Histone deacetylase inhibitors and retinoic acids inhibit growth of human neuroblastoma in vitro.
BACKGROUND
Neuroblastoma is a common childhood cancer with a poor overall prognosis. Retinoic acids (RAs) have been studied as a potential therapy, showing promise in recurrent disease. The histone deacetylase inhibitor (HDACI) M-carboxycinnamic acid bishydroxamide (CBHA) is another potential therapy, which we recently described. Combinations of RAs and HDACIs currently under investigation display synergy in certain neoplasms. In this study, we evaluate the effect of combinations of RAs and HDACIs on human neuroblastoma cells.


METHODS
Established cell lines were cultured in increasing concentrations of HDACIs, RAs, and combinations thereof. Following exposure, viable cell number was quantified by trypan blue dye exclusion on a hemacytometer. Cell cycle analysis was performed by propidium iodide staining and FACS.


RESULTS
All assayed HDACIs and RAs decreased viable cell number. Lower concentrations of each agent were effective when the two were combined. The primary reason for decreased cell number appears to be apoptosis following HDACI exposure and G1 arrest following RA exposure. Both effects are seen with cotreatment. Caspase inhibition abrogates the apoptotic response.


CONCLUSIONS
CBHA causes apoptosis of human neuroblastoma in vitro, an effect that can add to the effects of RA. HDACIs and RAs inhibit neuroblastoma in significantly lower concentrations when used together than when used individually. Combination therapy may improve the ultimate efficacy while reducing the side effects of these agents in clinical use.
Coffey
D C
DC
Department of Pediatrics, Sloan-Kettering Institute and Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kutko
M C
MC
Glick
R D
RD
Swendeman
S L
SL
Butler
L
L
Rifkind
R
R
Marks
P A
PA
Richon
V M
VM
LaQuaglia
M P
MP
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D016193:G1 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; C111238:carboxycinnamic acid bishydroxamide; D014212:Tretinoin