Medical Oncology

, 33:63 | Cite as

A look inside the mechanistic black box: Are red blood cells the critical effectors of RRx-001 cytotoxicity?

  • Pedro Cabrales
  • Jan Scicinski
  • Tony Reid
  • Frans Kuypers
  • Sandra Larkin
  • Marcel Fens
  • Arnold Oronsky
  • Bryan OronskyEmail author
Original Paper


The therapeutic potential of epi-immunotherapeutic anticancer agent RRx-001 in cancer has been validated with preclinical and clinical studies, since RRx-001 has successfully completed a phase 1 trial and multiple single-agent and combination phase 2 trials with preliminary evidence of promising activity are underway. Previous experimental work has implicated diverse anticancer mechanisms such as oxidative stress, ATP and NADPH depletion, anti-angiogenesis and epigenetic modulation in the overall antitumor effect of RRx-001. The hypothesis of this study was that the RRx-001 red blood cells are the essential and de facto intermediaries responsible for the reprograming of tumor behavior via transfer of their intracellular and membrane contents. To test this hypothesis, and thereby resolve the “black box” incompleteness in the continuity of the mechanism, the fate of red blood cells incubated with RRx-001 was explored in vitro and in vivo both in healthy animals and in tumor-bearing mice. The collective results establish that RRx-001-derivatized red blood cells are the critical “missing links” to explain the specificity and anticancer activity of RRx-001, including its immunomodulatory effects on tumor-associated macrophages. These experimental results delineate a novel erythrocyte-based mechanism without precedent in the annals of oncology and open the door to rational combination strategies with RRx-001 both in cancer therapy and beyond, particularly in disease states that affect red blood cell and vascular function such as malaria, leishmaniasis, sickle-cell disease and hemorrhagic shock.


Anticancer mechanisms Red blood cell Immunomodulation Anti-angiogenesis Epigenetic modulation RRx-001 



This work was supported by EpicentRx.

Author contributions

All authors contributed to all stages of work behind this manuscript: idea conception, design and execution of the studies, analysis, drafting, writing and editing of the manuscript.

Compliance with ethical standards

Conflict of interest

Authors J. S. and B. O. are employees of EpicentRx. The remaining authors declare no conflicts of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Pedro Cabrales
    • 1
  • Jan Scicinski
    • 2
  • Tony Reid
    • 3
  • Frans Kuypers
    • 4
  • Sandra Larkin
    • 4
  • Marcel Fens
    • 4
  • Arnold Oronsky
    • 5
  • Bryan Oronsky
    • 2
    Email author
  1. 1.Department of BioengineeringUniversity of California San DiegoLa JollaUSA
  2. 2.EpicentRx, Inc.Mountain ViewUSA
  3. 3.Moores Cancer CenterUniversity of California San DiegoLa JollaUSA
  4. 4.Children’s Hospital Oakland Research InstituteOaklandUSA
  5. 5.InterWest PartnersMenlo ParkUSA

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