Anticancer efficacy of p-dodecylaminophenol against high-risk and refractory neuroblastoma cells in vitro and in vivo. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Takahashi, Noriko; Koyama, Shunpei; Hasegawa, Shinya; Yamasaki, Masahiro; Imai, Masahiko
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 20(2017)
• Page Start: 4664
• Page End: 4672
• Publication Date: 2017-10-15
• Subjects: 1 RA, all-trans retinoic acid -- 2 4-HPR, N-(4-hydroxyphenyl)retinamide, fenretinide -- 3 p-DDAP, p-dodecylaminophenol, 4-(dodecylamino)phenol -- 4 p-DAP, p-decylaminophenol, 4-(decylamino)phenol -- 5 4-HPDD, N-(4-hydroxyphenyl)dodecananamide, p-dodecanoylaminophenol -- 6 4-HPD, N-(4-hydroxyphenyl)decananamide, p-decanoylaminophenol -- DMSO dimethylsulfoxide -- BSA bovine serum albumin -- PBS phosphate-buffered saline (1.5 mM KH2PO4, 8.1 mM Na2HPO4, 136.9 mM NaCl, pH 7.2) -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- EDTA ethylenediaminetetraacetic acid -- RT-PCR reverse transcription-polymerase chain reaction -- MRP1 multidrug resistance-related protein 1 -- SD standard deviation; Retinoid -- Neuroblastoma -- High-risk -- Refractory cancer -- Aminophenol; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.005
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 of1, since1 and2 are associated with the side-effect of nyctalopia. In order to evaluate the effects of3 on high-risk neuroblastomas, we employed SK-N-AS cells as well as a second high-risk human neuroblastoma cell line, IMR-32, which is derived from neuronal cells (amplified N-myc, drug sensitive). Compound3 suppressed cell growth of SK-N-AS and IMR-32 cells more effectively than1, 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 than1 and2 . In IMR-32 cells, 3 induced apoptosis to a similar extent as1 and2, potentially by inhibiting N-myc expression. In addition, i.p. administration of3 suppressed tumor growth in SK-N-AS-implanted mice in vivo . Since3 showed no effects on blood retinol concentrations, in contrast to reductions following the administration of2, it exhibited excellent anticancer efficacy against high-risk neuroblastoma SK-N-AS and IMR-32 expressing distinct levels of N-myc. Compound3 may have potential for clinical use in the treatment of refractory neuroblastoma with reduced side effects.