Background: The diuretic drug hydrochlorothiazide (HCTZ) has been associated with an increased risk of non-melanoma skin cancer upon UVA exposure. The United States Food and Drug Administration recommended continuation of HCTZ to reduce the risk of uncontrolled blood pressure–related cardiovascular events and advised protective skin care measures like using broad spectrum sunscreens (Ssc) to lower skin cancer risk. The effectiveness of these measures in patients on HCTZ therapy has not been verified because of the absence of an adequate model.
Method: To explore the effect of sunscreen on UVA-irradiated skin treated with HCTZ, we collected biopsies from the hip of five body donors (three female, two male, median age: 87.0±2.9 years), which consented to body donation for scientific studies (Ethical committee of the Medical Association of Saarland approval (number #162/20)). All biopsies were incubated in the presence of 1 mmol/L HCTZ for 12 hours. Thirty minutes prior to irradiation with 5 J/cm2 narrowband UVA (365nm), half of the biopsies were pre-treated with commercially available broad spectrum sunscreen with a sun protection factor (SPF) 50+ (HCTZ+UVA+Ssc) and were compared to irradiated biopsies without sunscreen protection (HCTZ+UVA) after six hours. HCTZ-treated biopsies not exposed to UVA radiation served as control (HCTZ).
Results: Protein expression analysis demonstrated that after six hours, 5 J/cm2 UVA resulted in upregulation and increased phosphorylation of tumor suppressor protein p53, distinct DNA-damage, as indicated by elevated γH2A.X levels, increased protein levels of cell cycle regulator protein p21WAF1/CIP1, and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) compared to unirradiated HCTZ control. In HCTZ+UVA+Ssc no UVA-mediated effect on p53, γH2A.X, p21WAF1/CIP1, or p38 MAPK could be observed. In the presence of HCTZ, UVA resulted in mRNA expression of inflammation marker genes, like tumor necrosis factor alpha (TNFα), and interleukin 1 beta (IL1β), while transcription of the tumor suppressor vitamin D receptor (VDR) was repressed. Activation of pro-inflammatory gene expression was prevented in HCTZ+UVA+Ssc and VDR mRNA levels were unaffected. The percentage of epidermal cells with DNA-damage and nuclear translocation of p53 was assessed by counting positively stained nuclei for γH2A.X or p53. Following 5 J/cm2 UVA, number of p53- and γH2A.X-positive nuclei were increased in HCTZ+UVA compared to HCTZ control but not in HCTZ+UVA+Ssc.
Conclusion: Commercially available SPF50+ sunscreen effectively protected HCTZ-treated human skin biopsies from UVA-induced activation of photocarcinogenic pathways, including DNA damage, p53 stabilization, and pro-inflammatory signaling. These data provide mechanistic experimental support for the consistent use of sunscreen and other sun-protective measures during HCTZ therapy and suggest that concerns about phototoxicity alone should not warrant discontinuation of HCTZ in patients requiring ongoing blood pressure control and cardiovascular risk reduction.
