Pentoxifylline Synergizes with All-Trans Retinoic Acid to Induce Differentiation of HL-60 Myelocytic Cells, but Suppresses tRA-Augmented Clonal Growth of Normal CFU-GM

Abstract

All-trans retinoic acid (tRA) has been shown to promote terminal differentiation of promyelocytic leukemia cells, but frequently induce hyperleukocytosis and pulmonary leakage syndrome. Employing pentoxifylline (PTX), a phosphodiesterase inhibitor which could raise intracellular cAMP and modulate leukocyte activation, we sought to investigate if PTX could enhance tRA-induced promyelocytic leukemic cell differentiation but suppress tRA-augmented growth and activation of human granulocytes. tRA could significantly suppress clonal growth of U937 and HL-60 leukemic cells but enhanced the CFU-GM formation of normal bone marrow cells (22 ± 6 vs. 90 ± 16 CFU/well). PTX significantly augmented tRA suppression of clonal growth of U937 and HL-60 leukemic cells but suppressed tRA-augmented CFU-GM formation of normal bone marrow cells (90 ± 16 vs. 25 ± 9 CFU/well). In addition, PTX enhanced tRA-induced growth inhibition and differentiation of promyelocytic HL-60 leukemic cells, but suppressed respiratory burst activation by the immature granulocytic HL-60 cells and suppressed CD11b adhesion molecule expression by mature granulocytes. PTX similar to dibutyric cAMP promoted HL-60 myelocytic leukemic cell differentiation and growth inhibition, whereas PTX, in contrast to dibutyric cAMP which could augment phorbol myristate acetate (PMA)-elicited respiratory burst activity by immature granulocytes, suppressed the PMA-elicited respiratory burst activity by immature and mature granulocytes. PTX did not raise the intracellular cAMP level of HL-60 cells, but partly suppressed the dibutyric cAMP-elicited elevation of intracellular cAMP level. Results from these studies suggest that PTX might act through different signaling pathways to enhance tRA-induced myelocytic leukemic cell differentiation but prevent from hyperreactive normal granulopoiesis and granulocyte activation.

Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

“…In APL, stimuli elevating cAMP potentiate the cytodifferentiating and anti-proliferative effects of ATRA [38,[217][218][219]. In the absence of retinoids, treatment of NB4 cells with cAMP elevating agents induces only growth inhibition, while HL-60 cells undergo granulocytic maturation in the same experimental conditions [217,218].…”

Shockwave Stimulates Oxygen Radical-Mediated Osteogenesis of the Mesenchymal Cells From Human Umbilical Cord Blood

“…(15) The CFU-Mix as-say was performed using semisolid agar plates containing 0.35% Agar Nobel (Difco) and Iscove's medium supplemented with autologous plasma 20% (vol/vol) for 12 days as modified from our previous description. (20,21) We further determine the influence of various SW impulses on osteogenesis and hematogenesis. MNCs harvested form HUCB with and without SW treatment (0.16 mJ/ mm 2 energy flux density; 100, 200, 500, and 1000 impulses) were used to determine CFU-stroma and CFU-Mix.…”

Superoxide Mediates Shock Wave Induction of ERK-dependent Osteogenic Transcription Factor (CBFA1) and Mesenchymal Cell Differentiation toward Osteoprogenitors

“…Bone marrow blood (0.4 ml) was aspirated with 20-gauge needle into a 1-ml syringe containing 20 units/ml heparin. The bone marrow mononuclear cells in the marrow blood were harvested from the interface of the Ficoll-Paque density gradient (d ϭ 1.007 g/ml, Amersham Biosciences AB) at 500 ϫ g for 30 min as described previously (28). Cell number and viability were determined with a hemocytometer after staining with 0.4% trypan blue in ammonium chloride.…”