Urra Félix A, Vivas-Ruiz Dan E, Sanchez Eladio Flores, Araya-Maturana Ramiro
Laboratorio de Plasticidad Metabólica y Bioenergética, Programa de Farmacología Clínica y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Network for Snake Venom Research and Drug Discovery, Santiago, Chile.
Front Oncol. 2022 Jul 18;12:938749. doi: 10.3389/fonc.2022.938749. eCollection 2022.
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.
除了线粒体在细胞凋亡起始/执行中的作用外，一些线粒体适应性变化还支持癌细胞的转移和化疗耐药性。这突出了线粒体作为新抗癌策略的一个有前景的靶点。新出现的证据表明，一些蛇毒毒素，包括具有酶活性和非酶活性的蛋白质，作用于癌细胞的线粒体代谢，展现出尚未完全了解的独特新颖机制。目前，已经描述了六种改变线粒体生物能量学的毒素类别（L-氨基酸氧化酶、凝血酶样酶、分泌型磷脂酶A2、三指毒素、富含半胱氨酸的分泌蛋白和蛇C型凝集素）。这些毒素通过抑制复合物IV活性、氧化磷酸化解偶联、活性氧介导的线粒体内膜通透性改变、通过心磷脂相互作用进行线粒体内膜重组以及线粒体碎片化，对癌细胞产生选择性迁移抑制和细胞毒性作用。值得注意的是，蛇毒毒素在肿瘤线粒体上的选择性内化和直接作用可由癌细胞中过表达的细胞表面蛋白（如核仁素和硫酸乙酰肝素蛋白聚糖）介导，或者与非肿瘤细胞相比，癌细胞升高的线粒体膜电位也有助于这种作用。在后一种情况下，与阳离子蛇肽相连的化合物以线粒体膜电位依赖的方式进行选择性线粒体积累，可被开发为一种新的抗癌药物递送系统。本综述分析了蛇毒毒素对癌细胞线粒体生物能量学的影响，其作用机制可能为基于毒素支架开发新的抗癌药物提供机会。
