Fulda Simone
University Children's Hospital, Eythstr. 24-89075, Ulm, Germany.
Expert Rev Anticancer Ther. 2007 Sep;7(9):1255-64. doi: 10.1586/14737140.7.9.1255.
Cell death by apoptosis plays a critical role in regulating the subtle balance between cell death and proliferation to maintain tissue homeostasis. Accordingly, tipping the balance in either direction may cause human disease. Too little cell death may promote tumor formation and progression. In addition, killing of cancer cells by current therapies is largely due to induction of apoptosis in tumor cells. Since a hallmark of human cancers is their resistance to apoptosis, there is a demand to develop novel strategies that restore the apoptotic machinery in order to overcome cancer resistance. Inhibitor of apoptosis proteins (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases. Elevated levels of IAPs are found in many human cancers and have been associated with poor prognosis. Recent insights into the role of IAPs have provided the basis for various exciting developments that aim to modulate the expression or function of IAPs in human cancers. Targeting IAPs (e.g., by antisense approaches or small-molecule inhibitors) presents a promising novel approach to either directly trigger apoptosis or to potentiate the efficacy of cytotoxic therapies in cancer cells. Thus, inhibition of IAPs such as X chromosome-linked IAP may prove to be a successful strategy to overcome apoptosis resistance of human cancers that deserves further exploitation.
细胞凋亡介导的细胞死亡在调节细胞死亡与增殖之间的微妙平衡以维持组织稳态方面发挥着关键作用。因此，向任何一个方向打破这种平衡都可能引发人类疾病。细胞死亡过少可能促进肿瘤的形成和进展。此外，目前的治疗方法杀死癌细胞很大程度上是由于诱导肿瘤细胞凋亡。由于人类癌症的一个标志是其对凋亡的抗性，因此需要开发新的策略来恢复凋亡机制以克服癌症抗性。凋亡抑制蛋白（IAPs）通过抑制半胱天冬酶在凋亡机制的核心部位阻断凋亡。在许多人类癌症中都发现IAPs水平升高，并且与预后不良有关。最近对IAPs作用的深入了解为旨在调节IAPs在人类癌症中的表达或功能的各种令人兴奋的进展提供了基础。靶向IAPs（例如，通过反义方法或小分子抑制剂）是一种有前景的新方法，可直接触发凋亡或增强癌细胞中细胞毒性疗法的疗效。因此，抑制诸如X染色体连锁IAP等IAPs可能被证明是克服人类癌症凋亡抗性的成功策略，值得进一步探索。
