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Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Differentiated human NBs are associated with better outcome and lower stage; induction of differentiation is considered to be therapeutically advantageous. All-trans retinoic acid (ATRA) has been shown to induce the differentiation of neuroblastoma (NB) cell lines. The proteasome inhibitor bortezomib inhibits cell growth and angiogenesis in NBs. Here, we investigated the synergistic effect between bortezomib and ATRA in inducing NB cell differentiation in different NB cell lines. Bortezomib combined with ATRA had a significantly enhanced antiproliferative effect. This inhibition was characterized by a synergistic increase in neuronal differentiation. At the same time, the combination therapy showed little neuronal toxicity which was assessed in primary cultures of rat cerebellar granule cells by the MTT assay, PI staining. The combination of bortezomib and ATRA triggered increased differentiation through the activation of proteins, including RARα, RARβ, RARγ, p-JNK and p21, compared with ATRA treatment alone. Using JNK inhibitor SP600125 to block JNK-dependent activity, the combination therapy-induced neuronal differentiation was partially attenuated. In addition, p21 shRNA had no effect on the combination therapy-induced neuronal differentiation. The in vivo antitumor activities were examined in human NB cell xenografts and GFP-labeled human NB cell xenografts. Treatment of human NB cell CHP126-bearing nude mice with ATRA plus bortezomib resulted in more significant tumor growth inhibition than mice treated with either drug alone. These findings provide the rationale for the development of a new therapeutic strategy for NB based on the pharmacological combination of ATRA and bortezomib.
Highlights
Therapeutic approaches based on the induced differentiation of transformed cells into mature cells are one of the most promising strategies in recent NB treatments [1]
The neuroblastoma cell lines SH-SY5Y and CHP126 were tested for sensitivity to bortezomib and all-trans retinoic acid (ATRA) in vitro by Trypan blue staining
The concentrations of bortezomib and ATRA used for differentiation therapy were determined according to the growth inhibition rates of bortezomib (5.0 nM) and ATRA (10.0 nM) in both cell lines; they did not induce cell death
Summary
Therapeutic approaches based on the induced differentiation of transformed cells into mature cells are one of the most promising strategies in recent NB treatments [1]. Retinoids represent the most frequently used group of differentiation inducers, which are used both in leukemias and in some types of solid tumors, like neuroblastoma (NB) [2,3]. Despite the current advances in treatment, the clinical prognosis of aggressive NB remains dismal. For these reasons, combination chemotherapy currently represents one of the major successes in oncology research, due to its acceptable systemic toxicity and appreciable efficacy [8]. Because NBs are classified as embryonal tumors that arise from immature cells of the neural crest, induced differentiation of NB cells has become a currently used therapeutic protocol. Prior clinical data had suggested that differentiation therapy might play a complementary role in the treatment of NB when used in combination with other therapies
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