Platelet inhibitory effects of the phase 3 anticancer and normal tissue cytoprotective agent, RRx-001

Abstract

The platelet inhibitory effects of the Phase 3 anticancer agent and nitric oxide (NO) donor, RRx‐001, (1‐bromoacetyl‐3,3‐dinitroazetidine) were examined ex vivo and compared with the diazeniumdiolate NO donor, diethylenetriamine NONOate (DETA‐NON-Oate), which spontaneously releases nitric oxide in aqueous solution. In the absence of red blood cells and in a dose‐dependent manner, DETA‐NONOate strongly inhibited platelet aggregation induced by several stimuli (ADP, epinephrine and collagen) whereas RRx‐001 only slightly inhibited platelet aggregation under the same conditions in a dose‐dependent manner; these antiaggregant effects were blocked when both DETA‐ NONOate and RRx‐001 were co‐incubated with carboxy‐PTIO (CPTIO 0.01‐100 micromol), a widely accepted NO scavenger. However, in the presence of red blood cells from healthy human donors, RRx‐001, which binds covalently to haemoglobin (Hb) and catal-yses the production of NO from endogenous nitrite, more strongly inhibited the aggregation of platelets than DETA‐NONOate in a dose‐dependent manner likely because haemoglobin avidly scavenges nitric oxide and reduces its half‐life; the RRx‐001‐ mediated platelet inhibitory effect was increased in the presence of nitrite. The results of this study suggest that RRx‐001‐bound Hb (within RBCs) plays an important role in the bioconversion of NO -2 to NO . ,whichmakesRRx‐001 a more physiologically relevant inhibitor of platelet aggregation than other nitric oxide donors, whose effects are attenuated in the presence of red blood cells. Therefore, RRx‐001‐mediated platelet inhibition is a potentially useful therapeutic property, especially in hypercoagulable cancer patients that are at an increased risk of thrombotic complications.