Anti-neuroblastoma activity of Helminthosporium carbonum (HC)-toxin is superior to that of other differentiating compounds in vitro.
Treatment of high-risk neuroblastoma (NB) is difficult. Novel therapeutics improving survival rates are urgently required. We have previously shown that the histone deacetylase inhibitor (HDACI) Helminthosporium carbonum (HC)-toxin induces differentiation of neuroblastoma (NB) cells. Here, we show that HC-toxin inhibits the growth of both established NB cell lines and primary cultures with and without amplified MYCN stronger than retinoids (RAs) and other HDACIs (MS-275, n-butyric acid, suberoylanilide hydroxamic acid, trichostatin A, valproic acid). Nanomolar dosages suppress E2F-1, N-myc, Skp2, Mad2 and survivin proteins, found at high levels in high-risk NBs, more efficiently than both RAs and other HDACIs. The level of hypophosphorylated active retinoblastoma (RB) tumor suppressor protein is increased most effectively. HC-toxin's epoxy group is essential for inhibiting HDACs and promoting anti-NB activity. Without this functional group, those cellular effects are not observed. In conclusion, the anti-NB activity of HC-toxin is superior to that of RAs and that of all other HDACIs tested.
Deubzer
Hedwig E
HE
Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center, Heidelberg, Germany. h.deubzer@dkfz.de
Ehemann
Volker
V
Kulozik
Andreas E
AE
Westermann
Frank
F
Savelyeva
Larissa
L
Kopp-Schneider
Annette
A
Riester
Daniel
D
Schwab
Manfred
M
Witt
Olaf
O
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006375:Helminthosporium / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D009183:Mycotoxins / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D009183:Mycotoxins; D010456:Peptides, Cyclic; D016160:Retinoblastoma Protein; C037654:HC toxin