The Triterpenoid CDDO-Me Promotes Hematopoietic Progenitor Expansion and Myelopoiesis in Mice

Abstract

The synthetic triterpenoid CDDO-Me has been shown to directly inhibit the growth of myeloid leukemias and lends itself to a wide array of therapeutic indications, including inflammatory conditions, due to its inhibition of NFκB. We have previously demonstrated protection from acute graft-versus-host disease (GVHD) after CDDO-Me administration in an allogeneic bone marrow transplant (BMT) model (Li, et al. BBMT, 2010). In the current study, we observed that CDDO-Me promoted myelopoiesis in both naïve and transplanted mice. This effect was dose-dependent as high doses of CDDO-Me inhibited myeloid growth in vitro. All lineages (CFU-GM, BFU-E) were promoted by CDDO-Me. We then compared the effects with G-CSF, a known inducer of myeloid expansion and mobilization from the bone marrow. Whereas both drugs induced terminal myeloid expansion in the spleen, peripheral blood and bone marrow, G-CSF only induced CFU-GM precursors in the spleen while CDDO-Me increased these precursors in the spleen and bone marrow. After sublethal total body irradiation, mice pretreated with CDDO-me further displayed an accelerated recovery of myeloid progenitors and total nucleated cells in the spleen. A similar expansion of myeloid and myeloid progenitors was noted with CDDO-Me treatment after syngeneic BMT. Combined, these data suggest that CDDO-Me may be of use post-transplant to accelerate myeloid recovery in addition to the prevention of GVHD.

Differential Sex Response to Aspirin in Decreasing Aneurysm Rupture in Humans and Mice

“…Cerebral aneurysms were induced in 2 groups of C57BL/6J mice: 1) 12 male mice receiving aspirin and 15-PGDH inhibitor (Cay10638; 0.25 mg/day IP, dose based on the literature 17 ), and 2) 12 female mice receiving aspirin and 15-PGDH agonist (CDDO-Me, 250 microgram per day IP – dose based on literature 18 ). Two male mice were excluded sue to death within 48 hours.…”

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

“…In this scenario, up-regulation of Nrf2 cytoprotective pathways by the SOs could protect normal cells and tissues without inhibiting the induction of oxidative stress by radiation or chemotherapeutic drugs required to apoptose cancer cells. The possibility that the SOs increase platelet production and myelopoiesis (Petronelli et al, 2011;Sardina et al, 2011;Ames et al, 2012) are especially germane to this hypothesis.…”

“…This response is dose-dependent, as high concentrations of the drug inhibit proliferation of myeloid cells. Moreover, in mice pretreated with CDDO-Me, myelopoiesis is accelerated after sublethal total-body irradiation or syngeneic bone marrow transplantation (Ames et al, 2012).…”

The Triterpenoid RTA 408 is a Robust Mitigator of Hematopoietic Acute Radiation Syndrome in Mice

“…This result was not surprising, since the percentage of neutrophils in the blood is typically increased in mice after receiving either bone marrow or hematopoietic stem cell transplant. This myeloid bias may be further amplified since the triterpenoid derivative CDDO-Me is known to promote myelopoiesis in mice (18). In LD (50/30) /LD (70/30) TBI mice that survive radiation-induced injury without any intervention, BM cellularity typically remains significantly decreased throughout life (19).…”