Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.
BACKGROUND
Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat).


METHODS
In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks.


RESULTS
Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively).


CONCLUSIONS
Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin.
Department of Surgery, Children's Memorial Hospital, Northwestern University, Chicago, IL 60614, USA.
Timothy B
TB
Lautz
Jessica A
JA
Naiditch
Sandra
S
Clark
Fei
F
Chu
Mary Beth
MB
Madonna
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009281:Naphthalenes; D009363:Neoplasm Proteins; D011744:Pyrimidinones; C510718:cambinol; D000077337:Vorinostat; D004317:Doxorubicin