Beyond the role of mitochondria in apoptosis initiation/execution, some mitochondrial adaptations support the metastasis and chemoresistance of cancer cells. This highlights mitochondria as a promising target for new anticancer strategies. Emergent evidence suggests that some snake venom toxins, both proteins with enzymatic and non-enzymatic activities, act on the mitochondrial metabolism of cancer cells, exhibiting unique and novel mechanisms that are not yet fully understood. Currently, six toxin classes (L-amino acid oxidases, thrombin-like enzymes, secreted phospholipases A2, three-finger toxins, cysteine-rich secreted proteins, and snake C-type lectin) that alter the mitochondrial bioenergetics have been described. These toxins act through Complex IV activity inhibition, OXPHOS uncoupling, ROS-mediated permeabilization of inner mitochondrial membrane (IMM), IMM reorganization by cardiolipin interaction, and mitochondrial fragmentation with selective migrastatic and cytotoxic effects on cancer cells. Notably, selective internalization and direct action of snake venom toxins on tumor mitochondria can be mediated by cell surface proteins overexpressed in cancer cells (e.g. nucleolin and heparan sulfate proteoglycans) or facilitated by the elevated Δψm of cancer cells compared to that non-tumor cells. In this latter case, selective mitochondrial accumulation, in a Δψm-dependent manner, of compounds linked to cationic snake peptides may be explored as a new anti-cancer drug delivery system. This review analyzes the effect of snake venom toxins on mitochondrial bioenergetics of cancer cells, whose mechanisms of action may offer the opportunity to develop new anticancer drugs based on toxin scaffolds.
Bibliographical noteFunding Information:
This work was funded by Agencia Nacional de Investigación y Desarrollo (ANID-Chile) FONDECYT grants #1221874 (RA-M), #11201322 (FU), VID-University of Chile #UI-024/20 (FU), International collaboration Project ANID #Redbio0027 (FU, RA-M, DV-R, ES), Anillo grant ACT210097 (RA-M, FU), Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica (FONDECYT-Perú) #079-2021-FONDECYT (DV-R), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), Grant #APQ-01724-18 (ES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil), and Grant #309823/2021-8 (ES).
Copyright © 2022 Urra, Vivas-Ruiz, Sanchez and Araya-Maturana.
- OXPHOS (oxidative phosphorylation)
- anticancer compounds
- electron transport chain
- mitochondrial dysfunction
- snake venom