Specific PAF antagonist WEB-2086 induces terminal differentiation of murine and human leukemia cells

A pharmacological approach to neoplasia by differentiation therapy relies on the availability of cytodifferentiating agents whose antitumor efficacy is usually assayed first on malignant cells in vitro. Using murine erythroleukemia cells (MELCs) as the model, we found that WEB-2086, a triazolobenzodiazepine-derived PAF antagonist originally developed as an anti-inflammatory drug, induces a dose-dependent inhibition of MELC growth and hemoglobin accumulation as a result of a true commitment to differentiation. MELCs treated for 5 days with 1 mM WEB-2086 show greater than or equal to 85% benzidine-positive cells, increased expression of alpha- and beta-globin genes, and down-regulation of c-Myb. This differentiation pattern, which does not involve histone H4 acetylation and is abrogated by the action of phorbol 12-myristate 13-acetate, recalls the pattern induced by hexamethylene bisacetamide (HMBA). In addition to MELCs, human erythroleukemia K562 and HEL and myeloid HL60 cells are massively committed to maturation by WEB-2086 and, with some differences, by its analog, WEB-2170. This suggests that WEB-2086, structurally distant from other known inducers, might be a member of a new class of cytodifferentiation agents active on a broad range of transformed cells in vitro and useful, prospectively, for anticancer therapy due to their high tolerability in vivo.