A reverse translational pharmacological approach to understand the underlying mechanisms of the reported association between hydrochlorothiazide and non-melanoma skin cancer

In the last three decades, a number of individual studies and meta-analyses have claimed that most antihypertensive drugs can be associated with an increased risk of a variety of neoplastic diseases [1–5]. This has not been confirmed by meta-analyses of randomized clinical trials or observational studies of longer duration, which have not seen any substantial antihypertensive drugs–cancer association or produced mechanistic evidence of its plausibility [6–8]. An exception, however, could be hydrochlorothiazide (HCTZ) as the reports that in the Danish population, the use of this drug was associated with an increased risk of non-melanoma skin cancers (NMSCs) [9,10], have been replicated in other populations and settings around the world [11–15], with few exceptions [16,17]. Furthermore, it has been observed that the association has a clear dose–response relationship, which supports a causal role of the drug, a conclusion that is further strengthened by the evidence, available already years ago, that HCTZ has photosensitizing effects [18–22]. This led the International Agency for research on Cancer to classify HCTZ as potentially carcinogenic in humans [23]. It has more recently led the European Medicines Agency and the US Food and Drug Administration to recommend updating the summary of product characteristics with safety warnings and advice on adequate ultraviolet (UV) protection in patients under HCTZ treatment [24,25].