The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death
The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death
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DOI：
10.1158/0008-5472.can-05-2097
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Juin, P
中科院分区：
文献类型：
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作者：
Manero, F;Gautier, F;Juin, P
促凋亡Bax和抗凋亡Bcl-2之间的功能失衡可能参与癌细胞对治疗的抗性。我们在这里显示，乙基2-氨基6-溴-4-（1-氰基-2-乙氧基-2-氧代乙基）-4H-色烯-3-羧酸酯（HA 14 -1），一个小的有机化合物，最近提出作为Bcl-2的抑制剂，增加人胶质母细胞瘤细胞对放疗和化疗的敏感性。如果Bcl-2表达而不是Bcl-xL表达被敲低，或者如果细胞仅表达不与Bcl-2相互作用的Bax突变体，则这种致敏作用丧失。这表明HA 14 -1具有特异性的Bcl-2抑制功能，并意味着它选择性地涉及阻碍Bcl-2与Bax的结合，HA 14 -1在无细胞测定中和在接受凋亡刺激的细胞中抑制Bax。此外，HA 14 -1与细胞毒性治疗相结合，减缓了胶质母细胞瘤的体内生长。因此，通过HA 14 -1实现的Bcl-2抑制可能改善治疗结果。
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-amino6-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 bindin g 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.