α1-Adrenoceptor agonist methoxamine inhibits base excision repair via inhibition of apurinic/apyrimidinic endonuclease 1 (APE1)

Abstract

Methoxamine (Mox) is a well-known α1-adrenoceptor agonist, clinically used as a longer-acting analogue of epinephrine. 1R,2S-Mox (NRL001) has been also undergoing clinical testing to increase the canal resting pressure in patients with bowel incontinence. Here we show, that Mox hydrochloride acts as an inhibitor of base excision repair (BER). The effect is mediated by the inhibition of apurinic/apyrimidinic endonuclease APE1. We link this observation to our previous report showing the biologically relevant effect of Mox on BER – prevention of converting oxidative DNA base damage to double-stranded breaks. We demonstrate that its effect is weaker, but still significant when compared to a known BER inhibitor methoxyamine (MX). We further determined Mox’s relative IC₅₀ at 19 mmol L⁻¹, demonstrating a significant effect of Mox on APE1 activity in clinically relevant concentrations.