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

J Cell Mol Med. 2018 Oct;22(10):5076-5082. doi: 10.1111/jcmm.13791. Epub 2018 Jul 16.


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-NONOate), 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 catalyses 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 NO2- to NO. , which makes RRx-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.

Keywords: RRx-001; cancer; haemoglobin; nitric oxide; red blood cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Azetidines / pharmacology*
  • Blood Platelets / drug effects*
  • Blood Platelets / pathology
  • Collagen / genetics
  • Cyclic GMP / blood
  • Erythrocytes / drug effects
  • Female
  • Hemoglobins / drug effects
  • Hemoglobins / metabolism*
  • Humans
  • Male
  • Neoplasms / blood*
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Nitric Oxide / blood
  • Nitric Oxide Donors / metabolism
  • Nitro Compounds / pharmacology*
  • Platelet Aggregation / drug effects
  • Thrombophilia / blood
  • Thrombophilia / pathology


  • Azetidines
  • Hemoglobins
  • Nitric Oxide Donors
  • Nitro Compounds
  • RRx-001
  • Nitric Oxide
  • Collagen
  • Cyclic GMP