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The Small Organic Compound HA14-1 Prevents Bcl-2 Interaction with Bax to Sensitize Malignant Glioma Cells to Induction of Cell Death

¹ Institut National de la Santé et de la Reserche Médicale U601, Département de Recherche en Cancérologie, Nantes, France; ² Cancer Research, Institut de Recherches Servier, Croissy/Seine, France; and ³ Université de Rennes 1, Synthèse et Electrosynthèse Organiques, Centre National de la Reserche Scientifique UMR 6510, Rennes, France

Requests for reprints: Philippe Juin, Institut National de la Santé et de la Reserche Médicale U601, Département de Recherche en Cancérologie, 9 Quai Moncousu, 44035 Nantes Cedex 035, France. Phone: 33-24-008-4083; Fax: 33-24-008-4082; E-mail: Philippe.Juin{at}univ-nantes.fr.

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. (Cancer Res 2006; 66(5): 2757-64)

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