EC Pharmacology and Toxicology

Review Article Volume 11 Issue 4 - 2023

The Sea Anemone Pore-Forming Toxins (PFTs): From Mechanism of Action to Perspectives in Pharmacology as Antitumor Agents

Monastyrnaya MM1*, Agafonova IG2, Tabakmakher VM3 and Kozlovskaya EP4

1Doctor of Chemistry, Leading Researcher, Laboratory of Peptide Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Russia
2Senior Researcher, Laboratory of biotesting and the mechanism of action of biologically active substances, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Russia
3Researcher, Laboratory of Biomolecular Modeling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Russia
4Doctor of Chemistry, Head of the Laboratory of Peptide Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Russia

*Corresponding Author: Monastyrnaya MM, Doctor of Chemistry, Leading Researcher, Laboratory of Peptide Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Russia.
Received: February 07, 2023; Published: March 31, 2023



It is known that venomous marine coelenterates, sea anemones, widespread in the World Ocean, are producers of various biologically active compounds of protein nature: neurotoxins, Kunitz-type inhibitors, pore-forming toxins, which are the part of venom secret used by these predatory organisms for attacking and protecting against potential enemies. The study of their structure, functional activity, specificity of interaction with biological targets showed the presence of pharmacological potential in some sea anemone protein compounds. In particular, it was found that pore-forming toxins (actinoporins) possessed antitumor activity due to high cytotoxicity of these polypeptides. The results of the study of the mechanisms of actinoporins interaction with biological targets are discussed in the review. It was carried out in vitro (the cytoplasmic membranes of a number of tumor cells, mammalian erythrocytes, sea urchin eggs and sperm) as well as by biophysical and calculation methods (differential scanning calorimetry, computer modeling). The combination of these approaches has made it possible to significantly deepen and expand the currently existing understanding of the mechanism of an actinoporins cytolytic action. Thus, in addition to the generally accepted mechanism of an interaction between actinoporin POC-binding site and sphingomyelin, a membrane “lipid receptor” discussed in this review, an hypothesis about possible alternative binding of actinoporin RGD-motif to membrane integrin, the minimal integrin-binding motif for RGD-recognizing integrins, is put forward. Both processes determine the experimentally proven antitumor effect of actinoporins and indicate their pharmacological potential.

Keywords: Sea Anemone; Pore-Forming Toxins (PFTs); Pharmacology; Antitumor Agents

