The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid.
Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.
Coffey
D C
DC
Department of Pediatrics, Joan and Sanford I. Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA.
Kutko
M C
MC
Glick
R D
RD
Butler
L M
LM
Heller
G
G
Rifkind
R A
RA
Marks
P A
PA
Richon
V M
VM
La Quaglia
M P
MP
D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002934:Cinnamates; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C111238:carboxycinnamic acid bishydroxamide; D014212:Tretinoin