Animal Venoms as Potential Antitumor Agents Against Leukemia and Lymphoma

Abstract

Leukemias and lymphomas are hematologic malignancies characterized by complex pathophysiological mechanisms and increasing global incidence. Despite advances in chemotherapy, immunotherapy, and targeted therapies, challenges such as drug resistance and relapse persist, necessitating novel therapeutic strategies. This review explores the cytotoxic potential of venoms derived from snakes, bees, and scorpions against leukemia and lymphoma cells. Numerous venom-derived components, such as L-amino acid oxidases (LAAOs), phospholipases A₂ (PLA₂s), and peptides like melittin, demonstrate selective antitumor activity through mechanisms involving oxidative stress, apoptosis induction, cell cycle arrest, and immunomodulation. These molecules exert their effects via mitochondrial pathways, caspase activation, and inhibition of pro-survival signaling cascades such as NF-κB and PI3K/Akt. Despite promising preclinical results, the clinical translation of these bioactive compounds remains limited due to challenges in standardization, delivery, and safety profiling. This review highlights recent advances in venom research, summarizes key molecular targets, and discusses future directions to harness venom-derived molecules as innovative therapies for hematological cancers.

Keywords: L-amino acid oxidase (LAAO); anticancer therapy; apoptosis; cytotoxicity; hematological malignancies; melittin; phospholipase A2 (PLA2).

Figure 1

Available treatments for leukemia and lymphoma. Created with Biorender.com.

Figure 2

Targeted therapies and immunotherapeutic approaches in the treatment of leukemias, with a focus on acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The figure illustrates various antineoplastic strategies, including CAR-T cell therapies, bispecific antibodies (such as blinatumomab, which targets CD3 on T cells and CD19 on malignant B cells), antibody–drug conjugates (ADCs), monoclonal antibodies targeting surface antigens (such as CD19, CD20, CD22, CD33, CD52), and small-molecule inhibitors with intracellular targets. Imatinib, dasatinib, and ponatinib inhibit BCR-ABL, a cytoplasmic tyrosine kinase characteristic of Philadelphia chromosome-positive (Ph⁺) ALL. Gemtuzumab ozogamicin, an ADC targeting CD33, is used for CD33-positive AML. The figure also includes therapies under investigation, such as BCL-2/BCL-XL inhibitors, KMT2A inhibitors, and proteasome inhibitors, which have shown promising results in AML. It is important to note that not all targets presented apply equally to both leukemias; for instance, CD33 is highly expressed in AML, while CD19, CD22, and CD20 are specific to ALL. Adapted and corrected from [63]. Created with Biorender.com.

Figure 3

Schematic representation of the main antitumor mechanisms induced by animal-venom-derived molecules in leukemia and lymphoma cells. These include the following: Membrane disruption, caused by peptides such as melittin and phospholipases A₂ (PLA₂s), leading to increased membrane permeability and cell lysis; ion channel blockade, triggered by neurotoxins like chlorotoxin and conotoxins, disturbing ion homeostasis and activating cell death pathways; the induction of oxidative stress, mainly mediated by L-amino acid oxidases (LAAOs), promoting excessive production of reactive oxygen species (ROS) and oxidative damage to cellular macromolecules; the inhibition of cell adhesion and migration, observed with disintegrins and snake venom metalloproteinases (SVMPs), which interfere with integrin-mediated cell–extracellular matrix interactions and reduce tumor cell invasiveness; and the activation of apoptotic pathways, involving both intrinsic (mitochondrial) and extrinsic (death-receptor-mediated) routes, often characterized by caspase activation, mitochondrial membrane permeabilization, and the modulation of apoptotic regulators such as Bcl-2 family proteins. Collectively, these mechanisms highlight the therapeutic potential of animal venom components as antitumor agents targeting leukemia and lymphoma cells. Created with Biorender.com.