Abstract
Rucaparib (RCP) is a potent selective inhibitor of both PARP-1 and PARP-2 enzymes that induces synthetic lethality in cancer cells. It is used for the treatment of breast and ovarian tumors harboring deleterious germline or somatic cancer susceptibility genes mutations. Although RCP has an indole chromophore in its structure, it displays a bathochromic shift of the absorption band towards the UVA region of sunlight, thus extending the active fraction of solar light able to produce photosensitivity reactions. In this context, it is highly interesting to study the photo(geno)toxicity disorders associated with this drug, bearing in mind that, for dermatologists it is crucial to understand the toxicity mechanism to improve clinical management. In the present work, RCP has shown to be potentially phototoxic, as observed in the neutral red uptake phototoxicity test. Moreover, this significant phototoxicity is attributed to both proteins and genomic DNA, as revealed in the protein photooxidation and comet assays. The results obtained are highly relevant concerning RCP photosafety and become clinically important in the context of identification of the cutaneous adverse events that can be associated with the targeted therapies. Interestingly, this is the first example of a PARP inhibitor able to induce photosensitized damage to biomolecules.
Highlights
Rucaparib (RCP) is a potent selective inhibitor of both poly(ADP-ribose) polymerases (PARPs)-1 and Poly(ADP-ribose) polymerase (PARP)-2 enzymes that induces synthetic lethality in cancer cells
Inhibition of PARP enzymes is a potentially lethal therapeutic strategy, consisting of provoking chromosomal uncertainty, cell-cycle arrest, and subsequent apoptosis, which seems to be attributable to the persistence of DNA lesions that are normally repaired by homologous r ecombination[4,6]
Rucaparib has been approved by the Food and Drug Administration (FDA) for the treatment of patients with deleterious BRCA mutation associated with metastatic castrate-resistant prostate cancer[12]
Summary
Rucaparib (RCP) is a potent selective inhibitor of both PARP-1 and PARP-2 enzymes that induces synthetic lethality in cancer cells. Rucaparib (RCP) is a potent selective inhibitor of both PARP-1 and PARP-2, which induces synthetic lethality in cancer cells that are not able to repair DNA damage by the HRR pathway It is especially used, for the treatment of breast and ovarian tumors harboring deleterious germline or somatic cancer susceptibility genes (BRCA) mutations[7–11]. RCP is well tolerated by patients but some adverse events can occur, including fatigue, dizziness, gastrointestinal disorders, thrombocytopenia, neutropenia, itching and skin sensitivity to sunlight[13] With this background, the present work aims to investigate photodamage to biochemical targets in living cells, using a methodology previously developed in our group to study photosensitivity reactions induced by drugs and metabolites[14–18]
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