Venom-Derived Peptides from Scorpions and Snakes as Emerging Therapeutics for Colorectal, Brain, and Uterine Cancers: Mechanisms, Species, and Translational Potential

Abstract

Peptides extracted from scorpion and snake venom exhibit high specificity toward malignant cells due to their ability to bind to tumor-associated ion channels, integrins, and proteolytic enzymes. These naturally evolved biomolecules have demonstrated cytostatic, anti-invasive, and pro-apoptotic properties in several cancer models, particularly colorectal, glioblastoma, and uterine cancers. This article presents a comprehensive review of venom-derived peptides, focusing on species of medical importance and the molecular mechanisms by which they exert anticancer effects. It also highlights ongoing translational research by G Biological Products, in collaboration with the Department of Biochemistry at Selçuk University, focused on the purification, pharmacological evaluation, and delivery system development for venom-based cancer therapeutics.

1. Introduction

Animal venoms are highly evolved biochemical systems that contain a multitude of bioactive peptides with potent and selective biological activities. These peptides typically range from 2 to 10 kDa and possess disulfide-rich scaffolds conferring remarkable stability and target selectivity. Scorpion and snake venom peptides have been shown to exert inhibitory effects on cancer cell proliferation, angiogenesis, invasion, and metastasis through interactions with tumor-specific ion channels, integrins, and signaling pathways. Their potential is especially notable in cancers with poor clinical outcomes such as colorectal carcinoma, glioblastoma multiforme, and uterine cancers.

2. Scorpion and Snake Venom Peptides in Colorectal Cancer

2.1 Scorpion-Derived Peptides

• BmKCT (Buthus martensii Karsch Chlorotoxin-like peptide):Targets MMP-2 expression in colorectal carcinoma (CRC) cells, reducing invasion and epithelial-mesenchymal transition (EMT). Also influences ERK/MAPK signaling cascades.

• AaCtx (Androctonus australis Chlorotoxin):Known to inhibit chloride ion channels and suppress the expression of metastasis-promoting enzymes, particularly MMP-9 and MMP-2.

2.2 Snake-Derived Peptides

• Disintegrins from Echis carinatus and Agkistrodon contortrix:These non-enzymatic peptides bind integrins (αvβ3, α5β1) on CRC cells, blocking adhesion to extracellular matrix (ECM) and suppressing tumor-induced angiogenesis.

• Contortrostatin (from Agkistrodon contortrix contortrix):Demonstrated both anti-adhesive and anti-angiogenic activity by inhibiting endothelial cell migration and integrin-mediated signaling.

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3. Peptides for Brain Tumors: Glioblastoma Multiforme (GBM)

3.1 Scorpion-Derived Peptides

• Chlorotoxin (CTX, from Leiurus quinquestriatus hebraeus):Specifically binds to glioma cells via interaction with MMP-2 and Annexin A2. CTX has been conjugated with Cy5.5 fluorophores in the clinical investigational product “Tumor Paint BLZ-100,” currently in human trials [2].

• Iberiotoxin (from Buthus tamulus):Blocks large-conductance calcium-activated potassium (BKCa) channels overexpressed in glioblastoma, limiting cellular excitability and proliferation.

3.2 Snake-Derived Peptides

• α-Cobratoxin (from Naja kaouthia):Binds to nicotinic acetylcholine receptors (nAChRs) on GBM cells. It initiates caspase-dependent apoptosis and suppresses neurosphere formation in stem-like glioma subpopulations.

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4. Uterine Cancer: Peptide-Induced Apoptosis and Angiostasis

• Cardiotoxin III (CTX-III from Naja naja atra):Induces mitochondrial pathway apoptosis in endometrial carcinoma cells via upregulation of pro-apoptotic proteins (Bax, cytochrome c) and activation of caspase-9 and -3.

• Crotoxin (from Crotalus durissus terrificus):This heterodimeric phospholipase A₂ complex selectively induces apoptosis in hormone-independent uterine sarcoma models and inhibits neovascularization.

• BmK AGAP (Analgesic-Antitumor Peptide, from Buthus martensii Karsch):Activates p53-mediated pathways while downregulating NF-κB, which is often overexpressed in uterine malignancies. Exhibits synergistic action with progestin-based therapies.

