Ritonavir and DNA Damage: A New Perspective on an Old Drug

Ritonavir (RTV), an effective aspartyl protease inhibitor, was originally developed to counter the replication of human immune deficiency virus and then employed as a pharmacokinetic enhancer in antiretroviral therapy. Yet unexpectedly, RTV exerted antitumor effects that added to its antiviral action, as it impacted the migration, invasion, oxidative stress, and proteasome function of human tumor cells. More recently, RTV was shown to directly inhibit DNA repair enzymes, thereby enhancing radiosensitivity and synergizing with chemotherapeutics across multiple cancer models. However, RTV induced oxidative stress and DNA damage also in non-tumor cells, including the reproductive ones. This duality highlights both the possibility of RTV anticancer use and the concern for its safety. In this Perspective, we propose the repurposing of RTV as a novel tool to potentiate DNA-damage-based antitumor therapies such as radiotherapy and/or chemotherapy. At the same time, we underscore the need for a careful assessment of RTV side effects.