Mimicking the BH3 domain to kill cancer cells.
Mimicking the BH3 domain to kill cancer cells.
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作者：
Ni Chonghaile T;Letai A
癌细胞表现出诱导凋亡信号传导的异常行为。为了生存，癌细胞通常会获得能够逃避死亡信号的变化。其中一种方法是增加抗凋亡BCL-2蛋白的表达。抗凋亡BCL-2家族蛋白通过与促死亡蛋白形成异二聚体来拮抗死亡信号传导。异源二聚体的形成通过促凋亡蛋白的BH 3结构域结合到抗凋亡蛋白的疏水裂缝中而发生。BH 3模拟物是抗凋亡BCL-2成员的小分子拮抗剂，其通过结合到疏水裂缝而作为竞争性抑制剂起作用。在某些条件下，抗凋亡BCL-2家族蛋白的拮抗作用可以释放癌细胞中的促死亡分子。因此，BH 3模拟物是一类新的癌症药物，其特异性靶向癌细胞存活机制，以选择性地杀死癌细胞。
Cancer cells demonstrate deviant behavior that induces apoptotic signaling. In order to survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death proteins. Heterodimer formation occurs via binding of the pro-apoptotic protein’s BH3 domain into the hydrophobic cleft of anti-apoptotic proteins. The BH3 mimetics are small molecule antagonists of the anti-apoptotic BCL-2 members that function as competitive inhibitors by binding to the hydrophobic cleft. Under certain conditions, antagonism of anti-apoptotic BCL-2 family proteins can unleash pro-death molecules in cancer cells. Thus, the BH3 mimetics are a new class of cancer drugs that specifically target a mechanism of cancer cell survival, to selectively kill cancer cells.
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