Assessment of the PARP inhibitor talazoparib photosafety profile

Autores de IIS La Fe

• Alejandro Mateos Pujante

  Autor

• María Consuelo Jiménez Molero

  Autor

• Inmaculada Andreu Ros

  Autor

Grupos

• Unidad Mixta de Investigación en Mecanismos moleculares de las Reacciones adversas de fármacos

Abstract

Talazoparib (TLZ) is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor employed for the treatment of breast cancer. This drug displays an absorption band in the UVA region, and therefore investigation of the possible phototoxic side-effects associated to its administration results of enormous relevance. In this context, we describe here a photochemical and photobiological study to ascertain the photosafety profile of TLZ. Concerning transient species, the singlet and triplet excited states of TLZ were detected by fluorescence (lambda max em = 440 nm) and laser flash photolysis experiments (lambda max abs = 400 nm), respectively. Remarkably, TLZ irradiation with UVA light in aqueous solution resulted in formation of a stable photooxidated product, TLZ-P, whose absorption band is extended until the visible region. From in vitro experiments, phototoxicity was revealed for the parent drug by neutral red uptake (NRU) assays, with a PIF value of ca 7; besides, TLZ induced formation of reactive oxygen species (ROS) and produced significant damage to both proteins and DNA. By contrast, the singlet and triplet excited states of TLZ-P were not detected, and no photodamage was observed in the NRU experiments. Overall, the results indicate that TLZ induces phototoxicity, whereas its photoproduct exhibits photosafety.

Keywords

• Comet assay; Fluorescence microscopy; Protein photooxidation; Photoproduct; Phototoxicity; Reactive oxygen species