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5. Mechanisms of Action Summary

Peptide	Source Species	Target Molecules	Application Area	Mechanism
Chlorotoxin (CTX)	L. quinquestriatus hebraeus	MMP-2, Annexin A2	GBM, Colorectal Cancer	Anti-invasion, tumor imaging
BmKCT	Buthus martensii Karsch	MMP-2, ERK pathway	Colorectal Cancer	Anti-metastatic
Contortrostatin	A. c. contortrix	αvβ3, α5β1 integrins	Colorectal, GBM	Anti-angiogenic, anti-adhesive
CTX-III	Naja naja atra	Mitochondrial apoptosis proteins	Uterine Cancer	Apoptosis induction
Crotoxin	C. durissus terrificus	Cell membrane, angiogenic proteins	Uterine, Colorectal Cancer	Apoptosis, angiogenesis inhibition
MeV	Mesobuthus eupeus	Wnt/β-catenin, PI3K/Akt pathways	Colorectal Cancer	Apoptosis, proliferation suppression

6. Translational Research: G Biological Products

G Biological Products has entered a formalized research partnership with Selçuk University, Department of Biochemistry, to explore venom-derived biopeptides for cancer therapeutics. The collaboration encompasses:

• Venom source acquisition and taxonomic profiling from Mesobuthus gibbosus, Androctonus crassicauda, Vipera ammodytes, and Montivipera xanthina, sourced ethically within Anatolia.

• Peptide purification and identification using HPLC, RP-UPLC, MALDI-TOF, and LC-MS/MS.

• Functional assays on cancer cell lines including HCT-116 (colorectal), U87-MG (glioblastoma), and Ishikawa (uterine).

• Molecular target validation through RT-qPCR, immunocytochemistry, and flow cytometry.

• Nanocarrier-based delivery system development for peptide encapsulation to improve pharmacokinetics and bioavailability.

“This interdisciplinary initiative aims to create a pipeline from raw venom extraction to preclinical therapeutic prototypes,” says the Lead Investigator at G Biological Products. “Selçuk University’s molecular platform and our industrial-grade bioprocessing capabilities align toward real translational outcomes.”

7. Future Perspectives

As oncology moves toward precision therapeutics, the structural uniqueness and target selectivity of venom peptides provide a critical opportunity. These molecules can function as direct cytotoxins, angiogenesis inhibitors, or even tumor-specific delivery ligands. Continued advancements in recombinant peptide synthesis, venom genomics, and nanocarrier delivery will further enhance the clinical viability of these biomolecules. The ongoing research by G Biological Products and Selçuk University offers a robust framework for transitioning venom peptides from experimental tools into clinically approved therapeutics.

References

[1] Ortiz, E., et al. (2020). Scorpion and snake venom-derived peptides for cancer therapy. Toxins, 12(4), 255.

[2] Veiseh, O., et al. (2007). Tumor paint: A chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Research, 67(14), 6882–6888.

[3] Jin, Y., et al. (2021). Snake venom disintegrins in cancer therapy: From bench to bedside. Biochemical Pharmacology, 183, 114316.

[4]Aliakbari, F., Moini Jazani, O., & Pooneh, N. (2025). Induction of apoptosis and inhibition of colorectal cancer cell proliferation by Mesobuthus eupeus venom via modulation of Wnt/β-catenin and PI3K/Akt pathways. Toxicon, 229, 107076. https://pubmed.ncbi.nlm.nih.gov/40229568/

[5]Vahidi, H., Ostadrahimi, A. R., & Zare, A. (2024). Evaluation of the anticancer effects of Androctonus crassicauda venom on HCT-8 human colorectal cancer cells. Medical Oncology, 41(4), 67. https://doi.org/10.1007/s12032-025-02689-2

[6]Canak, H.N., Bas, K., Yağmur, E.A. et al. Mesobuthus eupeus venom modulates colorectal carcinoma signaling pathways and induces apoptosis. Med Oncol 42, 163 (2025). https://doi.org/10.1007/s12032-025-02689-2