ATO (Arsenic Trioxide) Effects on Promyelocytic Leukemia Nuclear Bodies Reveals Antiviral Intervention Capacity

Abstract

Human adenoviruses (HAdV) are associated with clinical symptoms such as gastroenteritis, keratoconjunctivitis, pneumonia, hepatitis, and encephalitis. In the absence of protective immunity, as in allogeneic bone marrow transplant patients, HAdV infections can become lethal. Alarmingly, various outbreaks of highly pathogenic, pneumotropic HAdV types have been recently reported, causing severe and lethal respiratory diseases. Effective drugs for treatment of HAdV infections are still lacking. The repurposing of drugs approved for other indications is a valuable alternative for the development of new antiviral therapies and is less risky and costly than de novo development. Arsenic trioxide (ATO) is approved for treatment of acute promyelocytic leukemia. Here, it is shown that ATO is a potent inhibitor of HAdV. ATO treatment blocks virus expression and replication by reducing the number and integrity of promyelocytic leukemia (PML) nuclear bodies, important subnuclear structures for HAdV replication. Modification of HAdV proteins with small ubiquitin‐like modifiers (SUMO) is also key to HAdV replication. ATO reduces levels of viral SUMO‐E2A protein, while increasing SUMO‐PML, suggesting that ATO interferes with SUMOylation of proteins crucial for HAdV replication. It is concluded that ATO targets cellular processes key to HAdV replication and is relevant for the development of antiviral intervention strategies.

Arsenic in medicine: past, present and future

“…In vitro treatment of APL cells with ATO at micromolar concentrations produced significant anti-adenovirus activity. This activity was partly due to the ability of ATO to induce oxidation of PML nuclear bodies before multimerization by the virus, reconstituting the usual dot-like structure and restoring the antiviral function of PML nuclear bodies in the cells of APL patients’ cells (Hofmann et al 2020 ).…”

“…https:// clini caltr ials. gov/ ct2/ show/ NCT03 980665 ATO has been reported to exhibit potent inhibition of human adenovirus infection in vitro (Hofmann et al 2020). PML nuclear bodies, otherwise referred to as PML oncogenic domains, are IFN-inducible nuclear structures that participate in cellular processes including apoptosis, senescence and antiviral defense.…”

Interplay between RNA Viruses and Promyelocytic Leukemia Nuclear Bodies

“…Emerging evidence points to ATO-mediated therapeutic effects in the context of several viral infections and virus-induced cancers [ 112 , 113 ]. As described above, ATO+IFNα combination treatment has shown a synergistic effect in inducing cell cycle arrest and apoptosis in HTLV-1 transformed cells in vitro [ 114 ].…”

Arsenic induces two different interaction modes of SUMO with promyelocytic leukemia (PML) proteins

“…The integrity of PML-NB is known to be modified by viral infection [9][10][11] and its components such as PML, Sp100, DAXX, and ATRX are important for signaling of both Type I and II interferons [12,13]. PML may control the small ubiquitinlike modifier (SUMO) pool which is a critical regulator for human adenovirus replication [14].…”