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 cytoxic effects of chemotherapy are not known. Therefore, in the present 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 (GSH) to oxidized glutathione (GSSG) 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 has the potential to be utilized to reduce chemotherapy-induced hematopoietic and immune suppression.

SEP enhanced the antitumor activity of 5-fluorouracil by up-regulating NKG2D/MICA and reversed immune suppression via inhibiting ROS and caspase-3 in mice

“…BM-MNCs were prepared as described previously [52]. Briefly, the femora and tibiae were harvested from mice in each group immediately after euthanization.…”

Hematopoietic Stem Cells: NormalVersusMalignant

“…This is typified by a significant decrease in the GSH/oxidized glutathione (GSSG) ratio. Interestingly, the application of a glutathione disulfide mimetic significantly decreases the production of ROS and partially rescues the changes in cellular GSH (35). This GSSG mimetic also increases the number of HSPCs depleted by cyclophosphamide treatment and partially rescues HSPC function.…”

“…This GSSG mimetic also increases the number of HSPCs depleted by cyclophosphamide treatment and partially rescues HSPC function. Treatment also rescues cyclophosphamide suppression of antioxidant gene expression, particularly SOD3 (copper-zinc extracellular superoxide dismutase) and GPX2 (35).…”

Glutathion as an Important Component of Thiosulfid System of Infertility Pathogenesis in Overweight Men

“…Обнаружено модулирующее влияние окисленного глутатиона на регуляцию функций цитокинов и воспалительные процессы [18]. Весьма при-мечательно, что в ряде случаев проявление иммуномодули-рующего и гемопоэтического действия GSSG обусловлено его опосредованным антиоксидантным эффектом [19].…”