The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death.
A functional imbalance between proapoptotic Bax and antiapoptotic Bcl-2 is likely to participate in the resistance of cancer cells to therapy. We show here that ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), a small organic compound recently proposed to function as an inhibitor of Bcl-2, increases the sensitivity of human glioblastoma cells to radiotherapy and chemotherapy. This sensitizing effect is lost if Bcl-2 expression, but not Bcl-xL expression, is knocked down or if cells only express a mutant of Bax that does not interact with Bcl-2. This points to a specific Bcl-2 inhibitory function of HA14-1 and implies that it selectively involves hindrance of Bcl-2 binding to Bax, which HA14-1 inhibits in cell-free assays and in cells in receipt of an apoptotic stimulation. Moreover, HA14-1, in combination with a cytotoxic treatment, slows down the growth of glioblastoma in vivo. Thus, the inhibition of Bcl-2 achieved by HA14-1 might improve treatment outcome.
Manero
Florence
F
Institut National de la Santé et de la Reserche Médicale U601, Département de Recherche en Cancérologie, Nantes, France.
Gautier
Fabien
F
Gallenne
Tristan
T
Cauquil
Nicolas
N
Grée
Danielle
D
Cartron
Pierre-François
PF
Geneste
Olivier
O
Grée
René
R
Vallette
François M
FM
Juin
Philippe
P
D000595:Amino Acid Sequence; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001578:Benzopyrans / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004249:DNA Damage; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
C494826:BAX protein, human; D001578:Benzopyrans; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D005047:Etoposide