Anti-tumoral Effect of Enzymes Isolated from Bothrops Jararaca´s Venom (Bothrops spp.)

Cancer is one of the leading causes of death worldwide and, despite advances in medicine, currently available treatments still present high costs and limited efficacy. Conventional therapies, such as chemotherapy, are often unable to completely eliminate tumor cells and may cause severe side effects in healthy tissues (Bonassa & Santana, 2005). Therefore, there is growing interest in innovative alternatives that may be more effective and less harmful to the organism.

      Among these emerging possibilities, studies involving snake venoms have gained prominence, as they represent a promising source of bioactive molecules capable of directly interacting with biological structures within the organism. Proteomic analyses of these compounds have revealed the presence of enzymes such as phospholipases A₂ (PLA₂s) and metalloproteases, which are capable of performing several biological functions, some of them with potential applications in cancer treatment and other diseases (Furtado et al., 2012; Teixeira, 2009). PLA₂s constitute a significant portion of the proteins present in snake venoms and have attracted attention due to their therapeutic potential. The enzyme Bpir-I, isolated from Bothrops pirajai venom, for example, exhibits enzymatic, cytotoxic, antithrombotic, and anti-tumoral activities while maintaining low toxicity, making it an interesting candidate for the development of new pharmaceuticals. The studies were mainly conducted in genetics, toxicology, and biochemistry laboratories associated with the Federal University of Uberlândia and the University of São Paulo, using Drosophila strains provided by the Bloomington Drosophila Stock Center and ETH Zurich. The experiments involved stereoscopic microscopy analyses, toxicological, biochemical, cytotoxic, and pharmacological assays, and also included collaborations with the Fluminense Federal University and São Paulo State University.

      Another important example is BnSP-6, derived from Bothrops pauloensis, which demonstrated the ability to induce cell death through apoptosis and autophagy in breast cancer cells, in addition to inhibiting angiogenesis and metastasis, which are key factors in neoplasm dissemination. Similarly, recent studies involving the enzyme BnSP-7, also isolated from the same species, revealed a significant antiangiogenic effect. This enzyme was capable of reducing the proliferation and migration of human endothelial cells (HUVECs) without exhibiting toxicity, indicating a selective action on cells involved in the formation of new blood vessels. By preventing this process, BnSP-7 hinders tumor growth and reduces the likelihood of metastasis (Rodrigues et al., 1998).

Figure 1. In vitro angiogenesis inhibition assay using Matrigel. A: Positive control, untreated cells. B: Cells treated with BnSP-7 at 10 µg/mL. C: Cells treated with BnSP-7 at 40 µg/mL.The cells were photographed after 18 hours of treatment using a 20× objective lens. Source: Moura, 2016. 

Furthermore, PLA₂ MjTXII, obtained from Bothrops moojeni venom, also demonstrated anti-metastatic and anti-angiogenic effects in lung cancer cells. This enzyme acts on essential mechanisms involved in tumor growth and dissemination without causing significant damage to normal cells (Azevedo, 2015; Santos, 2021; Teixeira, 2009). Meanwhile, metalloproteases (SVMPs) have also been extensively studied. These enzymes may interfere with cellular adhesion and invasion processes, which are fundamental for tumor formation and progression. A study involving a metalloprotease isolated from Bothrops pauloensis demonstrated that the enzyme was capable of reducing epithelial tumor formation in the fruit fly (Drosophila melanogaster), a widely used model in carcinogenesis research (Furtado et al., 2012).

These findings reinforce the potential of venom-derived enzymes as tools for the development of innovative drugs. Laboratory experiments demonstrate that toxins present in venoms of the genus Bothrops may act selectively by inhibiting the proliferation and angiogenesis of tumor cells without compromising the viability of healthy cells, a characteristic considered essential for effective and safe treatment. Consequently, the continuation of these studies may pave the way for the development of more efficient medications, with lower toxicity and greater potential for success in the treatment of different types of cancer.

Author: Mariana Rezende Cardoso – Secretary Director of GEAS Brasil

Review: Iago Junqueira – Partner of GEAS Brasil through The Wild Place 

BIBLIOGRAPHICAL REFERENCES: 

AZEVEDO, F. V. P. de V. Morte de células de adenocarcinoma de mama humano por BnSP-6, uma fosfolipase A2 Lys-49 homóloga da peçonha de Bothrops pauloensis. Tese de mestrado. Universidade Federal de Uberlândia, Programa de Pós-graduação em Genética e Bioquímica, Ciências Biológicas, 2015. 

BONASSA, E. M. A.; SANTANA, T. R. Enfermagem em terapêutica oncológica. São Paulo: Atheneu, 2005.

FURTADO, S. G.; NEPOMUCENO, J. C. Redução de tumor epitelial em Drosophila melanogaster, pela enzima metaloprotease isolada da peçonha da serpente Bothrops pauloensis, por meio de teste wts (warts). Revista Perquirere. Centro Universitário de Patos de Minas (UNIPAM), 2012. 

MOURA, E. C. Atividade anti-angiogênica da fosfolipase A₂ (PLA₂ Lys-49) BnSP-7 isolada da peçonha de Bothrops pauloensis. 2016. Monografia (Bacharelado em Ciências Biológicas) – Instituto de Biologia, Universidade Federal de Uberlândia, Uberlândia, 2016.

SANTOS, L. C. Efeito antimetastático em células de câncer de pulmão e antiangiogênicoda PLA2 Lys49 MjTX-II, isolada da peçonha de Bothrops moojeni. Dissertação de mestrado. Universidade Federal da Bahia – Vitória da Conquista, 2021. 

TEIXEIRA, S.S. Caracterização funcional e estrutural de uma fosfolipase A2 ácida isolada do veneno de Bothrops pirajai. 2009. 96fl. Dissertação de mestrado. Faculdade de Ciências Farmacêuticas de Ribeirão Preto – Universidade de São Paulo, Ribeirão Preto, 2009.