title: The glutathione disulfide mimetic NOV-002 inhibits cyclophosphamide-induced hematopoietic and immune suppression by reducing oxidative stress.
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.
authors.affiliation: Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. cdiaz1@med.miami.edu
authors.forename: C Marcela
authors.initials: CM
authors.lastname: Diaz-Montero
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Abdel-Aziz
authors.initials: AA
authors.lastname: Zidan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pazoles
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Montero
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D017931:DNA Primers; D004338:Drug Combinations; D005434:Flow Cytometry; D019803:Glutathione Disulfide / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D007107:Immune System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017931:DNA Primers; D004338:Drug Combinations; C529375:NOV 002; D017382:Reactive Oxygen Species; D003520:Cyclophosphamide; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D002945:Cisplatin; D019803:Glutathione Disulfide