Squalamine

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Squalamine

Common Names

  • Squalamine lactate

For Patients & Caregivers

How It Works

Squalamine has anticancer effects but definitive evidence is lacking.

Squalamine is a compound derived from dogfish shark tissues. It has been shown to kill bacteria and block growth of new blood vessels in laboratory studies. Clinical studies show that squalamine is safe and well-tolerated when given to patients with cancer and age-related macular degeneration. However, these studies used the injectable form of squalamine. It is unclear if oral squalamine products have the same effects. Further research is needed.

Squalamine should not be confused with squalene, an oil found in shark liver.

Purported Uses
  • To treat cancer
    Clinical studies have shown that the injectable form of squalamine is safe in patients with solid tumors, but it is not known if it can treat cancer.
  • To treat age-related macular degeneration
    Clinical studies have shown that squalamine is safe and well tolerated, but it is not known if it can be used to treat this condition.
  • To treat bacterial infections
    Squalamine showed antibacterial effects in lab studies, but clinical trials have not been done to show that it can be used to treat bacterial infections.
Side Effects
  • Fatigue, nausea, anorexia, and liver toxicity have been reported following use of intravenous squalamine in a clinical study.
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For Healthcare Professionals

Clinical Summary

Squalamine is a water-soluble steroidal antibiotic first identified in the tissues of the dogfish shark Squalus acanthias (1), and is now produced synthetically. It has significant bactericidal and fungicidal effects, as well as enhances the bactericidal effects when used in combination with standard antibiotics (2) (3) (4); and significantly reduces aggregation of alpha-synuclein, a protein associated with Parkinson’s disease and related syndromes (18).

Squalamine was also shown to inhibit growth factor-dependent pathways in endothelial cells and has been studied since as a treatment for age-related macular degeneration and cancer (19) (20). The injectable form was reported to be well tolerated in patients with age-related macular degeneration (5), and in those with cancer, in Phase I and II trials (6) (7). But it is not known if oral squalamine would have similar effects.

Preliminary findings have shown that topical squalamine, when combined with ranibizumab, improved visual recovery in patients with retinal vein occlusion-related macular edema (21); and a squalamine ointment demonstrated partial clinical activity for the treatment of tinea capitis (22).

Squalamine analogues are currently being studied as potential agents for nasal decolonization of Staphyloccus aureus to prevent risk of associated infections (23). In  addition, eye drops are being developed for topical administration for various angiogenic inhibitors, including squalamine lactate, against neovascular age-related macular degeneration (24).

Squalamine should not be confused with squalene, an oil found in shark liver.

Food Sources
  • Dogfish shark, Squalus acanthias: Squalamine is found primarily in liver and gallbladder, but also in the spleen, testes, stomach, gills, and intestine.
  • Sea lamprey, Petromyzon marinus  (2)
Purported Uses
  • Cancer treatment
  • Age-related macular degeneration
  • Bacterial infections
Mechanism of Action

Squalamine is a cholestane steroid conjugated to a spermidine at position C-3. However, it does not have glucocorticoid and mineralocorticoid effects (8). Squalamine binds to cell membranes and inhibits the specific membrane Na+/H+ exchanger NHE3, causing an alteration in intracellular pH and a disruption of intracellular signaling induced by angiogenic growth factors (8).

Squalamine alters the shape and decreases volume of endothelial cells in embryonic vascular beds, causing narrowing of the vessel lumen and occluding blood flow (10). These actions inhibit multiple key steps in angiogenesis, including mitogen-induced actin polymerization, cell-cell adhesion, and cell migration, ultimately inhibiting endothelial cell proliferation. Squalamine blocks downstream signaling pathways of VEGF, including VEGF-induced phosphorylation of p44/p42 MAP kinase in vascular endothelial cells (11), disrupts F-actin fibers, and induces internalization of vascular endothelial-cadherin from the membrane into the intracellular compartment (12). It decreases retinal neovascularization that is thought to benefit macular degeneration (17).

Squalamine is an amphipathic compound that interacts with various membrane glycerophospholipids at unique affinities (4). It has a faster killing rate of gram-positive bacteria than gram-negative bacteria (3) (13) (14). It also enhances the cytotoxicity of chemotherapy drugs (15) by promoting tumor cell apoptosis and by reduced angiogenesis (16) (10). Its antiangiogenic effects are due to inhibition of endothelial cell proliferation and migration induced by various growth factors (9).

Adverse Reactions
  • Fatigue, nausea, anorexia, and hepatotoxicity have been reported following use of intravenous squalamine in a clinical study (9).
References
  1. Moore KS, Wehrli S, Roder H, et al. Squalamine: an aminosterol antibiotic from the shark.Proc Natl Acad Sci U S A. Feb 15 1993;90(4):1354-1358.

  2. Lavigne JP, Brunel JM, Chevalier J, Pages JM. Squalamine, an original chemosensitizer to combat antibiotic-resistant gram-negative bacteria. J Antimicrob Chemother. Apr 2010;65(4):799-801.

  3. Emerson MV, Lauer AK. Current and emerging therapies for the treatment of age-related macular degeneration.Clin Ophthalmol. Jun 2008;2(2):377-388.

  4. Hao D, Hammond LA, Eckhardt SG, et al. A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor. Clin Cancer Res. Jul 2003;9(7):2465-2471.

  5. Pietras RJ, Weinberg OK. Antiangiogenic Steroids in Human Cancer Therapy. Evid Based Complement Alternat Med. Mar 2005;2(1):49-57.

  6. Bhargava P, Marshall JL, Dahut W, et al. A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers. Clin Cancer Res. Dec 2001;7(12):3912-3919.

  7. Williams JI, Weitman S, Gonzalez CM, et al. Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies. Clin Cancer Res. Mar 2001;7(3):724-733.

  8. Alhanout K, Brunel JM, Ranque S, Rolain JM.In vitro antifungal activity of aminosterols against moulds isolated from cystic fibrosis patients. J Antimicrob Chemother. Jun 2010;65(6):1307-1309.

  9. Alhanout K, Brunel JM, Raoult D, Rolain JM. In vitro antibacterial activity of aminosterols against multidrug-resistant bacteria from patients with cystic fibrosis.J Antimicrob Chemother. Oct 2009;64(4):810-814.

  10. Teicher BA, Williams JI, Takeuchi H, Ara G, Herbst RS, Buxton D. Potential of the aminosterol, squalamine in combination therapy in the rat 13,762 mammary carcinoma and the murine Lewis lung carcinoma. Anticancer Res. Jul-Aug 1998;18(4A):2567-2573.

  11. Higgins RD, Sanders RJ, Yan Y, Zasloff M, Williams JI. Squalamine improves retinal neovascularization. Invest Ophthalmol Vis Sci. May 2000;41(6):1507-1512.

  12. Perni M, Galvagnion C, Maltsev A, et al. A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E1009-E1017.

  13. Genaidy M, Kazi AA, Peyman GA, et al. Effect of squalamine on iris neovascularization in monkeys. Retina. 2002 Dec;22(6):772-8.

  14. Coulibaly O, Thera MA, Koné AK, et al. A double-blind randomized placebo-controlled clinical trial of squalamine ointment for tinea capitis treatment. Mycopathologia. 2015 Apr;179(3-4):187-93.

  15. Sakr A, Brégeon F, Rolain JM, Blin O. Staphylococcus aureus nasal decolonization strategies: a review. Expert Rev Anti Infect Ther. 2019 May;17(5):327-340.

  16. Pecen PE, Kaiser PK. Current phase 1/2 research for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2015 May;26(3):188-93.

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