Received for publication June 14, 2004.
Revised September 20, 2004.
Accepted for publication September 20, 2004.

A RAR/Selective Pro-drug (Tazarotene) Plus an RXR Ligand Induces ERK Activation, RB Hypophosphorylation, G0 Arrest and Cell Differentiation

Abstract

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 pro-drug selective for RAR/, thereby motivating interest in determining if Tazarotene might activate putative tumor suppressor activity. Using HL-60 human myeloblastic leukemia cells, a cell line which undergoes G0 cell cycle arrest and myeloid differentiation in response to retinoic acid (RA), Tazarotene failed to cause ERK activation, a requirement for RA-induced G0 arrest and differentiation; 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 an RXR selective ligand, Tazarotene caused ERK activation, RB tumor suppressor protein hypophosphorylation, G0 arrest, and myeloid differentiation. The kinetics of G0 arrest and differentiation were 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 both Tazarotene or an RAR selective ligand, diminishing the co-administered 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 anti-neoplastic agent in differentiation induction therapy as exemplified by the prototypical RA treatment of acute promyelocytic leukemia.

Key words: Fluorescence techniques, Genetics, Mechanisms of cell killing/apoptosis, Tumor suppressors

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