Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo

Abstract

Neuroblastoma is an aggressive and drug-resistant refractory cancer. The human high-risk neuroblastoma cell line, SK-N-AS (non-amplified N-myc) is derived from stromal cells and it is resistant to treatment with retinoic acid (1, RA), which is a chemotherapeutic agent used to induce neuronal cellular differentiation of neuroblastomas. We have developed p-dodecylaminophenol (3, p-DDAP), based on N-(4-hydroxyphenyl)retinamide (2, 4-HPR), a synthetic amide of 1, since 1 and 2 are associated with the side-effect of nyctalopia. In order to evaluate the effects of 3 on high-risk neuroblastomas, we employed SK-N-AS cells as well asa second high-risk human neuroblastoma cell line, IMR-32, which is derived from neuronal cells (amplified N-myc, drug sensitive). Compound 3 suppressed cell growth of SK-N-AS and IMR-32 cells more effectively than 1, 2, p-decylaminophenol (4, p-DAP), N-(4-hydroxyphenyl)dodecananamide (5, 4-HPDD) or N-(4-hydroxyphenyl)decananamide (6, 4-HPD). In SK-N-AS cells, 3 induced G0/G1 arrest and apoptosis to a greater extent than 1 and 2. In IMR-32 cells, 3 induced apoptosis to a similar extent as 1 and 2, potentially by inhibiting N-myc expression. In addition, i.p. administration of 3 suppressed tumor growth in SK-N-AS-implanted mice in vivo. Since 3 showed no effects on blood retinol concentrations, in contrast to reductions following the administration of 2, it exhibited excellent anticancer efficacy against high-risk neuroblastoma SK-N-AS and IMR-32 expressing distinct levels of N-myc. Compound 3 may have potential for clinical use in the treatment of refractory neuroblastoma with reduced side effects.