Health Care Professional Information

Common Name

Squalamine lactate

Clinical Summary

Squalamine is a water-soluble substance derived from the internal organs of dogfish, Squalus acanthias, and is thought to act as a systemic antimicrobial agent (1) (2). The oral form is marketed as a dietary supplement but the parenteral form has been used in clinical studies. Squalamine demonstrated significant bactericidal and fungicidal effects and also enhances the bactericidal effects when used in combination with standard antibiotics (3) (4).

Squalamine exhibits antiangiogenic property, and has been studied as a treatment for age-related macular degeneration and cancer. The injectable form is well tolerated in those with age-related macular degeneration and cancer in Phase I and II trials (5) (6) (7). However, it is unclear if oral squalamine has similar effects. Further studies are necessary.
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 spleen, testes, stomach, gills, and intestine.
  • Sea lamprey, Petromyzon marinus
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, and (11) disrupts F-actin fibers (12). It also 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).
Squalamine 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).

Pharmacokinetics

The median time to achieve maximum concentration following intravenous administration of squalamine was 96 hours and ranged from 4 to 120 hours across all dose rate levels.

Squalamine was initially cleared rapidly from the circulation, with a median half-life being 49.2 min. The terminal squalamine plasma half-life is much longer, a median of 7.2 h. These values suggest that a residual amount of squalamine persists outside the circulatory system that slowly leaches back into the plasma (9).

Adverse Reactions

In clinical studies using the parenteral form of squalamine, symptoms including fatigue, nausea, anorexia, and hepatotoxicity have been reported (9).

Herb-Drug Interactions
  • Cisplatin, paclitaxel, and cyclophosphamide: Squalamine may increase cytotoxic effects (6) (8) (10).
  • Colistin and tobramycin: Squalamine may increase antibiotic effects (13).
Literature Summary and Critique

Hao D, Hammond LA, Eckhardt SG, et al. A phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor. Clinical Cancer Research. 2003;9:2465-71.
This Phase I study of squalamine examined 33 patients with advanced solid tumor malignancies. Squalamine was administered as a single-agent, 5-day continuous IV infusion, repeated every 3 weeks. The principal dose-limiting toxicity of squalamine was hepatotoxicity, which involved brief, asymptomatic elevations in transaminases, and hyperbilirubinemia.
The authors concluded that the recommended dose should not exceed 500 mg/m2/day as continuous IV infusion over 5 days every 3 weeks. Compared to the (Bhargava 2001) study's results on pharmacokinetics, squalamine demonstrated dose-proportional kinetics in this study.

Herbst RS, Hammond LA, Carbone DP, et al. A Phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clinical Cancer Research. 2003;9:4108-15.
This study was conducted to determine the antitumor efficacy of squalamine in combination with carboplatin and paclitaxel. Forty-five patients with stage IIIB or stage IV non-small cell lung cancer were given a 5-day continuous infusion of squalamine with standard chemotherapy. Toxicities were limited to mild myelosuppression. Squalamine showed linear pharmacokinetics. The plasma clearance of squalamine did not change by dose level. The maximum tolerated dose (MTD) recommended was found to be 300 mg/m2/day. The pharmacokinetic profile of paclitaxel remained unchanged, and clearance of carboplatin was also unaffected by co-administration with squalamine. Significantly, among the 35 evaluable patients in the study, 12 had documented partial responses, giving an objective clinical response rate of 34%.
Researchers concluded that given the safety profile and patient survival data, squalamine at its MTD combined with chemotherapy should be studied further as potential therapy for stage IIIB or IV non-small cell lung cancer.

Emerson MV, Lauer AK. Current and emerging therapies for the treatment of age-related macular degeneration. Clinical Ophthalmology. 2008;2(2):377-388.
Forty patients with age-related macular degeneration (AMD) received 25 or 50 mg/m2 of systemic squalamine lactate each week for a period of 4 weeks. It was found to be ineffective when administered intravitreally. No patients lost vision, and 26% of patients showed improvement in vision by 3 lines.
This study was supported by Geneara Corporation, which also initiated a phase III study of squalamine lactate to treat AMD, but the study was terminated.

