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

Department of Biomedical Sciences, Cornell University, Ithaca, New York (A.Y., R.F., S.V.); and Allergan, Inc., Irvine, California (P.W., R.C.)

Retinoic acid receptor (RAR) 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 RAR/, 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 RAR-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 RAR-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.

Address correspondence to: Dr. Andrew Yen, Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853. E-mail: ay13{at}cornell.edu

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