A Retinoic Acid Receptor β/γ-Selective Prodrug (tazarotene) Plus a Retinoid X Receptor Ligand Induces Extracellular Signal-Regulated Kinase Activation, Retinoblastoma Hypophosphorylation, G₀Arrest, and Cell Differentiation

Abstract

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 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 RAR␣-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 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.

From carrot to clinic: an overview of the retinoic acid signaling pathway

“…In more recent studies, tazarotene has been shown to have chemopreventive efficacy against anti-basal cell carcinomas [205]. In addition, tazarotene has been proposed to act as an anti-neoplastic agent, when used in conjunction with rexinoids [206].…”

Actions of a Histone Deacetylase Inhibitor NSC3852 (5-Nitroso-8-quinolinol) Link Reactive Oxygen Species to Cell Differentiation and Apoptosis in MCF-7 Human Mammary Tumor Cells

“…One important finding was the enrichment of Rb in its hypophosphorylated state in NSC3852-treated cells. Hypophosphorylated Rb is the active tumor suppressor state of Rb and is a marker of cells arrested in G 1 , cell differentiation, and cell senescence (Yen and Varvayanis, 1995;Knudsen et al, 1998;Yen et al, 2004). We also showed that NSC3852 is a redox-active compound that stimulates superoxide production and a transient rise in intracellular redox potential.…”

Retinoid‐mediated stimulation of steroid sulfatase activity in myeloid leukemic cell lines requires RARα and RXR and involves the phosphoinositide 3‐kinase and ERK‐MAP kinase pathways

“…Other workers have shown at concentration ranging from 1 to 100 nM, ATRA, acting via RAR/RXR heterodimers, stimulates a slow but long‐lasting RAF‐1 driven increase in the activity of the MEK‐ERK map kinase signaling pathway in HL60 and other myeloid leukemic cell lines [Marchinkowska et al, 1997; Yen et al, 1999, 2004; Hong et al, 2001; Miranda et al, 2002; Glasow et al, 2005]. To test whether the RAF‐MEK‐ERK kinase pathway plays any role in the retinoid driven upregulation of steroid sulfatase activity, HL60 cells were pre‐incubated with the specific RAF inhibitor GW‐5074 or the MEK inhibitors U0126 and PD098059 for 2 h prior to treatment with 100 nM ATRA.…”

“…The PKC inhibitors GF 109293X, Gö 6976, HBBDE, and rottlerrin, the NF‐κB pathway inhibitors SN‐50, parthenolide, and MG‐132 were purchased from Affiniti Research products (Exeter, UK). We were guided in our choice of inhibitor combinations and incubation conditions by previous studies performed in HL60 and other myeloid cell lines, in which the pharmacological specificities of the inhibitors had been previously characterized [Bertagnolo et al, 1999, 2004; Cambien et al, 1999; El Marjou et al, 2000; Slosberg et al, 2000; Lopez‐Pedrera et al, 2001, 2004; Wang and Studzinski, 2001a,b; Lewandowski et al, 2002; Neri et al, 2002; Martelli et al, 2003, Wang et al, 2003; Yen et al, 2004; Zhao et al, 2004; Fong et al, 2005; Glasow et al, 2005; Lal et al, 2005]. In these experiments, we have, where possible, followed the ‘rules’ proposed by Davies et al [2000] for the evaluation of the effects of pharmacological inhibitors on cellular processes.…”

“…The mitogen‐activated protein kinase (MAPK) and CREB signaling cascades are activated during ATRA‐induced differentiation of human neuroblastoma and other neuronal cell lines [Chu et al, 2003; Canon et al, 2004]. Activation of the MAPK pathway has been shown to be essential for granulocytic differentiation of myeloid cell precursors [Hong et al, 2001; Miranda et al, 2002; Yen et al, 2004], and for the retinoid‐mediated differentiation of embryonic stem cells into adipocytes [Bost et al, 2002].…”