  1. Norton RS. “Sea anemone venom peptides”. In Handbook of Biologically Active Peptides; Kastin, A.J. (Edition.) Elsevier (Academic): San Diego, CA, USA (2013): 430-436.
  2. Ashwood LM., et al. “Tentacle morphological variation coincides with differential expression of toxins in sea anemones”. Toxins 13 (2021): 452.
  3. Macrander J., et al. “Tissue-specific venom composition and differential gene expression in sea anemones”. Genome Biology and Evolution 8 (2016): 2358-2375.
  4. Madio B., et al. “Sea anemone toxins: A structural overview”. Marine Drugs 17 (2019): 325.
  5. Moran Y., et al. “Sea anemone toxins affecting voltage-gated sodium channels - molecular and evolutionary features”. Toxicon 54 (2009): 1089-1101.
  6. Bosmans F and Tytgat J. “Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels”. Toxicon 49 (2007): 550-560.
  7. Liao Q., et al. “Cnidarian peptide neurotoxins: a new source of various ion channel modulators or blockers against central nervous systems disease”. Drug Discovery Today 1 (2019): 189-197.
  8. Monastyrnaya MM., et al. “The sea anemone neurotoxins modulating sodium channels: an insight at structure and functional activity after four decades of investigation”. Toxins1 (2023): 8.
  9. Niklas B., et al. “Interactions of sea anemone toxins with insect sodium channel - insights from electrophysiology and molecular docking studies”. Molecules 26 (2021): 1302.
  10. Oliveira JS., et al. “Binding specificity of sea anemone toxins to Na(v) l.1-1.6 sodium channels-Unexpected contributions from differences in the IV/S3-S4 outer loop”. Journal of Biological Chemistry 279 (2004): 33323-33335.
  11. Valle A., et al. “The multigene families of actinoporins (part I): Isoforms and genetic structure”. Toxicon 103 (2015): 176-187.
  12. Leychenko E., et al. “Multigene family of pore-forming toxins from sea anemone Heteractis crispa”. Marine Drugs 16 (2018): 183.
  13. Anderluh G and Maček P. “Cytolytic peptide and protein toxins from sea anemones (Anthozoa: Actiniaria)”. Toxicon2 (2002): 111-124.
  14. Kristan K., et al. “Pore formation by equinatoxin, a eukaryotic pore-forming toxin, requires a flexible N-terminal region and a stable beta-sandwich”. Journal of Biological Chemistry 45 (2004): 46509-46517.
  15. Bakrač B and Anderluh G. “Molecular mechanism of sphingomyelin-specific membrane binding and pore formation by actinoporins”. Advances in Experimental Medicine and Biology 677 (2010): 106-115.
  16. Alvarez C., et al. “The role of ionic strength on the enhancement of the hemolytic activity of sticholysin I, a cytolysin from Stichodactyla helianthus”. Toxicon 1 (1998): 165-178.
  17. Palacios-Ortega J., et al. “Evaluation of different approaches used to study membrane permeabilization by actinoporins on model lipid vesicles”. BBA - Biomembranes 9 (2020): 183311.
  18. Tejuca M., et al. “Sea anemone cytolysins as toxic components of immunotoxins”. Toxicon 54 (2009): 1206-1214.
  19. Zykova TA., et al. “Amino acid sequence of trypsin IV inhibitor from Radianthus macrodactylus”. Russian Journal of Bioorganic Chemistry 11 (1985): 293-301.
  20. Sokotun IN., et al. “Proteinase inhibitors from the tropical sea anemone Radianthus macrodactylus: Isolation and characteristic”. Russian Journal of Bioorganic Chemistry 72 (2007): 301-306.
  21. Gladkikh I., et al. “New HCRG-polypeptides of Kunitz-type from the sea anemone, Heteractis crispa”. Marine Drugs 13 (2015): 6038-6063.
  22. Isaeva M., et al. “A new multigene superfamily of Kunitz-type protease inhibitors from sea anemone Heteractis crispa”. Peptides 34 (2012): 88-97.
  23. Sintsova ОV., et al. “Kunitz-type peptides of the sea anemone Heteractis crispa - potential anti-inflammatory compounds”. Russian Journal of Bioorganic Chemistry 1 (2017): 91-97.
  24. Andreev YA., et al. “Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1)”. Journal of Biological Chemistry 283 (2008): 23914-23921.
  25. Monastyrnaya M., et al. “Kunitz-type peptide HCRG21 from the sea anemone Heteractis crispa is a full peptide antagonist of the TRPV1 receptor”. Marine Drugs 14 (2016): 229.
  26. Peigneur S., et al. “A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties”. Biochemical Pharmacology 82 (2011): 81-90.
  27. Gladkikh I., et al. “Kunitz-type peptides from the sea anemone Heteractis crispa demonstrate potassium channel blocking and anti-inflammatory activities”. Biomedicines 8 (2020): 473.
  28. Mancheno JM., et al. “Crystal and electron microscopy structures of Sticholysin II actinoporin reveal insights into the mechanism of membrane pore formation”. Structure 11 (2003): 1319-1328.
  29. Malovrh P., et al. “A Novel mechanism of pore formation: membrane penetration by the N-terminal amphipathic region of equinatoxin”. Journal of Biological Chemistry 278 (2003): 22678-22685.
  30. Ros U., et al. “Differences in activity of actinoporins are related with the hydrophobicity of their N-terminus”. Biochimie 116 (2015): 70-78.
  31. Tanaka K., et al. “Structural basis for self-assembly of a cytolytic pore lined by protein and lipid”. Nature Communications 6 (2015): 6337.
  32. Fedorov S., et al. “The anticancer effects of actinoporin RTX-A from the sea anemone Heteractis crispa (=Radianthus macrodactylus)”. Toxicon 55 (2010): 811-817.
  33. Kvetkina A., et al. “Sea anemone Heteractis crispa actinoporin demonstrates in vitro anticancer activities and prevents HT-29 colorectal cancer cell migration”. Molecules 25 (2020): 5979.
  34. Morante K., et al. “Functional characterization of Val60, a key residue involved in the membrane-oligomerization of fragaceatoxin C, an actinoporin from Actinia fragacea”. FEBS Letters 589 (2015): 1840-1846.
  35. Danhier F., et al. “RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis”. Molecular Pharmaceutics 11 (2012): 2961-2973.
  36. García Linares S., et al. “The sea anemone actinoporin (Arg-Gly-Asp) conserved motif is involved in maintaining the competent oligomerization state of these pore-forming toxins”. The FEBS Journal 5 (2014): 1465-1478.
  37. Shnyrov VL., et al. “Calorimetric study of interactions of toxin from Radianthus macrodactylus with erythrocyte membrane”. Biochem International 26 (1992): 219-229.
  38. Monastyrnaya MM., et al. “9th IST Asia Pacific meet”. on Animal, Plant and Microbial Toxins, Vladivostok, Russia 4-8 (2011): 53.
  39. Burke RD., et al. “Integrin signaling in early sea urchin development”. Signal Transduction 7 (2007): 207-215.
  40. Murray G., et al. “The αBβC Integrin is expressed on the surface of the sea urchin egg and removed at fertilization”. Developmental Biology 227 (2000): 633-647.
  41. Rivera-de-Torre E., et al. “Pore-forming proteins from cnidarians and arachnids as potential biotechnological tools”. Toxins 11 (2019): 370.

Monastyrnaya MM.,et al. The Sea Anemone Pore-Forming Toxins (PFTs): From Mechanism of Action to Perspectives in Pharmacology as Antitumor Agents. EC Pharmacology and Toxicology 11.4 (2023): 20-26.

ECronicon Journal

Our Services

Quick Links

Information

Creative Commons LicenseOpen Access by ECronicon is licensed under a Creative Commons Attribution 4.0 International License
Based on a work at www.ecronicon.net