Ruxolitinib treatment reduces monocytic superoxide radical formation without affecting hydrogen peroxide formation or systemic oxidative nucleoside damage in myelofibrosis

Abstract

The role of excess reactive oxygen species (ROS) with consequent DNA/RNA damage is now recognized as a hallmark of cancer. In JAK2V617F mutated myeloproliferative neoplasms, ROS have been suggested to be important factors in disease initiation and progression. Ruxolitinib is the most widely used drug for myelofibrosis, because it improves symptom-score. However, both the anti-clonal potential and improvement in overall survival are limited. We investigated the impact of ruxolitinib on formation of superoxide radical and hydrogen peroxide by monocytes in sequentially acquired blood samples from patients with myelofibrosis. We also investigated the impact on RNA and DNA damage by measuring urinary excretion of 8-oxo-Guo and 8-oxo-d-Guo. The formation of superoxide by monocytes was reduced significantly during ruxolitinib therapy, but no impact on the formation of hydrogen peroxide by monocytes or the systemic amount of oxidatively damaged RNA or DNA could be demonstrated. We conclude that ruxolitinib holds little anti-oxidative potential.

Keywords:

• Reactive oxygen species
• superoxide radical
• hydrogen peroxide
• myelofibrosis
• ruxolitinib
• DNA damage

Acknowledgments

The statistics were evaluated by Professor Lene Theil Skovgård, Department of Biostatistics, Copenhagen University. The authors are most grateful for her aid!

Mads Emil Bjørn performed the cellular studies. Mads Emil Bjørn, Sif Gudbrandsdottir and Christen Lykkegård Andersen purified PBMCs. Marie Brimnes supervised the flowcytometric analyses. Trine Henrik and Henrik Enghusen Poulsen made the UPLC urinalyses. Hans Carl Hasselbalch and Claus Henrik Nielsen designed the study. Mads Emil Bjørn, Henrik Enghusen Poulsen, Hans Carl Hasselbalch, and Claus Henrik Nielsen analyzed the data and wrote the first draft of the manuscript, which all other authors read critically and approved before submission of the final version.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2019.1579323.

Additional information

Funding

This work was supported financially by Region Zealand. Mads Emil Bjørn has received partial funding for his PhD-study from Novartis Oncology. Hans Carl Hasselbalch has received research-grants from Novartis Oncology. Sif Gudbrandsdottir received research support from Amgen and GSK from 2009 to 2013.