Modulating sensitivity to drug-induced apoptosis: the future for chemotherapy?

Improvements in chemotherapy for some malignancies, such as childhood leukaemia, have resulted in considerable increases in survival. However, many of the more common adult cancers, including carcinoma of the breast, remain stubbornly resistant to drug treatment, despite dose escalation and the increasing use of stem cell support [1]. The explosion of interest in apoptosis in the past 10 years has been underpinned by the hope that a greater understanding of the way in which cancer cells die after chemotherapy-induced damage would allow the development of a more rational approach to overcoming the problem of drug resistance. Unless cells receive external survival signals, they will 'default' to apoptosis [2]. These signals are provided by soluble cytokines and growth factors, cell–extracellular matrix contact and cell–cell contact. The overall survival threshold is probably determined by the balance of interactions between members of the Bcl-2 family of proteins on the cytoplasmic surface of internal membranes, such as the outer mitochondrial membrane. These pro-apoptotic or anti-apoptotic proteins can homodimerise or heterodimerise, and a satisfying but still unproven hypothesis is that, by doing so, they either activate or neutralise each other depending on the balance of death and survival stimuli.A wide range of chemotherapeutic agents is able to trigger apoptosis (reviewed in [3]). In this model of their action, chemotherapeutic drugs drive cell death by generating damage signals at their locus of action (eg DNA damage), and these signals become integrated at Bcl-2 family protein containing complexes where the decision to undergo apoptosis is taken and signalled to apoptosis effector molecules. This is classical stimulus response coupling, and it is the efficiency of this coupling that determines the threshold for survival. A complex of proteins, describing this coupling and activation centre, has been conceptualised as an 'apoptosome', and contains the precurso