Mofarotene (Ro 40-8757) inhibits hematopoiesis in vitro by preventing maturation from primitive progenitor cells

Abstract

The effect of the arotinoid mofarotene (Ro 40–8757; 4-[2-[p-[(E)- 2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)- propenyl]phenoxy]ethyl]morpholine) on stromal cell-mediated hematopoiesis was examined in murine long-term bone marrow cultures. Whether added at week 2 to regenerating cultures or at week 4 to plateau-phase cultures, mofarotene strongly inhibited total cell production in a dose-dependent manner. Progenitor cell production was also inhibited, but to a lesser extent. When added at the initiation of culture, 1 mumol/L mofarotene did not affect formation of the adherent layer, but production of total nucleated cells and progenitors was inhibited over the next 10 weeks by 95% and 96%, respectively. However, after mofarotene treatment ceased, progenitor cell levels began increasing immediately, and cell production reached plateau levels comparable with those of control cultures within 4 weeks. Hematopoiesis was maintained for 14 more weeks, indicating that long-term culture- initiating cells survived the treatment. Assays of spleen colony- forming units (CFU-S) in the adherent layers showed an enrichment of day-13 CFU-S relative to the more mature day-9 CFU-S. Mofarotene did not inhibit colony formation by bone marrow cells stimulated by exogenous growth factors and did not decrease production of growth factors by stromal cells in the cultures, as determined by functional assays and by mRNA levels. These results suggest that mofarotene blocks differentiation of very primitive progenitors, inhibiting production of more mature hematopoietic elements.

Bone marrow stem cell protection from chemotherapy by low–molecular-weight compounds

“…The cellular sources of AcSDKP have yet to be identified, but recent evidence suggests that macrophages secrete the peptide in the bone marrow microenvironment and that stromal cells degrade it via angiotensin-1 converting enzyme (ACE) [107]. It appears that ACE mediates the first, Decreased entry of hematopoietic cells into S phase [131], possibly mediated by: downregulation of subunit 1 of mitochondrial NADH dehydrogenase gene transcription* [132]; upregulation of p21 and p27 and induction of hypophosphorylation of retinoblastoma protein* [133] AS101, ammonium trichloro(dioxyethylene-0,0 Ј )tellurate; CSF, colony-stimulating factor; DTC, dithiocarbamates; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HSC, hematopoietic stem cell; IFN, interferon; IL, interleukin; NADH, nicotinamide adenine dinucleotide (reduced form); NF-B, nuclear factor-B; p21/27, cyclin-dependent kinase inhibitors; TNF, tumor necrosis factor; *, not yet documented in hematopoietic cells.…”