Alpha-1 Adrenergic Antagonists Sensitize Neuroblastoma to Therapeutic Differentiation

Neuroblastoma (NB) is an aggressive childhood tumor, with high -risk cases having a 5-year overall survival probability of approxi-mately 50%. The multimodal therapeutic approach for NB includes treatment with the retinoid isotretinoin (13-cis retinoic acid; 13cRA), which is used in the post-consolidation phase as an antiproliferation and prodifferentiation agent to minimize residual disease and pre-vent relapse. Through small-molecule screening, we identified iso-rhamnetin (ISR) as a synergistic compound with 13cRA in inhibiting up to 80% of NB cell viability. The synergistic effect was accompanied by a marked increase in the expression of the adrenergic receptor a1B (ADRA1B) gene. Genetic knockout of ADRA1B or its specific blockade using & alpha;1/& alpha;1B adrenergic antagonists led to selective sen-sitization of MYCN-amplified NB cells to cell viability reduction and neural differentiation induced by 13cRA, thus mimicking ISR activ-ity. Administration of doxazosin, a safe a1-antagonist used in pediatric patients, in combination with 13cRA in NB xenografted mice exerted marked control of tumor growth, whereas each drug alone was ineffective. Overall, this study identified the a1B adren-ergic receptor as a pharmacologic target in NB, supporting the evaluation of adding a1-antagonists to the post-consolidation ther-apy of NB to more efficiently control residual disease. Significance: Targeting a-adrenergic receptors synergizes with isotretinoin to suppress growth and to promote differentiation of neuroblastoma, revealing a combinatorial approach for more effective management of the disease and prevention of relapse.