TY - JOUR T1 - A Retinoic Acid Receptor β/γ-Selective Prodrug (tazarotene) Plus a Retinoid X Receptor Ligand Induces Extracellular Signal-Regulated Kinase Activation, Retinoblastoma Hypophosphorylation, G<sub>0</sub> Arrest, and Cell Differentiation JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1727 LP - 1737 DO - 10.1124/mol.104.003475 VL - 66 IS - 6 AU - Andrew Yen AU - Robert Fenning AU - Roshantha Chandraratna AU - Patricia Walker AU - Susi Varvayanis Y1 - 2004/12/01 UR - http://molpharm.aspetjournals.org/content/66/6/1727.abstract N2 - 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 G0 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 G0 arrest and differentiation; retinoblastoma (RB) hypophosphorylation, another characteristic of RA-induced G0 arrest and cell differentiation; G0 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, G0 arrest, and myeloid differentiation. The kinetics of G0 arrest and differentiation was similar to that of RA. Dose-response studies showed that diminishing tazarotene progressively diminished both induced cell differentiation and G0 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 G0 arrest. Tazarotene could propel either early or late portions of the period leading to differentiation and G0 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. ER -