A Retinoic Acid Receptor β/γ-Selective Prodrug (tazarotene) Plus a Retinoid X Receptor Ligand Induces Extracellular Signal-Regulated Kinase Activation, Retinoblastoma Hypophosphorylation, G0 Arrest, and Cell Differentiation

Retinoic acid receptor (RAR)β is perceived to function as a tumor suppressor gene in various contexts where its absence is associated with tumorigenicity and its presence causes cell cycle arrest. Tazarotene is a prodrug selective for RARβ/γ, thereby motivating interest in determining whether tazarotene might activate putative tumor suppressor activity. Using HL-60 human myeloblastic leukemia cells, a cell line that undergoes G 0 cell cycle arrest and myeloid differentiation in response to retinoic acid (RA), tazarotene failed to cause extracellular signal-regulated kinase (ERK) activation, a requirement for retinoic acid (RA)-induced G 0 arrest and differentiation; retinoblastoma (RB) hypophosphorylation, another characteristic of RA-induced G 0 arrest and cell differentiation; G 0 arrest; or differentiation into mature myeloid cells. However, when used in combination with a retinoid X receptor (RXR)-selective ligand, tazarotene caused ERK activation, RB tumor suppressor protein hypophosphorylation, G 0 arrest, and myeloid differentiation. The kinetics of G 0 arrest and differentiation was similar to that of RA. Dose-response studies showed that diminishing tazarotene progressively diminished both induced cell differentiation and G 0 arrest, where the doses for cellular effects were consistent with the transcriptional transactivation data. For either tazarotene or an RARα-selective ligand, diminishing the coadministered RXR-selective ligand diminished both induced differentiation and G 0 arrest. Tazarotene could propel either early or late portions of the period leading to differentiation and G 0 arrest and was interchangeable with an RARα-selective ligand. Tazarotene used with RXR-selective ligand may thus be a useful antineoplastic agent in differentiation induction therapy as exemplified by the prototypical RA treatment of acute promyelocytic leukemia.