Multiple intracellular thiol-containing proteins and mitochondrial components

Multiple intracellular thiol-containing proteins and mitochondrial components refers to a broad set of cellular targets rather than a single molecular entity, often cited as the primary site of action for arsenic-based therapeutics like arsenic trioxide (FDA Label, Trisenox). These targets include various enzymes and structural proteins that possess reactive sulfhydryl (-SH) groups, which are susceptible to covalent modification by heavy metals and certain electrophilic drugs (Flora et al., 2008, Interdiscip Toxicol). In the mitochondria, these interactions disrupt the respiratory chain and the mitochondrial permeability transition pore, leading to the loss of membrane potential and the generation of reactive oxygen species (ROS) (Miller et al., 2002, Cancer Research). This cascade ultimately triggers the release of pro-apoptotic factors such as cytochrome c, inducing programmed cell death. In the context of Acute Promyelocytic Leukemia (APL), a key specific target within this group is the PML-RARA fusion protein, where arsenic binding to cysteine residues in the zinc-finger domains leads to its degradation (Zhang et al., 2010, Science). While effective for certain malignancies, the non-specific nature of targeting multiple thiol-containing proteins across various tissues results in significant safety concerns, including cardiotoxicity and neurotoxicity.

Other names

Thiol-containing proteinsSulfhydryl-containing proteinsMitochondrial componentsIntracellular thiolsSulfhydryl-binding targets

Covalent binding to sulfhydryl (-SH) groups of cysteine residues, leading to enzyme inhibition, protein degradation (notably PML-RARA), and mitochondrial dysfunction characterized by reactive oxygen species (ROS) generation and cytochrome c release (FDA Label, Trisenox; Zhang et al., 2010, Science).