Drug Discovery Opinion

For many people, the word ‘arsenic’ conjures up thoughts of murder mysteries and, in fact, arsenic has been a popular murder weapon since the middle ages. In the Victorian era, arsenic trioxide found favour as a cosmetic and it has also been used in both Chinese and Western medicine. Most recently, arsenic trioxide has been used to treat acute promyelocytic leukaemia (APL) that is unresponsive to first line therapies.

Arsenic trioxide is able to induce complete remission in patients with relapsed or refractory APL and is generally well-tolerated with minimal chemotherapy-related side effects. How arsenic trioxide kills cancer cells is not clear but scientists in China and France believe they have made a key step towards solving the mystery. APL cells are characterised by the occurrence of chromosomal translocations involving the retinoic acid receptor α gene (RARα)and the promyelocytic leukaemia gene (PML). These translocations lead to production of a fusion protein, PML-RORα that has altered functions and protects the cells from apoptosis. Arsenic trioxide triggers small ubiquitin-like modifier (SUMO) proteins to tag PML-RORα as part of a degradation mechanism. The new study has shown that the arsenic binds directly to cysteine residues in zinc fingers located within RBCC (N-terminal RING finger/B-box/coiled coil) domains of PML causing cross-linking and oligomerisation. The aggregated protein then undergoes SUMO modification and degradation. The identification of PML as a direct target of arsenic trioxide provides new insights into how the drug is able to treat APL and may lead to new treatment options.

The study is published in the journal Science.

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