drive, Plymouth Meeting, Pennsylvania 19462, USA.

Seven new aminosterols related to squalamine (8) were isolated from the liver of the dogfish shark Squalus acanthias. Their structures (1-7) were determined using spectroscopic methods, including 2D NMR and HRFABMS. These aminosterols possess a relatively invariant cholestane skeleton with a trans AB ring junction, a spermidine or spermine attached equatorially at C3, and a steroidal side-chain that may be sulfated. The structure of the lone spermine conjugate, 7 (MSI-1436), was confirmed by its synthesis from (5alpha,7alpha, 24R)-7-hydroxy-3-ketocholestan-24-yl sulfate. Some members of this family of aminosterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.

Squalamine: a polyvalent drug of the future?

Brunel JM, Salmi C, Loncle C, Vidal N, Letourneux Y.
Laboratoire SESNAB Faculté de St Jérôme, Université Paul Cézanne, Av. Escadrille Normandie Niemen, 13397 Marseille, Cedex 20, France. bruneljm@yahoo.fr

The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future?

 

Antiangiogenic Steroids in Human Cancer Therapy.

Pietras RJ, Weinberg OK.

Despite advances in the early detection of tumors and in the use of chemotherapy, radiotherapy and surgery for disease management, the worldwide mortality from human cancer remains unacceptably high. The treatment of cancer may benefit from the introduction of novel therapies derived from natural products. Natural products have served to provide a basis for many of the pharmaceutical agents in current use in cancer therapy. Emerging research indicates that progressive growth and spread of many solid tumors depends, in part, on the formation of an adequate blood supply, and this process of tumor-associated angiogenesis is reported to have prognostic significance in several human cancers.

This review focuses on the potential application in antitumor therapy of naturally-occurring steroids that target tumor-associated angiogenesis. Squalamine, a 7,24 dihydroxylated 24-sulfated cholestane steroid conjugated to a spermidine at position C-3, is known to have strong antiangiogenic activity in vitro, and it significantly disrupts tumor proliferation and progression in laboratory studies. Work on the interactions of squalamine with vascular endothelial cells indicate that it binds with cell membranes, inhibits the membrane Na(+)/H(+) exchanger and may further function as a calmodulin chaperone. These primary actions appear to promote inhibition of several vital steps in angiogenesis, such as blockade of mitogen-induced actin polymerization, cell-cell adhesion and cell migration, leading to suppression of endothelial cell proliferation.

Preclinical studies with squalamine have shown additive benefits in tumor growth delay when squalamine is combined with cisplatin, paclitaxel, cyclophosphamide, genistein or radiation therapy. This compound has also been assessed in early phase clinical trials in cancer; squalamine was found to exhibit little systemic toxicity and was generally well tolerated by treated patients with various solid tumor malignancies, including ovarian, non-small cell lung and breast cancers.

Clinical trials with squalamine alone or combined with standard chemotherapies or other biologic therapies, including antiangiogenic agents, should be considered for selected cancer patients, and further study of the mechanism of action and bioactivity of squalamine is warranted.