The arsenic proteome in cancer: Unravelling molecular mechanisms of anticancer drugs

Arsenic is a dual-natured element, functioning as both a carcinogen and a therapeutic agent in cancer treatment. Arsenic trioxide is a clinically approved drug for acute promyelocytic leukaemia, administered either alone or in combination with all-trans retinoic acid. Additionally, arsenic trioxide and organic arsenic compounds, such as darinaparsin, show promising efficacy against various cancers. Given the multi-targeted nature of metallodrugs, a comprehensive understanding of their molecular mechanisms is critical for the rational design of more potent and less toxic therapeutics. In this review, we first outline the structures and activities of key arsenic-based anticancer agents, encompassing both inorganic and organic forms. We then provide a comprehensive overview of proteome-wide identification of arsenic-binding proteins in cancer cells, utilizing metalloproteomic approaches such as immobilized metal affinity chromatography, continuous-flow electrophoresis coupled with inductively coupled plasma mass spectrometry, biotinylated arsenical pull-down, and fluorescence-based metalloproteomics. Subsequently, we discuss how the identified arsenic proteome facilitates elucidation of the molecular mechanisms of arsenic trioxide and darinaparsin from a systems perspective. We also evaluate studies on the cytotoxicity of arsenic compounds at the single-cell level, highlighting their role in improving our understanding of the mode of action of a drug. Finally, we prospect future research direction in this field. This review aims to stimulate further investigation into the molecular mechanisms of arsenic-based drugs at a systems level, guiding the development of more effective and safer arsenic-based therapeutics for cancer treatment.