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. Yun SS, Li W. Identification of squalamine in the plasma membrane of white blood cells in the sea lamprey, Petromyzon marinus. J Lipid Res. Dec 2007;48(12):2579-2586.
  3. 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.
  4. Salmi C, Loncle C, Vidal N, et al. Squalamine: an appropriate strategy against the emergence of multidrug resistant gram-negative bacteria?PLoS One. 2008;3(7):e2765.
  5. Emerson MV, Lauer AK. Current and emerging therapies for the treatment of age-related macular degeneration.Clin Ophthalmol. Jun 2008;2(2):377-388.
  6. Herbst RS, Hammond LA, Carbone DP, et al. A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res. Sep 15 2003;9(11):4108-4115.
  7. 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.
  8. Pietras RJ, Weinberg OK. Antiangiogenic Steroids in Human Cancer Therapy. Evid Based Complement Alternat Med. Mar 2005;2(1):49-57.
  9. 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.
  10. Schiller JH, Bittner G. Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization. Clin Cancer Res. Dec 1999;5(12):4287-4294.
  11. Soker S, Fidder H, Neufeld G, Klagsbrun M. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J Biol Chem. Mar 8 1996;271(10):5761-5767.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Li D, Williams JI, Pietras RJ. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without HER-2 gene overexpression. Oncogene. Apr 25 2002;21(18):2805-2814.
  17. Higgins RD, Sanders RJ, Yan Y, Zasloff M, Williams JI. Squalamine improves retinal neovascularization. Invest Ophthalmol Vis Sci. May 2000;41(6):1507-1512.

Consumer Information

How It Works

Bottom Line: Squalamine has anticancer effects but definitive evidence is lacking.

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

Purported Uses
  • To treat cancer
    Clinical studies have shown that the injectable form of squalamine is safe to give to human subjects with solid tumors, but they have not proven that squalamine is an effective anticancer drug.
  • To treat age-related macular degeneration
    Clinical studies have shown that squalamine is safe to give to human subjects, but they have not proven that squalamine is an effective drug to treat the condition.
  • To treat bacterial infections
    Experimental studies show that squalamine kills gram-positive and gram-negative bacteria, but clinical studies have not been done in humans to show that squalamine can be used to treat bacterial infections.
Research Evidence

Cancer
This Phase I study of squalamine examined 33 patients with advanced solid tumor malignancies. Squalamine was administered as a single-agent, 5-day continuous IV infusion, repeated every 3 weeks. The principal dose-limiting toxicity of squalamine was hepatotoxicity, which involved brief, asymptomatic elevations in liver enzymes. The authors concluded that the recommended dose should not exceed 500 mg/m2/day as continuous IV infusion over 5 days every 3 weeks.

This study was conducted to determine the antitumor efficacy of squalamine in combination with carboplatin and paclitaxel. Forty-five patients with stage IIIB or stage IV non-small cell lung cancer were given a 5-day continuous infusion of squalamine with standard chemotherapy. Toxicities were limited to mild myelosuppression. The maximum tolerated dose (MTD) recommended was found to be 300 mg/m2/day. Researchers concluded that given the safety profile and patient survival data, squalamine at its MTD combined with chemotherapy should be studied further as potential therapy for stage IIIB or IV non-small cell lung cancer.

Age-related Macular Degeneration
Forty patients with age-related macular degeneration (AMD) received 25 or 50 mg/m2 of systemic squalamine lactate each week for a period of 4 weeks. It was found to be ineffective when administered intravitreally. None of the patients lost vision; 26% of patients showed improvement in vision by 3 lines.

Do Not Take If
  • You are taking cisplatin, paclitaxel, and cyclophosphamide (Squalamine may increase cytotoxic effects).
  • You are taking colistin and tobramycin (Squalamine may increase antibiotic effects).
Side Effects
  • Liver toxicity
  • Nausea
  • Fatigue
  • Anorexia
  • Muscle weakness
E-mail your questions and comments to aboutherbs@mskcc.org.