Retinoid therapy of high-risk neuroblastoma

All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo

“…ATRA exclusively activates RARs, whereas 9-cis RA stimulates both RARs and RXRs. The upregulation of the RARs by ATRA has been described previously (Farias et al, 2002;Reynolds et al, 2003). As a consequence of ATRA exposure in Wilms tumor cells, we found the RARs RARB and RARG to be upregulated (Table 1), whereas RARA remained unchanged in both types of ATRA-treated Wilms tumor cells.…”

“…A direct consequence of these experimental data has been the use of ATRA in the induction treatment of acute promyelocytic leukemia leading to high rates of complete remission and cure in combination with chemotherapy (for a review see Freemantle et al, 2003). In several other cancer types, clinical trials with retinoic acid are currently performed, for example, in advanced neuroblastoma (Reynolds et al, 2003).…”

Combined IFN-γ and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells

“…Today, RA is used successfully in therapy for patients with acute promyelocytic leukemia (43) and treatment of neuroblastoma patients with high-dose 13-cis RA treatment after myeloablative therapy and autologous bone marrow transplantation have shown encouraging results (1,19,44). The synergistic effects of RA+IFN-g for differentiation of MYCN-amplified neuroblastoma cells, shown in vitro (20,22,23) as well as in vivo by inhibition of tumor formation of LA-N-5 neuroblastoma cells injected in nude mice (21), are further substantiated here by the demonstration of direct effects on the N-Myc/Max/Mad1 network.…”

“…IFN-g acts synergistically with a number of signal pathways, for instance, in the induction of apoptosis by Fas-L and TRAIL in neuroblastoma cells (46 -49). It would be interesting to study if IFN-g can cooperate also with other retinoids, such as fenretinide (4HPR), which, unlike at-RA and 13-cis-RA, induces apoptosis rather than differentiation and has also been used in clinical trials in neuroblastoma (44). Although the clinical use of RA and IFN-g may also have limitations due to side effects and development of drug resistance, insights into the precise molecular mechanisms by which IFN-g, RA, and other agents cooperatively regulate the N-Myc/ Max/Mad1 network will be essential for the development of novel therapeutic strategies, including new drug design for treatment of patients with high-risk neuroblastoma with MYCN amplification.…”

An Autocrine Loop Involving Ret and Glial Cell–Derived Neurotrophic Factor Mediates Retinoic Acid–Induced Neuroblastoma Cell Differentiation

“…Retinoic acid (RA) is a naturally occurring compound related to vitamin A that induces several human neuroblastoma cells to differentiate in vitro toward a neuronal-like phenotype characterized by neurite outgrowth, changes in the distribution of neurofilaments, and organization of these neuron-like cells into ganglion-like clusters (2,3). RA derivatives are being employed in the therapy of neuroblastoma, and patients treated with RA have increased survival rates (4)(5)(6). Although little is known about the specific pathways that mediate RA action, in most cases, the expression and function of the TrkB receptor is required.…”