The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress

C. Marcela Diaz-Montero, Yong Wang, Lijian Shao, Wei Feng, Abdel Aziz Zidan, Christopher J. Pazoles, Alberto J. Montero, Daohong Zhou

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The oxidized glutathione mimetic NOV-002 is a unique anti-tumor agent that not only has the ability to inhibit tumor cell proliferation, survival, and invasion, but in some settings can also ameliorate cytotoxic chemotherapy-induced hematopoietic and immune suppression. However, the mechanisms by which NOV-002 protects the hematopoietic and immune systems against the cytotoxic effects of chemotherapy are not known. Therefore, in this study we investigated the mechanisms of action of NOV-002 using a mouse model in which hematopoietic and immune suppression was induced by cyclophosphamide (CTX) treatment. We found that NOV-002 treatment in a clinically comparable dose regimen attenuated CTX-induced reduction in bone marrow hematopoietic stem and progenitor cells (HSPCs) and reversed the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), which led to a significant improvement in hematopoietic and immune functions. These effects of NOV-002 may be attributable to its ability to modulate cellular redox. This suggestion is supported by the finding that NOV-002 treatment upregulated the expression of superoxide dismutase 3 and glutathione peroxidase 2 in HSPCs, inhibited CTX-induced increases in reactive oxygen species production in HSPCs and MDSCs, and attenuated CTX-induced reduction of the ratio of reduced glutathione to oxidized glutathione in splenocytes. These findings provide a better understanding of the mechanisms whereby NOV-002 modulates chemotherapy-induced myelosuppression and immune dysfunction and a stronger rationale for clinical utilization of NOV-002 to reduce chemotherapy-induced hematopoietic and immune suppression.

Original languageEnglish (US)
Pages (from-to)1560-1568
Number of pages9
JournalFree Radical Biology and Medicine
Volume52
Issue number9
DOIs
StatePublished - May 1 2012
Externally publishedYes

Keywords

  • Cyclophosphamide
  • Free radicals
  • Glutathione disulfide
  • NOV-002
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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