Biting Back at Cancer: Snake Venom in Cancer Therapies

Authored By: Neanth Suresh

Art By: Fiona Reilly

When we hear about snakes, we often think about the lethal venom that these beasts deliver, which can cause nausea, necrosis, and even death. Did you know, however, that the same cytotoxins that are delivered in the quick strike of a serpent can be repurposed into soldiers in the fight against cancer? Cytotoxins are compounds that kill cells [1], a perfect candidate to combat the uncontrolled cell growth in a tumor. But with so many substances available in the cornucopia of snake venoms, which ones should we use?

One major compound that shows promise is leucurogin, found in the genus Bothrops, a type of pit viper native to South and Central America. Leucurogin contains enzymes that can produce a class of compounds called disintegrins, which counteract the effects of another group called integrins [2]. Integrins are known to play an incredibly important role in tumor progression. They are a part of almost the entire metastatic cascade, which is the series of steps that a tumor takes to spread [3]. Additionally, integrins are expressed in tumor-associated blood vessels, which lead researchers to believe that they facilitate the binding of endothelial cells necessary for angiogenesis [4]. Angiogenesis is the synthesis of new blood vessels, and it contributes significantly to tumor metastasis as it allows the tumor to absorb nutrients and grow [5]. Clearly, it would be beneficial to inhibit integrins. Higuchi and his colleagues studied the effects of a certain purified protein from Bothrops leucurus on Ehrlich tumors [2], which are a type of tumor that is commonly transplanted into mice for research purposes [6]. They found a 60% decrease in tumor growth [2]. Based on their observations of hemoglobin levels, angiogenesis resulted in at least part of the tumor suppression [2]. Another more recent study obtained similar results, with leucurogin proteins seeming to inhibit angiogenesis in melanoma cells [7]. Based on this evidence, leucurogin seems like a promising candidate for further investigation. 

Another potential compound is phospholipase A2 (PLA2), which is found in snakes in the Elapidae (e.g. cobras, mambas, etc.) and Viperidae (vipers) families. It is believed to cleave the phospholipid bonds that make up cell membranes, leading to cell death [8]. There is also evidence that PLA2 can inhibit angiogenesis [8]. Additionally, it is linked to processes such as the suppression of anti-apoptotic proteins, cell cycle regulation, and DNA damage [8]. It is not entirely known which of these attributes of PLA2 are most relevant for slowing tumorigenesis, but it is nevertheless a clear choice for cancer research in the future. 

In fact, PLA2 is presently playing a large role in a new cancer therapy. The compound is found in a type of toxin called Crotoxin, which induces cell apoptosis [9]. This toxin is being leveraged currently by Celtic Biotech, a biotech startup that has found success in Phase 1 human trials of their compound CB-24. CB-24 is made from crotoxin, and it demonstrated effectiveness against tumors in Lewis lung carcinoma and MX-1 human mammary carcinoma [10]. It works by employing the cleavage of phospholipid bonds mentioned above to “attack the cancer cell surfaces” [9]. Hopefully, with continued research, this treatment will be the next cutting-edge cancer therapy. 

In short, snake venom is more than a deadly cocktail to be feared. The compounds that compose the venom, such as leucurogin and PLA2, are incredibly useful, and should be researched further. By studying the weapon of these menacing creatures, we can find remedies for the world’s worst diseases. 

References

1. NCI Dictionary of Cancer terms. Comprehensive Cancer Information - NCI. (n.d.). https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytotoxin 

2. Higuchi, D. A., Almeida, M. C., Barros, C. C., Sanchez, E. F., Pesquero, P. R., Lang, E. A. S., Samaan, M., Araujo, R. C., Pesquero, J. B., & Pesquero, J. L. (2011). Leucurogin, a new recombinant disintegrin cloned from Bothrops leucurus (white-tailed-jararaca) with potent activity upon platelet aggregation and tumor growth. Toxicon, 58(1), 123–129. https://doi.org/10.1016/j.toxicon.2011.05.013 

3. Hamidi, H., & Johanna, I. (2018). Every step of the way: integrins in cancer progression and metastasis. Nature Reviews Cancer, 18, 533-548. https://doi.org/10.1038/s41568-018-0038-z

4. Desgrosellier, J.S., & Cheresh, D.A. (2010). Integrins in cancer: biological implications and therapeutic opportunities. Nature Reviews Cancer 10(1), 9-22. https://doi.org/10.1038/nrc2748

5. Angiogenesis inhibitors. NCI. (n.d.). https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet#:~:text=have%20side%20effects%3F-,What%20is%20angiogenesis%3F,chemical%20signals%20in%20the%20body 

6. Ehrlich ascites tumor. Ehrlich Ascites Tumor - an overview | ScienceDirect Topics. (n.d.). https://www.sciencedirect.com/topics/medicine-and-dentistry/ehrlich-ascites-tumor#definition  

7. Almeida, M. C., Santos, I. C., Paschoalin, T., Travassos, L. R., Mauch, C., Zigrino, P., Pesquero, J. B., Pesquero, J. L., & Higuchi, D. A. (2019). Leucurogin and melanoma therapy. Toxicon, 159, 22–31. https://doi.org/10.1016/j.toxicon.2018.12.005 

8. Hiu, J. J., & Yap, M. K. K. (2020). Cytotoxicity of snake venom enzymatic toxins: Phospholipase A2 and l-amino acid oxidase. Biochemical Society Transactions, 48(2), 719–731. https://doi.org/10.1042/bst20200110

9. Alves, B.F.A. & Ferreira Jr, R.S. (2022). Antineoplastic properties and pharmacological applications of Crotalus durissus terrificus snake venom. Revista da Sociedade Brasileira de Medicina Tropical, 55. https://doi.org/10.1590/0037-8682-0323-2022

10. Shah-Neville, W. (2023, September 6). Meet the startup developing novel cancer therapies from snake venom crotoxin. Labiotech. https://www.labiotech.eu/startup-scout/snake-venom-cancer-therapy