Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells.
The physiologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24-diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45-55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a functional measure of differentiation, was also exhibited. Previous reports have shown that treatment doses needed to achieve 24 nM serum concentrations of D3 in patients would result in hypercalcemia. EB 1089 and KH 1060 can cause the same in vitro effects on LA-N-5 human neuroblastoma cells at 1/100 of the concentration required of D3. These data suggest a potential clinical efficacy of EB 1089 and KH 1060 as biological response modifiers.
Moore
T B
TB
Department of Pediatrics, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA 90024, USA.
Koeffler
H P
HP
Yamashiro
J M
JM
Wada
R K
RK
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D013194:Staining and Labeling; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C074279:KH 1060; D002762:Cholecalciferol; D000110:Acetylcholinesterase; D002117:Calcitriol; C078903:seocalcitol