A potential therapeutic role for small nonpeptidyl compounds that mimic human granulocyte colony-stimulating factor

Abstract

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation of bone marrow granulocytic progenitor cells and promotes their differentiation into granulocytes. G-CSF is therefore an important component of immune defense against pathogenic microorganisms: recombinant human G-CSF (rhG-CSF) is used to treat patients with a variety of neutropenias. In the present study, we screened approximately 10 000 small nonpeptidyl compounds and found 3 small compounds that mimic G-CSF in several in vitro and in vivo assays. These compounds induced G-CSF-dependent proliferation, but had no effect on interleukin-3-dependent, interleukin-2-dependent, interleukin-10-dependent, thrombopoietin (TPO)-dependent, or erythropoietin (EPO)-dependent proliferation. Each compound induced the phosphorylation of signal transducers and activators of transcription-3 (STAT3) and mitogen-activated protein kinase (MAPK) in a G-CSFdependent cell line and in human neutrophils. In addition, these compounds induced hematopoietic colony formation from primary rat bone marrow cells in vitro. When subcutaneously injected into normal rats, they caused an increase in peripheral blood neutrophil counts. Furthermore, when they were administered to cyclophosphamide-induced neutropenic rats, blood neutrophil levels increased and remained elevated up to day 8. We therefore suggest that these small nonpeptidyl compounds mimic the activity of G-CSF and may be useful in the treatment of neutropenic patients. (Blood. 2004;103:836-842)

The Ethanol Extract of the Inner Bark of Caesalpinia pyramidalis (Tul.) Reduces Urinary Bladder Damage during Cyclophosphamide‐Induced Cystitis in Rats

“…Cyclophosphamide is also well known by its damaging effects in the hematopoietic stem cells and precursor cells and to the hematopoietic microenvironment, leading to myelosuppression [28, 29]. In our study, we detected a decrease in the total leukocyte number in peripheral blood that was not changed by EECp, indicating that this extract does not have any effect on the negative hematopoietic effects of cyclophosphamide.…”

Functional regulation and proteomic characterization of human natural killer cells through recombinant human granulocyte‐colony stimulating factor treatment

“…G-CSF also plays an important role in immune cell defense against pathogenic microorganisms. Mice with G-CSF deficiency have chronic neutropenia and impaired neutrophil mobilization, resulting in a marked inability to control infection by Listeria monocytogenes [3]. Recombinant human G-CSF (rhG-CSF)-stimulated donors exhibit decreased interferon (IFN)-g and increased interleukin (IL)-4 production by lymphocytes, favoring a Th2 predominant change [4].…”

Flavonoids That Mimic Human Ligands from the Whole Plants of Euphorbia lunulata

“…5) pIRESpuro-InsR was electroporated with a GenePulser apparatus (Bio-Rad, Hercules, CA, U.S.A.) with a 250-V pulse at 960 mF. The clone resistant to puromycin (2 mg/ml) (Sigma) was selected by limiting dilution in Dulbecco's modified Eagle's medium (DMEM; Sigma, St. Louis, MO, U.S.A.) supplemented with 10% fetal bovine serum (FBS) and rhIns (1 U/ml).…”

“…5) Insulin receptor (InsR) cDNA was amplified from Quick-clone (human spleen, Clontech, Palo Alto, CA, U.S.A.) by PCR. The primer pairs used were: InsR forward 1, 5Ј-ACCGGGAGCGCGCGCTCTGA-3Ј, InsR reverse 1, 5Ј-GATTGGATCCAGGGGCACAGA-3Ј, InsR forward 2, 5Ј-TGGATC-CAATCTCAGTGTCTAAC-3Ј and InsR reverse 2, 5Ј-TTAGGAAGGATTG-GACCGAGGCA-3Ј.…”

“…5) These cell lines were originally derived from a mouse interleukin-3 (mIL-3)-dependent cell line, BAF/B03. The BAF/GCSFR, BAF/EPOR, BAF/TPOR, BAF/IL10R and BAF/InsR cells proliferate in response to the corresponding ligand or rmIL-3, and undergo apoptosis when deprived of these growth factors.…”